Biochemistry - First Aid Flashcards
Chromatin Structure
DNA exists in the condensed _____ form to fit into the nucleus.
chromatin
DNA loops twice around a _____ to form a _____ (“beads on a string”).
histone octamer
nucleosome
H1 binds to the _____ and to the _____, thereby stabilizing the _____.
nucleosome
linker DNA
chromatin fiber
_____ groups give DNA a (-) charge.
Phosphate
_____ give histones a (+) charge.
Lysine
Arginine
In _____, DNA condenses to form _____.
mitosis
chromosomes
DNA and histone synthesis occurs during the _____.
S phase
Mitochondria have their own DNA which is _____ and does not utilize _____.
circular
histones
Chromatin:
- condensed
- darker on EM
- transcriptionally inactive
- sterically inaccessible
- ↑ methylation
- ↓ acetylation
heterochromatin
Hetero-Chromatin = Highly Condensed
_____ are inactive X chromosomes which may be visible on the periphery of the nucleus.
Barr bodies
*heterochromatin
Chromatin:
- less condensed
- lighter on EM
- transcriptionally active
- sterically inaccessible
euchromatin
Euchromatin = Expressed
_____ changes the expression of a DNA segment without changing the sequence.
DNA Methylation
_____ is involved with genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging and carcinogenesis.
DNA Methylation
Methylation within _____ typically represses gene transcription.
gene promoter (CpG islands)
CpG Methylation Makes DNA Mute
_____ usually causes reversible transcriptional suppression, but can also cause activation depending on location of methyl groups.
Histone Methylation
Histone Methylation Mostly Makes DNA Mute
_____ relaxes DNA coiling, allowing for transcription.
Histone Acetylation
Histone Acetylation makes DNA Active
Purine
Pyrimidine
Nucleoside Composition
NucleoSide = base + (deoxy)ribose (Sugar)
Nucleotide Composition
NucleoTide = base + (deoxy)ribose + phosphaTe
*linked by 3’-5’ phosphodiester bond
5’ end of incoming nucleotide bears the _____.
triphosphate
*energy source for the bond
Triphosphate bond is the target of _____ attack.
3’ hydroxyl
Purines
A, G - 2 rings
PURe As Gold
Pyrimidines
C, U, T - 1 ring
CUT the PY (pie)
Deamination of cytosine forms _____.
uracil
Deamination of adenine forms _____.
hypoxanthine
Deamination of guanine forms _____.
xanthine
Deamination of 5-methylcytosine forms _____.
thymine
Uracil is found in _____.
RNA
Thymine is found in _____.
DNA
Methylation of uracil makes _____.
thymine
THYmine has meTHYl
G-C bonds have _____ H bonds.
3
A-T bonds have _____ H bonds.
2
Higher G-C bonds means _____ of DNA.
higher melting T
C-G bonds are like Crazy Glue
Amino Acids Essential for Purine Synthesis
Glycine
Aspartate
Glutamine
Cats Purr until they GAG
De novo Pyrimidine and Purine Synthesis
Pyrimidine Synthesis Blockers:
inhibits dihydroorotate dehydrogenase
Leflunomide
Pyrimidine Synthesis Blockers:
inhibits dihydrofolate reductase (↓ deoxythymidine monophosphate [dTMP])
Methotrexate (MTX) - humans
Trimethoprim (TMP) - bacteria
Pyrimethamine - protozoa
Pyrimidine Synthesis Blockers:
inhibits thymidylate synthase (↓ dTMP)
5-fluorouracil (5-FU)
5-FU + capecitabine = 5-F-dUMP
Purine Synthesis Blockers:
inhibit de novo purine synthesis
6-mercaptopurine (6-MP)
*Azathioprine - prodrug
Purine Synthesis Blockers:
inhibit inosine monophosphate dehydrogenase
Mycophenolate
Ribavirin
Purine and Pyrimidine Synthesis Blockers:
inhibits ribonucleotide reductase
Hydroxyurea
Carbamoyl Phosphate Synthase I is found in the _____.
Mitochondria
CPS1 = m1tochondria (urea cycle)
Carbamoyl Phosphate Synthase II is found in the _____.
Cytosol
CPS2 = cyTWOsol
Purine Salvage Deficiencies
_____ is required for degradation of adenosine and deoxyadenosine.
Adenosine Deaminase (ADA)
In ADA deficiency, ↓ dATP → _____.
lymphotoxicity
Adenosine Deaminase Deficiency is one of the major causes of _____.
autosomal recessive SCID
_____ is caused by defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP.
Lesch-Nyhan Syndrome
_____ results in excess uric acid production and de novo purine synthesis.
Lesch-Nyhan Syndrome
Lesch-Nyhan Syndrome is an _____ disease.
X-linked recessive
Lesch-Nyhan Syndrome Findings
HGPRT
- Hyperuricemia
- Gout
- Pissed off (aggression, self-mutilation)
- Retardation (intellectual disability)
- DysTonia
Lesch-Nyhan Syndrome Treatment
Allopurinol
Febuxostat
Genetic Code Features
- Unambiguous
- Degenerate/Redundant
- Commaless, Non-Overlapping
- Universal
Genetic Code Features:
each codon specifies only 1 amino acid
Unambiguous
Genetic Code Features:
most amino acids are coded by multiple codons
Degenerate/Redundant
Codons that differ in the 3rd (_____) position may code for the same tRNA/amino acid.
wobble
Specific base pairing is usually required only in the _____ of the mRNA codon.
first 2 nucleotide positions
_____ are encoded by only 1 codon.
Methionine (AUG)
Tryptophan (UGG)
Genetic Code Features:
read from a fixed starting point as a continuous sequence of bases
Commaless, Non-Overlapping
Genetic Code Features:
genetic code is conserved throughout evolution
Universal
DNA Replication
In both prokaryotes and eukaryote, DNA replication is _____ and involves both _____ synthesis and occurs in the _____ direction.
- semiconservative
- continuous and discontinuous (Okazaki fragments)
- 5’ → 3’
_____ is the particular consensus sequence of base pairs in genome where DNA replication begins.
Origin of Replication
*prokaryotes - single
*eukaryotes - multiple
_____ sequences are found in promoters and origins of replication.
AT-rich sequences
*TATA box
The _____ is a Y-shaped region along the DNA template where leading and lagging straands are synthesized.
Replication Fork
_____ unwinds the DNA template at the replication fork.
Helicase
Helicase Halves DNA
_____ prevents DNA strands from reannealing.
Single-Stranded Binding Proteins
_____ create a single- or double-stranded break in the helix to add or remove supercoils.
DNA Topoisomerases (TOP)
In eukaryotes, _____ inhibit TOP I.
Irinotecan
Topotecan
In eukaryotes, _____ inhibit TOP II.
Etoposide
Teniposide
In prokaryotes, _____ inhibit TOP II (DNA Gyrase) and TOP IV.
Fluoroquinolones
_____ makes an RNA primer on which DNA Polymerase III can initiate replication.
Primase
_____ elongates the leading strand by adding deoxynucleotides to the 3’ end.
DNA Polymerase III
*only in prokaryotes
_____ elongates the lagging strand until it reaches the primer of the preceding fragment.
DNA Polymerase III
*only in prokaryotes
DNA Polymerase III has _____ synthesis.
5’ → 3’
DNA Polymerase III proofreads with _____ exonuclease.
3’ → 5’
Drugs blocking DNA replication often have a _____ thereby preventing addition of the next nucleotide (“chain termination”).
modified 3’ OH
_____ degrades the RNA primer and replaces it with DNA.
DNA Polymerase I
*only in prokaryotes
DNA Polymerase I excises the RNA primer with _____.
5’ → 3’ exonuclease
_____ catalyzes the formation of a phosphodiester bond within a strand of double-stranded DNA.
DNA Ligase
Ligase Links DNA
_____ joins the Okazaki fragments.
DNA Ligase
Ligase Links DNA
_____ is a reverse transcriptase (RNA-dependent DNA Polymerase) that adds DNA (TTAGGG) to 3’ ends of chromosomes to avoid loss of genetic material with every duplication.
Telomerase
Telomerase TAGs for Greatness and Glory
*only in eukaryotes
_____ is often dysregulated in cancer cells, allowing unlimited replication.
Telomerase
Severity of DNA Mutations
silent << missense < nonsense < frameshift
Purine → Purine or Pyrimidine → Pyrimidine Mutation
Transition
Purine ⇆ Pyrimidine Mutation
Transversion
DNA Mutations:
nucleotide substitution but codes for same (synonymous) amino acid, often base in 3rd position of codon (tRNA wobble)
Silent
DNA Mutations:
nucleotide substitution resulting in changes amino acid (conservative if new amino acid is similar in chemical structure)
Missense
Sickle Cell Disease is caused by the _____.
substitution of glutamic acid with valine
*missense
DNA Mutations:
nucleotide substitution resulting in early stop codon (UAA, UAG, UGA), usually results in nonfunctional protein
Nonsense
Stop the Nonsense!
DNA Mutations:
deletion or insertion of a number of nucleotides not divisible by 3, resulting in misreading of all nucleotides downstream
Frameshift
Duchenne Muscular Dystrophy and Tay-Sachs Disease is caused by _____ mutation.
Frameshift
Mutation at a _____ → retained intron in the mRNA → protein with impaired or altered function
splice site
Lac Operon Mechanism
Lac Operon and Glucose
Glucose is the preferred metabolic substrate in E. coli, but when glucose is absent and lactose is available, the _____ is activated to switch to lactose metabolism.
Lac Operon
Lac Operon Mechanism:
Low Glucose
↓ glucose → ↑ adenylate cyclase activity → ↑ generation of cAMP from ATP → activation of catabolite activator protein (CAP) → ↑ transcription
Lac Operon Mechanism:
High Glucose
↑ glucose → unbinds repressor protein from repressor/operator site → ↑ transcription
Single Strand DNA Repair:
specific endonucleases release the oligonucleotides containing damaged bases, DNA polymerase and ligase fill and reseal the gap
Nucleotide Excision Repair
Single Strand DNA Repair:
repairs bulky helix-distorting lesions
Nucleotide Excision Repair
Single Strand DNA Repair:
occurs in G1 phase of the cell cycle
Nucleotide Excision Repair
Single Strand DNA Repair:
defective in xeroderma pigmentosum (inability to repair DNA pyrimidine dimers cause by UV exposure) which causes dry skin, extreme light sensitivity and skin cancer
Nucleotide Excision Repair
Single Strand DNA Repair:
base-specific Glycosylase removes altered base and creates AP site (apurinic/apyramidinic), one or more nucleotides are removed by AP-Endonuclease which cleaves the 5’ end, Lyase cleaves the 3’ end, DNA Polymerase-β fills the gap and DNA Ligase seals it
Base Excision Repair
GEL PLease
Single Strand DNA Repair:
occurs throughout the cell cycle
Base Excision Repair
Single Strand DNA Repair:
important in the repair of spontaneous/toxic deamination
Base Excision Repair
Single Strand DNA Repair:
newly synthesized strand is recognized, mismatched nucleotides are removed and the gap is filled and resealed
Mismatch Repair
Single Strand DNA Repair:
occurs predominantly in the S phase of the cell cycle
Mismatch Repair
Single Strand DNA Repair:
defective in Lynch Syndrome (hereditary nonpolyposis colorectal cancer [HNPCC])
Mismatch Repair
Double Strand DNA Repair:
brings together 2 ends of DNA fragments to repair double-stranded breaks, no requirement for homology, some DNA may be lost
Nonhomologous End Joining
Double Strand DNA Repair:
defective in Ataxia Telangiectasia and Fanconi Anemia
Nonhomologous End Joining
Double Strand DNA Repair:
requires 2 homologous DNA duplexes, a strand from the damaged dsDNA is repaired using a complementary strand from the intact homologous dsDNA as a template, restores duplexes accurately without loss of nucleotides
Homologous Recombination
Double Strand DNA Repair:
defective in breast/ovarian cancers with BRCA1 mutation
Homologous Recombination
mRNA Start Codon
AUG
*methionine - eukaryotes
*N-formylmethionine (fMet) - prokaryotes
mRNA Stop Codons
UAA, UAG, UGA
Functional Organization of a Eukaryotic Gene
The _____ is the site where RNA Polymerase II and other transcriptions factors bind to DNA upstream from gene locus (AT-rich upstream sequence with TATA and CAAT boxes).
Promoter
_____ mutation commonly results in dramatic ↓ in level of gene transcription.
Promoter
The _____ is the DNA locus where regulatory proteins (“activators”) bind → increasing expression of a gene on the same chromosome.
Enhancer
The _____ is the DNA locus where regulatory proteins (“repressors”) bind → decreasing expression of a gene on the same chromosome.
Silencers
In eukaryotes, RNA Polymerase I makes _____, present only in the nucleolus.
rRNA
r = rampant
* most common
In eukaryotes, RNA Polymerase II makes _____, which is read 5’ → 3’.
mRNA
m = massive
*largest
In eukaryotes, RNA Polymerase III makes _____.
tRNA
t = tiny
*smallest
_____ opens DNA at the promoter site.
RNA Polymerase II
_____ found in _____ inhibits RNA Polymerase II and causes severe hepatotoxicity if ingested.
α-amanitin
Amanita phalloides (death cap mushrooms)
_____ inhibits RNA Polymerase in both prokaryotes and eukaryotes.
Actinomycin D
In prokaryotes, _____ (multisubunit complex) makes all 3 kinds of RNA.
1 RNA Polymerase
_____ inhibits DNA-dependent RNA Polymerase in prokaryotes.
Rifampin
RNA Processing in Eukaryotes
_____, the initial transcript in eukaryote RNA processing, is modified and becomes mRNA.
heterogenous nuclear RNA (hnRNA)
RNA Processing
- capping of 5’ end (addition of 7-methylguaanosine cap)
- polyadenylation of 3’ end (~ 200 A’s)
- splicing out of introns
Capped, tailed and spliced transcript is called _____.
mRNA
_____ is transported out of the nucleus into the cytosol, where it is translated.
mRNA
mRNA quality control occurs at _____, which contain exonucleases, decapping enzymes, and microRNAs.
cytoplasmic processing bodies (P-bodies)
mRNAs may be degraded or stored in _____ for future translation.
cytoplasmic processing bodies (P-bodies)
_____ Polymerase does not require a template.
Poly-A
Polyadenylation Signal
AAUAAA
Splicing of Pre-mRNA
_____ contain the actual genetic information coding for protein.
Exons
Exons Exit and are Expressed.
_____ are intervening noncoding segments of DNA.
Introns
Introns Intervene In the nucleus.
_____ can produce a variety of products from a single hnRNA sequence.
Alternative Splicing
Alternative Splicing
_____ are small, conserved, noncoding RNA molecules that posttranscriptionally regulate gene expression by targeting the 3’ untranslated region of specific mRNAs for degradation or translational repression.
MicroRNAs (miRNAs)
_____ has 75-90 nucleotides, 2° structure, cloverleaf form, and anticodon end is opposite 3’ aminoacyl end.
tRNA
All tRNAs have _____ at the 3’ end with a high percentage of chemically modified bases.
CCA
Can Carry Amino acids
The amino acid is covalently bound to the _____ of the tRNA.
3’ end
The _____ of the tRNA contains the TΨC (ribothymidine, pseudouridine, cytidine) sequence necessary for tRNA-ribosome binding.
T-arm
T-arm Tethers tRNA to ribosome
The _____ of the tRNA contains dihydrouridine residues necessary for tRNA recognition by the correct aminoacyl-tRNA synthetase.
D-arm
D-arm Detects the aminoacyl-tRNA synthetase
The _____ is the amino acid acceptor site.
5’-CCA-3’ (Acceptor Stem)
_____ scrutinizes the amino acid before and after it binds to tRNA.
Aminoacyl-tRNA Synthetase
If incorrect, the tRNA-amino acid bond is _____.
hydrolyzed
The tRNA-amino acid bond has energy for the formation of _____.
peptide bond
A mischarged tRNA reads the usual codon but _____.
inserts the wrong amino acid
_____ and _____ are responsible for the accuracy of amino acid selection.
- Aminoacyl-tRNA Synthetase
- binding of charged tRNA to the codon
tRNA charging requires _____.
ATP
ATP = tRNA Activation (charging)
tRNA Structure
Protein Synthesis Initiation: identify either the 5’ cap or an internal ribosome entry site (IRES)
eukaryotic initiation factors (eIFs)
Protein Synthesis Initiation: can be located at many places in an mRNA, most often at the 5’UTR
internal ribosome entry site (IRES)
Protein Synthesis Initiation: help assemble the 40S ribosomal subunit with the initiator tRNA and are released when the mRNA and the ribosomal 60S subunit assemble with the complex
eukaryotic initiation factors (eIFs)
Protein synthesis initiation requires _____.
GTP
GTP = tRNA Gripping and Going places (translocation)
Eukaryotic Ribosomal Subunits
40S + 60S → 80S
Eukaryotes = Even
Prokaryotic Ribosomal Subunits
30S + 50S → 70S
prOkaryotes = Odd
Protein Elongation Process
- Aminoacyl-tRNA binds to A site (except for initiator methinine), requires an elongation factor and GTP
- rRNA (“ribozyme”) catalyzes peptide bond formation, transfers growing polypeptide to amino acid in A site
- Ribosome advances 3 nucleotides toward 3’ end of mRNA, moving peptidyl tRNA to P site (translocation)
Protein Elongation Process: Step 1
Aminoacyl-tRNA binds to A site (except for initiator methinine), requires an elongation factor and GTP
Protein Elongation Process: Step 2
rRNA (“ribozyme”) catalyzes peptide bond formation, transfers growing polypeptide to amino acid in A site
Protein Elongation Process: Step 3
Ribosome advances 3 nucleotides toward 3’ end of mRNA, moving peptidyl tRNA to P site (translocation)
Protein Elongation Process
APE
- A site = incoming Aminoacyl-tRNA
- P site = accommodates growing Peptide
- E site = holds Empty tRNA as it Exits
Posttranslational Modifications:
removal of N- or C-terminaal propeptides from zymogen to generate mature protein (e.g. trypsinogen → trypsin
Trimming
Posttranslational Modifications:
Covalent Alterations
- phosphorylation
- glycosylation
- hydroxylation
- methylation
- acetylation
- ubiquitination
Posttranslational Modifications:
intracellular protein involved in facilitationg and/or maintaining protein folding
Chaperone Protein
Cell cycle phases are regulated by _____,
- cyclins
- cyclin-dependent kinases (CDKs)
- tumor suppressors
The _____ is the shortest phase of the cell cycle and includes _____.
M Phase
- Mitosis
- Cytokinesis
Mitosis Steps
- Prophase
- Prometaphase
- Metaphase
- Anaphase
- Telophase
_____ occurs when the cytoplasm splits into 2.
Cytokinesis
Cell Cycle
Cell Cycle Regulation:
- constitutive
- inactive
Cyclin-Dependent Kinases (CDKs)
Cell Cycle Regulation:
- regulatory proteins to coordinate cell cycle progression
- phase specific
- activate CDKs
Cyclins
Cell Cycle Regulation:
- phosphorylate other proteins to coordinate cell cycle progression
- must be activated and inactivated at appropriate times for the cell cycle to progress
Cyclin-CDK Complexes
Cell Cycle Regulation:
- supresses cell division
- mutations can lead to tumors
Tumor Suppressors
Tumor Suppression
p53 induces p21 → inhibits CDKs → hypophosphrylation (activation) of Rb → inhibition of G1-S progression
Growth factors bind _____ to transition the cell from G1 to S phase.
tyrosine kinase receptors
Cell Types:
- remain in G0
- regenerate from stem cells
- neurons, skeletal and cardiac muscle, RBCs
Permanent
Cell Types:
- enter G1 from G0 when stimulated
- hepatocytes, lymphocytes, PCT, periosteal cells
Stable (Quiescent)
Cell Types:
- never go to G0
- divide rabpidly with a short G1
- most affeced by chemotherapy
- bone marrow, gut epithelium, skin, hair follicles, germ cells
Labile
The _____ is the site of synthesis of secretpry ((exported) proteins and of N-linked oligosaccharide addition to many proteins.
Rough Endoplasmic Reticulum
_____ are RER in neurons which synthesize peptide neurotansmitters for secretion.
Nissl Bodies
_____ are the site of synthesis of cytosolic and organellar proteins.
Free Ribosomes
Mucus-secreting goblet cells of the small intestine and antibody-secreting plasma cells are rich in _____.
RER
The _____ is the site of steroid synthesis and detoxification of drugs and poisons.
Smooth Endoplasmic Reticulum
Liver hepatocytes and steroid hormone-producing cells of the adrenal cortex and gonads are rich in _____.
SER
Cell Trafficking
The _____ is the distribution center for proteins and lipids from the ER to the vesicles and plasma membrane.
Golgi Apparatus
The golgi apparatus modifies N-oligosaccharides on _____.
Asparagine
The golgi apparatus adds O-oligosaccharides on _____.
Serine
Threonine
The golgi apparatus adds _____ to proteins for trafficking to lysosomes.
mannose-6-phosphate
_____ are sorting centers for material from outside the cell or from the Golgi, sending it to lysosomes for destruction or back to the membrane/Golgi for further use.
Endosomes
_____ is an inherited lysosomal storage disorder which causes coarse facial features, gingival hyerplasia, clouded corneas, restricted joint movements, clawhand deformities, kyphoscoliosis and high levels of lysosomal enzymes. It is often fatal in childhood.
Inclusion Cell Disease
(I-Cell DIsease/Mucolipidosis type II)
Inclusion Cell Disease Pathogensis
defect in N-acetylglucosaminyl-1-phosphotransferase → failure of the Golgi to phosphorylate mannose residues (↓ mannose-6-phosphate) on glycoproteins → proteins are secreted extracellularly rather than delivered to lysosomes
_____ is an abundant, cytosolic ribonucleoprotein that traffics proteins from the ribosome to the RER.
Signal Recognition Paticle (SRP)
Absent or dysfunctional _____ leads to protein accumulation in the cytosol.
SRP
Vesicular Trafficking Proteins:
- Golgi → Golgi (retrograde)
- cis-Golgi → ER
COPI
Vesicular Trafficking Proteins:
ER → cis-Golgi (anterograde)
COPII
Vesicular Trafficking Proteins:
- trans-Golgi → lysosomes
- plasma membranes → endosomes (receptor -mediated endocytosis)
Clathrin
_____ are membrane-enclosed organelles involved in :
- β-oxidation of very-long-chain fatty acids (VLCFA)
- α-oxidation
- catabolism of branched-chain fatty acids, amino acids and ethanol
- synthesis of cholesterol, bile acids and plasmalogens (important membrane phospholipid, especially in white matter of brain)
Peroxisomes
_____ is an autosomal recessive disorder of peroxisome biogenesis due to mutated PEX genes cauzing hypotonia, seizures, hepatomegaly and early death.
Zellweger Syndrome
_____ is an autosomal recessive disorder of α-oxidation → phytanic acid is not metabolized to pristanic acid causing scaly skin, ataxia, cataracts, night blindness, shortening of the 4th toe, epiphyseal dysplasia.
Refsum Disease
Refsum Disease:
Treatment
diet
plasmapheresis
_____ is an X-linked recessive disorder of β-oxidation → VLCFA buildup in adrenal glands, white matter and testes → adrenal gland crisis, coma and death.
Adrenoleukodystrophy
The _____ is a barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins.
Proteasome
Defects in the _____ have been implicated in some cases of Parkinson Disease.
Ubiquitin-Proteasome System
_____ is a network of protein fibers within the cytoplasm that supports cell structure, cell and organelle movement and cell division.
Cytoskeletal Elements
Types of Filaments:
- muscle contraction
- cytokinesis
Microfilaments
Types of Filaments:
- actin
Microfilaments
Types of Filaments:
- microvilli
Microfilaments
Types of Filaments:
maintains cell structure
Intermediate Filaments
Types of Filaments:
vimentin
Intermediate Filaments
Types of Filaments:
desmin
Intermediate Filaments
Types of Filaments:
cytokeratin
Intermediate Filaments
Types of Filaments:
lamins
Intermediate Filaments
Types of Filaments:
glial fibrillary acidic protein (GFAP)
Intermediate Filaments
Types of Filaments:
neurofilaments
Intermediate Filaments
Types of Filaments:
- movement
- cell division
Microtubules
Types of Filaments:
cilia
Microtubules
Types of Filaments:
flagella
Microtubules
Types of Filaments:
mitotic spindle
Microtubules
Types of Filaments:
axonal trafficking
Microtubules
Types of Filaments:
centrioles
Microtubules
_____ have a cylindrical outer structure composed of a helical array of polymerized heterodimers of α- and β-tubulin.
Microtubules
Each dimer on a microtubule has a _____ bond.
2 GTP
_____ are incorporated into flagella, cilia and mitotic spindles.
Microtubules
Microtubules grow _____ and collapse _____.
grow slowly
collapse quickly
Microtubule Structure
_____ transport cellular cargo toward opposite ends of microtubule tracks.
Molecular Motor Proteins
Molecular Motor Proteins:
retrograde to microtubule (+ → -)
Dynein
Negative end Near Nucleus
Molecular Motor Proteins:
anterograde to microtubule (- → +)
Kinesin
Positive end Points to Periphery
Drugs that act on Microtubules
Microtubules Get Constructed Very Poorly
- Mebendazole (antihelmintic)
- Griseofulvin (antifungal)
- Colchicine (antigout)
- Vincristine/Vinblastine (anticancer)
- Paclitaxel (anticancer)
Cilia microtubules are arranged as _____.
- 9 doublet + 2 singlet
- 9 triplets (basal body)
_____ is an ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets.
Axonemal Dynein
_____ enable coordinated ciliary movement.
Gap Junctions
_____ is an autosomal recessive disease which causes immotile cilia due to a dynein arm defect. It causes ↓ fertility due to immotile sperm and dysfunctional fallopian tube cilia (↑ ectopic pregnancy). It also presents with bronchiectasis, recurrent sinusitis, chronic ear infections, conductive hearing loss and situs inversus.
Kartagener Syndrome
(1° Ciliary Dyskinesia)
Sodium-Potassium Pump
Na+-K+ ATPase is located in the plasma membrane with the ATP site on the _____.
cytosolic side
For each ATP consumed by Na+-K+ ATPase, _____ go out of the cell and _____ come into the cell.
- 3Na+ out - pump phosphorylated
- 2K+ in - pump dephosphorylated
Pumpkin = pump K+ in
The _____ is an asymmetric lipid bilayer containing cholesterol, phospholipids, sphingolipids, glycolipidsand proteins.
plasma membrane
_____ inhibits Na+-K+ ATPase by binding to the K+ site.
Ouabain
*cardiac glycoside
_____ directly inhibit the Na+-K+ ATPase, which leads to the indirect inhibition of Na+/Ca2+ exchange → ↑ [Ca2+]i → ↑ cardiac contractility.
Digoxin and Digitoxin
* cardiac glycosides
_____ is the most abundant protein in the body, is extensively modified by posttranslational modification and organizes and strengthens extracellular matrix.
Collagen
Collagen Types
Be So Totally Cool, Read Big Books.
- Bone, Skin, Tendon
- Cartilage
- Reticulin, Blood vessels
- Basement membrane
Collagen Types:
most common (90%)
Type I
Collagen Types:
bone (made by osteoblasts)
Type I
*↓ production in osteogenesis Imperfecta type I
Collagen Types:
skin
Type I
Collagen Types:
tendon
Type I
Collagen Types:
dentin
Type I
Collagen Types:
fascia
Type I
Collagen Types:
cornea
Type I
Collagen Types:
late wound repair
Type I
Collagen Types:
cartilage
Type II
CarTWOlage
Collagen Types:
vitreous body
Type II
Collagen Types:
nucleus pulposus
Type II
Collagen Types:
reticulin
Type III
Collagen Types:
blood vessels
Type III
Collagen Types:
uterus
Type III
Collagen Types:
fetal tissue
Type III
Collagen Types:
granulation tissue
Type III
Collagen Types:
deficient in the uncommon, vascular type of Ehlers-Danlos syndrome
Type III
Ehlers-Danlos = ThreE D
Collagen Types:
basement membrane
Type IV
Type 4 = under the floor (basement)
Collagen Types:
basal lamina
Type IV
Collagen Types:
lens
Type IV
Collagen Synthesis and Structure
Collagen Synthesis
- Synthesis
- Hydroxylation
- Glycosylation
- Exocytosis
- Proteolytic Processing
- Cross-Linking
Collagen synthesis begins with the translation of _____.
collagen α chains
(preprocollagen)
*usually Gly-X-Y
*X - proline
*Y - lysine
_____ content best reflects collagen synthesis.
Glycine
*collagen is 1/3 glycine
During collagen synthesis, _____ redidues are hydroxylated.
proline
lysine
Collagen hydroxylation requires _____.
Vitamin C
*deficiency → scurvy
During collagen synthesis, _____ are glycosylated.
pro-α-chain hydroxylysine residues
During collagen glycosylation, procollagen is formed via _____.
hydrogen and disulfide bonds
(triple helix of 3 collagen α chains)
*problems forming triple helix → osteogenesis imperfecta
During collagen synthesis, _____ is exocytosed into the extracellular space.
procollagen
During proteolytic processing of collagen, cleavage of disulfide-rich terminal regions of procollagen forms _____.
insoluble tropocollagen
*problems with cleavage → Ehlers-Danlos
During collagen cross-linking, staggered tropocollagen molecules are reinforced by _____ to make collagen fibrils.
covalent lysine-hydroxylisine cross-linkage
(by copper-containing lysyl oxidase)
*problems with cross-linking → Ehler-Danlos, Menkes
_____ is a genetic bone disorder caused by a variety of gene defeccts (most commonly COL1A1 and COL1A2).
Osteogenesi Imperfecta
(brittle bone disease)
The most common form of osteogenesis imperfecta in _____ with ↓ production of _____.
autosomal dominant
Type I collagen
Osteogenesis Imperfecta Manifestations
Patients cam’t BITE.
- Bones = multiple fractures with minimal trauma
- I (eye) = blue sclerae - translucent connective tissue overchoroidal veins
- Teeth = tooth abnormalities - opalescent teeth that wear easily due to lack of dentin (dentinogenesis imperfecta)
- Ear = hearing loss (abnormal ossicles)
Osteogenesis Imperfecta is treated with _____.
biphosponates
_____ is a disease with faulty collagen synthesis causing hyperextensible skin, hypermobile joints and a tendency to bleed (easy bruising).
Ehlers-Danlos Syndrome
The most common type of Ehlers-Danlos Syndrome is _____.
Hypermobility Type
(joint instability)
The classical type of Ehlers-Danlos Syndrome is caused by a mutation in _____.
Type V Collagen
(joint and skin)
The vascular type of Ehlers-Danlos Syndrome is caused by a deficiency in _____ which affects fragile tissues, vessels, muscles and organs that are prone to rupture.
Type III Procollagen
_____ disease is an X-linked recessive connective tissue disease caused by impaired copper absorption and transfport due to defective ATP7A (_____ protein).
Menkes
Menkes disease causes ↓ activity of _____ → defective collagen.
lysyl oxidase
*copper is a necessary cofactor
_____ disease causes brittle, “kinky” hair, growth retardation and hypotonia.
Menkes
_____ is a stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords and ligamenta flava.
Elastin
Elastin Structure
Elastin is rich in _____.
nonhydroxylated proline, glycine and lysine residues.
Elastin is composed of _____.
tropoelastin with fibrillin scaffolding
Elastin cross-linking takes place _____ and gives it elastic properties.
extracellularly
Elastin is broken down by _____.
Elastase
Elastase is inhibited by _____.
α1-antitrypsin
_____ deficiency results in unopposed elastase activity which can cause emphysema.
α1-antitrypsin
Changes with Aging
- ↓ dermal collagen and elastin
- ↓ synthesis of collagen fibrils
- crosslinking remains normal
_____ is an autosomal dominant connective tissue disorder affecting skeleton, heart and eyes because of FBN1 gene mutation on chromosome 15.
Marfan Syndrome
In Marfan Syndrome, FBN1 gene mutation on chromosome 15 results in defective _____, a glycoprotein that forms a sheath around elastin.
fibrillin
_____ manifests with tall stature, long extremities, pectus carinatum (more specific) or pectus excavatum, hypermobile joints, long tapering fingers and toes (arachnodactyly), cystic medial necrosis of the aorta, aortic incompetence, dissecting aortic aneurysms, floppy mitral valve and subluxation of lenses (upward and temporally).
Marfan Syndrome
_____ is a molecular biology lab procedure used to amplify a desired fragment of DNA.
Polymerase Chain Reaction
Polymerase Chain Reaction
Polymerase Chain Reaction
- Denaturation
- Annealing
- Elongation
In PCR, DNA is heated to _____ to separate strands.
95°C
During the annealing process of PCR, the sample is cooled to _____.
55°C
During the annealing process of PCR, _____ are added.
- DNA primers
- heat-stable DNA polymerase (Taq)
- deoxynucleotide triphosphates (dNTPs)
During the elongation process of PCR, the temperature is increased to _____.
72°C
During the elongation process of PCR, DNA polymerase attaches _____ to the strand to replicate the sequence after each primer.
dNTPs
_____ is a genome editing tool derived from bacteria.
CRISPR
CRISPR is composed of an endonuclease, _____, which cleaves dsDNA and a guide RNA (gRNA) sequence that binds to complementary target DNA sequence.
Cas9
CRISPR:
cell DNA repair machinery (nonhomologous end joining) fills in the gap introduced by the system
knock-out
knock-out = removing a gene, taking it out
CRISPR:
a donor DNA can be added to the system to fill the gap
knock-in
knock-in = inserting a gene.
Blotting Procedures
SNoW DRoP
- Southern = DNA
- Northern = RNA
- Western = Protein
Southern Blot
Southern Blot Procedure
- DNA sample is enzymatically cleaved into smaller pieces,which are separated on a gel by electrophoresis, and then transferred to a filter.
- Filter is exposed to radiolabeled DNA probe that recognizes and anneals to its complementary strand.
- Resulting double-stranded, labeled piece of DNA is visualized when filter is exposed to film.
_____ is similar to Southern Blot, except that an RNA sample is electrophoresed. It is useful of studying mRNA levels, which are reflective of gene expression.
Northern Blot
In _____, a sample protein is separated via gel electrophoresis and transferred to a membrane. The labeled antibody is used to bind to relevant protein.
Western Blot
_____ identifies DNA-binding proteins (eg. transcription factors) using labeled oligonucleotide probes.
Southwestern Blot
_____ is a laboratory technique which assesses the size, granularity, and protein expression (immunophenotype) of individual cells in a sample.
Flow Cytometry
In _____, cells are tagged with antibodies specific to surface or intracellular proteins. Antibodies are then tagged with a unique fluorescent dye. The sample is analyzed one cell at a time by focusing a laser on the cell and measuring light scatter and intensity of fluorescence.
Flow Cytometry
_____ is a laboratory technique commonly used in workup of hematologic abnormalities (eg. paroxysmal nocturnal hemoglobinuria, fetal RBCs in mother’s blood) and immunodeficiencies (eg. CD4 cell count in HIV).
Flow Cytometry
Flow Cytometry data are plotted either as _____ or _____.
- histogram (one measure)
- scatter plot (any two measures)
Flow Cytometry
In _____, thousands of nucleic acid sequences are arranged in grids on glass or silicon. DNA or RNA probes are hybridized to the chip, and a scanner detects the relative amounts of complementary binding.
Microarrays
_____ are used to profile gene expression levels of thousands of genes simultaneously to study certain diseases and treatments. Able to detect single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) for a variety of applications including genotyping, clinical genetic testing, forensic analysis, cancer mutations, and genetic linkage analysis.
Microarrays
_____ is an immunologic test used to detect the presence of either a specific antigen (eg. HBsAg) or antibody (eg. anti-HBs) in a patient’s blood sample.
Enzyme-Linked Immunosorbent Assay (ELISA)
In _____, detection involves the use of an antibody linked to an enzyme. Added substrate reacts with enzyme, producing a detectable signal. It can have high sensitivity and specificity, but is less specific than Western blot.
Enzyme-Linked Immunosorbent Assay (ELISA)
Direct ELISA tests for the _____.
antigen
Indirect ELISA tests for the _____.
antibody
_____ is a process in which metaphase chromosomes are stained, ordered, and numbered according to morphology, size, arm-length ratio, and banding pattern.
Karyotyping
Karyotyping can be performed on a sample of _____.
- blood
- bone marrow
- amniotic fluid
- placental tissue
In _____, a fluorescent DNA or RNA probe binds to
specific gene site of interest on chromosomes. Used for specific localization of genes and direct
visualization of chromosomal anomalies at the
molecular level.
Fluorescence In Situ Hybridization (FISH)
FISH:
no fluorescence on a chromosome compared to fluorescence at the same locus on the second copy of that chromosome
Microdeletion
FISH:
fluorescence signal that corresponds to one chromosome is found in a different chromosome
Translocation
FISH:
a second copy of a chromosome, resulting in a trisomy or tetrasomy
Duplication
_____ is the production of a recombinant DNA molecule in a bacterial host.
Molecular Cloning
Molecular Cloning
- Isolate eukaryotic mRNA (post-RNA processing) of interest.
- Add reserve transcriptase (an RNA-dependent DNA polymerase) to produce complementary DNA (cDNA, lacks introns).
- Insert cDNA fragments into bacterial plasmids containing antibiotic resistance genes.
- Transform (insert) recombinant plasmid into bacteria.
- Surviving bacteria on antibiotic medium produce cloned DNA (copies of cDNA).
Transgenic strategies in mice involve _____.
- Random insertion of gene into mouse genome
- Targeted insertion or deletion of gene through homologous recombination with mouse gene
Gene Expression Modifications:
Random Insertion
Constitutive
Gene Expression Modifications:
Targeted Insertion
Conditional
_____ can inducibly manipulate genes at specific developmental points (eg. to study a gene whose deletion causes embryonic death).
Cre-Lox System
In _____, dsRNA is synthesized that is complementary to the mRNA sequence of interest. When transfected into human cells, dsRNA separates and promotes degradation of target mRNA, “knocking down” gene expression.
RNA Interference
Genetics:
both alleles contribute to the phenotype of the heterozygote
Codominance
Genetics:
- blood groups A, B, AB
- α1-antitrypsi deficiency
- HLA groups
Codominance
Genetics:
patients with the same genotype have varying phenotypes
Variable Expressivity
Genetics:
2 patients with neurofibromatosis type 1 (NF1) may have varying disease severity
Variable Expressivity
Genetics:
not all individuals with a mutant genotype show the mutant phenotype
Incomplete Penetrance
% penetrance × probability of inheriting genotype = risk of expressing phenotype.
Genetics:
BRCA1 gene mutations do not always result in breast or ovarian cancer
Incomplete Penetrance
Genetics:
one gene contributes to multiple phenotypic effects
Pleiotropy
Genetics:
untreated phenylketonuria (PKU) manifests with light skin, intellectual disability, and musty body odor
Pleiotropy
Genetics:
increased severity or earlier onset of disease in succeeding generations
Anticipation
Genetics:
trinucleotide repeat diseases (eg. Huntington disease)
Anticipation
Genetics:
if a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops (not true of oncogenes)
Loss of Heterozygosity
Genetics:
- Retinoblastoma and the “two-hit hypothesis”
- Lynch Syndrome (HNPCC)
- Li-Fraumen Syndrome
Loss of Heterozygosity
Genetics:
exerts a dominant effect, a heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
Dominant Negative Mutation
Genetics:
mutation of a transcription factor in its allosteric site, nonfunctioning mutant can still bind DNA preventing wild-type transcription factor from binding
Dominant Negative Mutation
Genetics:
tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance, measured in a population, not in a family, and often varies in different populations
Linkage Disequilibrium
Genetics:
presence of genetically distinct cell lines in the
same individual
Mosaicism
Genetics:
mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs
Somatic Mosaicism
Genetics:
mutation only in egg or sperm cells, if parents and relatives do not have the disease suspect gonadal (or germline) mosaicism
Gonadal Mosaicism
_____ is due to a mutation affecting G-protein signaling. It presents with unilateral café-au-lait spots with ragged edges, polyostotic fibrous dysplasia (bone is replaced by collagen and fibroblasts), and at least one endocrinopathy (eg. precocious puberty). Lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism.
McCune-Albright Syndrome
Genetics:
mutations at different loci can produce a similar phenotype
Locus Heterogeneity
Genetics:
albinism
Locus Heterogeneity
Genetics:
different mutations in the same locus produce the same phenotype
Allelic Heterogeneity
Genetics:
β-thalassemia
Allelic Heterogeneity
Genetics:
presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease
Heteroplasmy
Genetics:
mtDNA passed from mother to all children
Heteroplasmy
Genetics:
offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent
Uniparental Disomy
Heterodisomy (heterozygous) indicates a _____.
meiosis I error
HeterodIsomy = meiosis I error
Isodisomy (homozygous) indicates a _____ or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair.
meiosis II error
IsodIsomy = meiosis II error
Uniparental disomy (UPD) is _____. Most occurrences of uniparental disomy → normal phenotype. Consider UPD in an individual manifesting a recessive disorder when only one parent is a carrier. Examples: Prader Willi and Angelman Syndromes
euploid
(correct number of chromosomes)
Genetics:
Prader Willi and Angelman Syndromes
Uniparental Disomy
If a population is in Hardy-Weinberg equilibrium and if p and q are the frequencies of separate alleles, then _____.
p2 + 2pq + q2 = 1 and p + q = 1, which implies that:
- p2 = frequency of homozygosity for allele A
- q2 = frequency of homozygosity for allele a
- 2pq = frequency of heterozygosity (carrier frequency, if an autosomal recessive disease).
The frequency of an X-linked recessive disease in males = q and in females = q2.
Hardy-Weinberg law assumptions include:
- No mutation occurring at the locus
- Natural selection is not occurring
- Completely random mating
- No net migration
Genetics:
one gene copy is silenced by methylation, and only the other copy is expressed → parent-of-origin effects
Imprinting
_____ occurs when maternally derived genes are silenced (imprinted). Disease occurs when the paternal allele is deleted or mutated. Results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia. Associated with a mutation or deletion of chromosome 15 of paternal origin. 25% of cases due to maternal uniparental disomy.
Prader-Willi Syndrome
Prader-Willi = Paternal
_____ occurs when paternally derived UBE3A gene is silenced (imprinted). Disease occurs when the maternal allele is deleted or mutated. Results in inappropriate laughter (“happy puppet”), seizures, ataxia, and severe intellectual disability. Associated with mutation or deletion of the UBE3A gene on the maternal copy of chromosome 15. 5% of cases due to paternal uniparental disomy.
Angelman Syndrome
AngelMan = Maternal
Modes of Inheritance
Autosomal Dominant
Modes of Inheritance
Autosomal Recessive
Modes of Inheritance
X-linked Recessive
Modes of Inheritance
X-linked Dominant
Modes of Inheritance
Mitochondrial Inheritance
Modes of Inheritance:
- often due to defects in structural genes
- many generations, both males and females are affected
- often pleiotropic (multiple apparently unrelated effects) and variably expressive (different between individuals)
- with one affected (heterozygous) parent 1/2 of children are affected.
Autosomal Dominant
Modes of Inheritance:
- often due to enzyme deficiencies
- usually seen in only 1 generation
- commonly more severe than dominant disorders
- patients often present in childhood.
- ↑ risk in consanguineous families.
- With 2 carrier (heterozygous) parents, on average: ¼ of children will be affected (homozygous), ½ of children will be carriers, and ¼ of children will be neither affected nor carriers.
Autosomal Recessive
Modes of Inheritance:
- sons of heterozygous mothers have a 50% chance of being affected
- no male-to-male transmission
- skips generations
- commonly more severe in males
- females usually must be homozygous to be affected
X-linked Recessive
Modes of Inheritance:
- transmitted through both parents
- mothers transmit to 50% of daughters and sons
- fathers transmit to all daughters but no sons
X-linked Dominant
Modes of Inheritance:
Hypophosphatemic Rickets
X-linked Dominant
Modes of Inheritance:
Fragile X Syndrome
X-linked Dominant
Modes of Inheritance:
Alport Syndrome
X-linked Dominant
_____, formerly known as vitamin D-resistant rickets, is an inherited disorder resulting in ↑ phosphate wasting at the proximal tubule.
Hypophosphatemic Rickets
Modes of Inheritance:
- transmitted only through the mother
- all offspring of affected females may show signs of disease
- variable expression in a population or even within a family due to heteroplasmy
Mitochondrial Inheritance
Modes of Inheritance:
Mitochondrial Myopathies
Mitochondrial Inheritance
Modes of Inheritance:
Leber Hereditary Optic Neuropathy
Mitochondrial Inheritance
_____ are rare disorders, often presenting with myopathy, lactic acidosis, and CNS disease.
Mitochondrial Myopathies
_____ is 2° to failure in oxidative phosphorylation. Muscle biopsy often shows “ragged red fibers” (due to accumulation of diseased mitochondria).
MELAS Syndrome
- Mitochondrial Encephalomyopathy
- Lactic Acidosis
- Stroke-like episodes
_____ causes cell death in optic nerve neurons → subacute bilateral vision loss in teens/young adults, 90% males. It is usually permanent.
Leber Hereditary Optic Neuropathy
Modes of Inheritance:
Achondroplasia
Autosomal Dominant
Modes of Inheritance:
Familial Adenomatous Polyposis
Autosomal Dominant
Modes of Inheritance:
Familial Hypercholesterolemia
Autosomal Dominant
Modes of Inheritance:
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)
Autosomal Dominant
Modes of Inheritance:
Hereditary Spherocytosis
Autosomal Dominant
Modes of Inheritance:
Huntington Disease
Autosomal Dominant
Modes of Inheritance:
Li-Fraumeni Syndrome
Autosomal Dominant
Modes of Inheritance:
Marfan Syndrome
Autosomal Dominant
Modes of Inheritance:
Multiple Endocrine Neoplasias
Autosomal Dominant
Modes of Inheritance:
Myotonic Muscular Dystrophy
Autosomal Dominant
Modes of Inheritance:
Neurofibromatosis Type 1
(von Recklinghausen Disease)
Autosomal Dominant
Modes of Inheritance:
Neurofibromatosis Type 2
Autosomal Dominant
Modes of Inheritance:
Tuberous Sclerosis
Autosomal Dominant
Modes of Inheritance:
von Hippel-Lindau Disease
Autosomal Dominant
Modes of Inheritance:
Albinism
Autosomal Recessive
Modes of Inheritance:
Cystic Fibrosis
Autosomal Recessive
Modes of Inheritance:
Friedreich Ataxia
Autosomal Recessive
Modes of Inheritance:
Glycogen Storage Diseases
Autosomal Recessive
Modes of Inheritance:
Hemochromatosis
Autosomal Recessive
Modes of Inheritance:
Kartagener Syndrome
Autosomal Recessive
Modes of Inheritance:
Mucopolysaccharidoses
(except Hunter Syndrome)
Autosomal Recessive
Modes of Inheritance:
Phenylketonuria
Autosomal Recessive
Modes of Inheritance:
Sickle Cell Anemia
Autosomal Recessive
Modes of Inheritance:
Sphingolipidoses
(except Fabry Disease)
Autosomal Recessive
Modes of Inheritance:
Thalassemias
Autosomal Recessive
Modes of Inheritance:
Wilson Disease
Autosomal Recessive
_____ is an autosomal recessive disease caused by a defect in CFTR gene on chromosome 7, commonly a deletion of Phe508.
Cystic Fibrosis
_____ is the most common lethal genetic disease in Caucasian population.
Cystic Fibrosis
- CFTR encodes an ATP-gated Cl− channel that secretes Cl− in lungs and GI tract, and reabsorbs Cl− in sweat glands.
- Most common mutation: misfolded protein → protein retained in RER and not transported to cell membrane, causing ↓ Cl− (and H2O) secretion; ↑ intracellular Cl− results in compensatory ↑ Na+ reabsorption via epithelial Na+ channels → ↑ H2O reabsorption → abnormally thick mucus secreted into lungs and GI tract.
- ↑ Na+ reabsorption also causes more negative transepithelial potential difference.
Cystic Fibrosis
- ↑ Cl− concentration in pilocarpine-induced sweat test is diagnostic.
- Can present with contraction alkalosis and hypokalemia (ECF effects analogous to a patient taking a loop diuretic) because of ECF H2O/Na+ losses and concomitant renal K+/H+ wasting.
- ↑ immunoreactive trypsinogen (newborn screening).
Cystic Fibrosis
- Recurrent pulmonary infections (eg. S aureus [early infancy], P aeruginosa [adolescence]), chronic bronchitis and bronchiectasis → reticulonodular pattern on CXR, opacification of sinuses.
- Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D, E, K), biliary cirrhosis, liver disease.
- Meconium ileus in newborns.
- Infertility in men (absence of vas deferens, spermatogenesis may be unaffected) and subfertility in women (amenorrhea, abnormally thick cervical mucus).
- Nasal polyps, clubbing of nails.
Cystic Fibrosis
Cystic Fibrosis Treatment
- Multifactorial: chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), and hypertonic saline facilitate mucus clearance. Azithromycin used as anti-inflammatory agent. Ibuprofen slows disease progression.
- In patients with Phe508 deletion: combination of lumacaftor (corrects misfolded proteins and improves their transport to cell surface) and ivacaftor (opens Cl– channels → improved chloride transport).
X-linked Recessive Disorders
Oblivious Female Will Often Give Her Boys Her x-Linked Disorders
- Ornithine Transcarbamylase Deficiency
- Fabry Disease
- Wiskott-Aldrich Syndrome
- Ocular Albinism
- G6PD Deficiency
- Hunter Syndrome
- Bruton Agammaglobulinemia
- Hemophilia A and B
- Lesch-Nyhan Syndrome
- Duchenne (and Becker) Muscular Dystrophy
In _____, female carriers are variably affected depending on the pattern of inactivation of the X chromosome carrying the mutant vs. normal gene.
X-Inactivation
(Lyonization)
Females with _____ are more likely to have an X-linked recessive disorder.
Turner Syndrome (45,XO)
_____ is an X-linked disorder typically due to frameshift or nonsense mutations → truncated or absent dystrophin protein → progressive myofiber damage.
Duchenne Muscular Dystrophy
In Duchenne Muscular Dystrophy, weakness begins in the _____ and progresses _____ leading to a _____ gait.
pelvic girdle muscles
superiorly
waddling
In Duchenne Muscular Dystrophy, pseudohypertrophy of calf muscles is due to _____.
fibrofatty replacement of muscle
The onset of Duchenne Muscular Dystrophy is _____.
before 5 y.o.
In Duchenne Muscular Dystrophy, the most common cause of death is _____.
dilated cardiomyopathy
_____ is deomonstrated when a patient uses upper extremities to help stand up.
Gower Sign
_____ is the largest protein-coding human gene → ↑ chance of spontaneous mutation.
Dystrophin Gene
_____ helps anchor muscle fibers, primarily in skeletal and cardiac muscle. It connects the intracellular cytoskeleton (actin) to the transmembrane proteins α- and β-dystroglycan, which are connected to the extracellular matrix (ECM).
Dystrophin
_____ presents with ↑ CK and aldolase; genetic testing confirms the diagnosis.
Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy
_____ is an X-linked disorder typically due to nonframeshift deletions in dystrophin gene
(partially functional instead of truncated).
Becker Muscular Dystrophy
*less severe than Duchenne
Th onset of Becker Muscular Dystrophyis in _____.
adolescence
early adulthood
_____ is an autosomal dominant disease. CTG trinucleotide repeat expansion in the DMPK gene → abnormal expression of myotonin protein kinase → myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia.
Myotonic Type 1 Muscular Dystrophy
CTG trinucleotide repeat
- Cataracts
- Toupee (early balding in men)
- Gonadal atrophy
_____ is a sporadic disorder seen almost exclusively in girls (affected males die in utero or shortly after birth). Most cases are caused by de novo mutation of MECP2 on X chromosome.
Rett Syndrome
The symptoms of Rett Syndrome usually appear between _____.
1-4 y.o.
Rett Syndrome is characterized by _____.
- regression (Retturn) in motor, verbal, and cognitive abilities
- ataxia
- seizures
- growth failure
- stereotyped handwringing
_____ is an X-linked Dominant disease. Trinucleotide repeat in FMR1 gene → hypermethylation → ↓ expression.
Fragile X Syndrome
_____ is the most common cause of inherited intellectual disability and 2nd most common cause of genetically associated mental deficiency (after Down syndrome).
Fragile X Syndrome
_____ presents with post-pubertal macroorchidism (enlarged testes), long face with a large jaw, large everted ears, autism, mitral valve prolapse.
Fragile X Syndrome
The trinucleotide repeat expansionin Fragile X Syndrome [(CGG)n] occurs during _____.
oogenesis
Trinucleotide repeat expansion diseases may show _____ (disease severity ↑ and age of onset ↓ in successive generations).
genetic anticipation
Trinucleotide Repeat Expansion Diseases
Try (trinucleotide) hunting for my fragile cagefree eggs (X).
- Huntington Disease
- Myotonic Dystrophy
- Fragile X Syndrome
- Friedreich Ataxia
Huntington Disease Trinucleotide Repeat
CAG
Caudate has ↓ ACh and GABA
Myotonic Gystrophy Trinucleotide Repeat
CTG
- Cataracts
- Toupee (early balding in men)
- Gonadal atrophy
Fragile X Syndrome Trinucleotide Repeat
CGG
- Chin (protruding)
- Giant Gonads
Friedreich Ataxia Trinucleotide Repeat
GAA
Ataxic GAAit
_____ presents with intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (eg. atrioventricular septal defect), Brushfield spots, early-onset Alzheimer disease (chromosome 21 codes for amyloid precursor protein) and ↑ risk of ALL and AML.
Down Syndrome
Drinking age (21)
(Trisomy 21)
95% of Down Syndrome cases are due to _____.
meiotic nondisjunction
*↑ with advanced maternal age; from 1:1500 in women < 20 to 1:25 in women > 45 years old
4% of Down Syndrome cases are due to _____, most typically between _____.
unbalanced Robertsonian translocation
chromosomes 14 and 21
Only 1% of Down Syndrome cases are due to _____.
postfertilization mitotic error
The incidence of Down Syndrome is _____.
1:700
_____ is the most common viable chromosomal disorder and most common cause of genetic intellectual disability.
Down Syndrome
First-trimester ultrasound of Down Syndrome commonly shows _____.
↑ nuchal translucency
hypoplastic nasal bone
Down Syndrome Findings
The 5 A’s of Down Syndrome:
- Advanced maternal age
- Atresia (duodenal)
- Atrioventricular septal defect
- Alzheimer disease (early onset)
- AML/ALL
_____ presents with prominent occiput, rocker-bottom feet, intellectual disability, nondisjunction, clenched fists (with overlapping fingers), low-set ears, micrognathia (small jaw), congenital heart disease. Death usually occurs by age 1.
Edwards Syndrome
Election age (18)
(Trisomy 18)
The incidence of Edwards Syndrome is _____.
1:8000
_____ is the 2nd most common autosomal trisomy resulting in live birth.
Edwards Syndrome
Edwards Syndrome Findings
PRINCE Edward
- Prominent occiput
- Rocker-bottom feet
- Intellectual disability
- Nondisjunction
- Clenched fists (with overlapping fingers)
- low-set Ears,
_____ presents with severe intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, cutis aplasia, congenital heart disease, polycystic kidney disease. Death usually occurs by age 1.
Patau Syndrome
Puberty (13)
(Trisomy 13)
The incidence of Patau Syndrome is _____.
1:15,000
Patau Syndrome Findings
The 5 P’s of Patau Syndrome:
- cleft liP/Palate
- holoProsencephaly
- Polydactyly
- cutis aPlasia
- Polycystic kidney disease
Trisomies
Genetic Disorders:
Chromosome 3
von Hippel-Lindau Disease
Renal Cell Carcinoma
Genetic Disorders:
Chromosome 4
ADPKD (PKD2)
Achondroplasia
Huntington Disease
Genetic Disorders:
Chromosome 5
Cri-du-chat Syndrome
Familial Adenomatous Polyposis
Genetic Disorders:
Chromosome 6
Hemochromatosis (HFE)
Genetic Disorders:
Chromosome 7
Williams Syndrome
Cystic Fibrosis
Genetic Disorders:
Chromosome 9
Friedreich Ataxia
Tuberous Sclerosis (TSC1)
Genetic Disorders:
Chromosome 11
Wilms Tumor
β-globin Gene Defects
(eg. sickle cell disease, β-thalassemia)
MEN1
Genetic Disorders:
Chromosome 13
Patau Syndrome
Wilson Disease
Retinoblastoma (RB1)
BRCA2
Genetic Disorders:
Chromosome 15
Prader-Willi Syndrome
Angelman Syndrome
Marfan Syndrome
Genetic Disorders:
Chromosome 16
ADPKD (PKD1)
α-globin Gene Defects
(eg. α-thalassemia)
Tuberous Sclerosis (TSC2)
Genetic Disorders:
Chromosome 17
Neurofibromatosis Type 1
BRCA1
p53
Genetic Disorders:
Chromosome 18
Edwards Syndrome
Genetic Disorders:
Chromosome 21
Down Syndrome
Genetic Disorders:
Chromosome 22
Neurofibromatosis Type 2
DiGeorge Syndrome (22q11)
Genetic Disorders:
X Chromosome
Fragile X Syndrome
X-linked Agammaglobulinemia
Klinefelter Syndrome (XXY)
_____ is a chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22. It is one of the most common types of translocation. It occurs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost.
Robertsonian Translocation
Unbalanced _____ can result in miscarriage, stillbirth, and chromosomal imbalance (eg. Down Syndrome, Patau Syndrome).
Robertsonian Translocation
_____ is caused by the congenital deletion on the short arm of chromosome 5 (46,XX or XY, 5p−).
Cri-du-chat Syndrome
_____ presents with microcephaly, moderate to severe intellectual disability, high-pitched crying/ meowing, epicanthal folds, cardiac abnormalities (VSD).
Cri-du-chat Syndrome
_____ is caused by the congenital microdeletion of the long arm of chromosome 7 (deleted region includes elastin gene).
Williams Syndrome
_____ presents with distinctive “elfin” facies, intellectual disability, hypercalcemia (↑ sensitivity to vitamin D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems (eg. supravalvular aortic stenosis, renal artery stenosis).
Williams Syndrome
22q11 Deletion Syndromes
DiGeorge Syndrome
Velocardiofacial Syndrome
22q11 Deletion Syndrome Findings
CATCH-22
microdeletion at chromosome 22q11 → Cleft palate, Abnormal facies, Thymic aplasia → T-cell deficiency, Cardiac defects, and Hypocalcemia 2° to parathyroid aplasia
22q11 Deletion Syndromes result in the aberrant development of the _____.
3rd and 4th branchial (pharyngeal) pouches
22q11 Deletion Syndromes:
thymic, parathyroid, and cardiac defects
DiGeorge Syndrome
22q11 Deletion Syndromes:
palate, facial, and cardiac defects
Velocardiofacial Syndrome
Fat Soluble Vitamins
A, D, E, K
Absorption of fat soluble vitamins is dependent on the _____.
gut and pancreas
Toxicity more common in fat-soluble
vitamins than for water-soluble vitamins because _____.
fat-soluble vitamins accumulate in fat
Malabsorption syndromes with steatorrhea (eg. cystic fibrosis and celiac disease) or mineral oil intake can cause _____.
fat-soluble vitamin deficiencies
Water Soluble Vitamins
- B1 (thiamine: TPP)
- B2 (riboflavin: FAD, FMN)
- B3 (niacin: NAD+)
- B5 (pantothenic acid: CoA)
- B6 (pyridoxine: PLP)
- B7 (biotin)
- B9 (folate)
- B12 (cobalamin)
- C (ascorbic acid)
B Vitamins
The Regular Night Pub Provided Beer For Coby.
- B1 (Thiamine: TPP)
- B2 (Riboflavin: FAD, FMN)
- B3 (Niacin: NAD+)
- B5 (Pantothenic acid: CoA)
- B6 (Pyridoxine: PLP)
- B7 (Biotin)
- B9 (Folate)
- B12 (Cobalamin)
Water soluble vitamins all wash out easily from body except _____.
B9 and B12
B9 and B12 are stored in the _____.
liver (~3-4 years)
B-complex deficiencies often result in _____.
- dermatitis
- glossitis
- diarrhea
Vitamin A is also called _____.
Retinol
_____ is an antioxidant; a constituent of visual pigments (retinal); essential for normal differentiation of epithelial cells into specialized tissue (pancreatic cells, mucus-secreting cells); prevents squamous metaplasia; used to treat measles and acute promyelocytic leukemia (APL).
Vitamin A
Vitamin A is found in _____.
liver
leafy vegetables
_____ is used to treat severe cystic acne.
oral isotretinoin
_____ is used to treat acute promyelocytic leukemia.
all-trans retinoic acid
_____ causes night blindness (nyctalopia), dry scaly skin (xerosis cutis), corneal degeneration (keratomalacia), Bitot spots (foamy appearance) on conjunctiva and immunosuppression.
Vitamin A Deficiency
_____ causes nausea, vomiting, vertigo, and blurred vision.
Acute Vitamin A Toxicity
_____ causes alopecia, dry skin (eg. scaliness), hepatic toxicity and enlargement, arthralgias, and pseudotumor cerebri.
Chronic Vitamin A Toxicity
A ⊝ pregnancy test and two forms of contraception are required before isotretinoin (vitamin A derivative) is prescribed because it is _____.
teratogenic
(cleft palate, cardiac abnormalities)
Vitamin B1 is also called _____.
Thiamine
In thiamine pyrophosphate (TPP), vitamin B3 is a cofactor for several dehydrogenase enzyme reactions:
ATP
- α-ketoglutarate dehydrogenase (TCA cycle)
- Transketolase (HMP shunt)
- Pyruvate dehydrogenase (links glycolysis to TCA cycle)
- Branched-chain ketoacid dehydrogenase
_____ causes impaired glucose breakdown → ATP depletion worsened by glucose infusion; highly aerobic tissues (eg. brain, heart) are affected first.
Vitamin B1 Deficiency
(Beriberi)
Ber1Ber1
Diagnosis of Vitamin B1 Deficiency is made by _____ following vitamin B1 administration.
↑ in RBC transketolase activity
_____ causes confusion, ophthalmoplegia, ataxia, confabulation, personality change, memory loss (permanent) and damage to medial dorsal
nucleus of thalamus and mammillary bodies.
Wernicke-Korsakoff Syndrome
Triad:
- confusion
- ophthalmoplegia
- ataxia
In alcoholic or malnourished patients, give thiamine before dextrose to ↓ risk of precipitating _____.
Wernicke Encephalopathy
_____ causes polyneuropathy and symmetrical
muscle wasting.
Dry beriberi
_____ causes high-output cardiac failure (dilated cardiomyopathy), edema.
Wet Beriberi
Vitamin B2 is also called _____.
Riboflavin
_____ is a component of flavins FAD and FMN, used as cofactors in redox reactions, eg. the succinate dehydrogenase reaction in the TCA cycle.
Vitamin B2
FAD and FMN are derived from riboFlavin (B2 ≈ 2 ATP).
_____ causes cheilosis (inflammation of lips, scaling and fissures at the corners of the mouth), corneal vascularization.
Vitamin B2 Deficiency
The 2 C’s of B2:
- Cheilosis
- Corneal vascularization
Vitamin B3 is also called _____.
Niacin
_____ is a constituent of NAD+, NADP+ (used in redox reactions). Derived from tryptophan. Synthesis requires vitamins B2 and B6. Used to treat dyslipidemia; lowers levels of VLDL and raises levels of HDL.
Vitamin B3
NAD derived from Niacin (B3 ≈ 3 ATP).
Synthesis of Vitamin B3 requires _____.
Vitamins B2 and B6
Vitamin B3 is derived from _____.
Tryptophan
_____ causes glossitis and severe deficiency leads to pellagra, which can also be caused by Hartnup disease, malignant carcinoid syndrome (↑ tryptophan metabolism), and isoniazid (↓ vitamin B6).
Vitamin B3 Deficiency
(Pellagra)
Symptoms of Pellagra
The 3 D’s of B3:
- Diarrhea
- Dementia (also hallucinations)
- Dermatitis (C3/C4 dermatome circumferential “broad collar” rash [Casal necklace], hyperpigmentation of sunexposed limbs).
_____ is an autosomal recessive disease which causes deficiency of neutral amino acid (eg. tryptophan) transporters in proximal renal tubular cells and on enterocytes → neutral aminoaciduria and ↓ absorption from the gut → ↓ tryptophan for conversion to niacin → pellagra-like symptoms. Treat with high protein diet and nicotinic acid.
Hartnup Disease
_____ causes facial flushing (induced by prostaglandin, not histamine; can be avoided by taking aspirin), hyperglycemia, hyperuricemia.
Vitamin B3 Toxicity
(Podagra)
Vitamin B5 is also called _____.
Pantothenic Acid
_____ is an Eessential component of coenzyme A (CoA, a cofactor for acyl transfers) and fatty acid synthase.
Vitamin B5
_____ causes dermatitis, enteritis, alopecia, adrenal insufficiency.
Vitamin B5 Deficiency
Vitamin B6 is also called _____.
Pyridoxine
_____ is converted to pyridoxal phosphate (PLP), a cofactor used in transamination (eg. ALT and AST), decarboxylation reactions, glycogen phosphorylase, synthesis of cystathionine, heme, niacin, histamine, and neurotransmitters including serotonin, epinephrine, norepinephrine (NE), dopamine, and GABA.
Vitamin B6
_____ causes convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by isoniazid and oral contraceptives), sideroblastic anemias (due to impaired hemoglobin synthesis and iron excess).
Vitamin B6 Deficiency
Vitamin B7 is also called _____.
Biotin
Vitamin B7 is a cofactor for carboxylation enzymes (which add a 1-carbon group):
- Pyruvate carboxylase: pyruvate (3C) → oxaloacetate (4C)
- Acetyl-CoA carboxylase: acetyl-CoA (2C) → malonyl-CoA (3C)
- Propionyl-CoA carboxylase: propionyl-CoA (3C) → methylmalonyl-CoA (4C)
_____ presents with dermatitis, enteritis and alopecia. It is caused by antibiotic use or excessive ingestion of raw egg whites (avidin).
Vitamin B7 Deficiency
Vitamin B9 is also called _____.
Folate
_____ is converted to tetrahydrofolic acid (THF), a coenzyme for 1-carbon transfer/methylation reactions. Important for the synthesis of nitrogenous bases in DNA and RNA.
Vitamin B9
Vitamin B9 is found in _____.
leafy green vegetables
Folate from Foliage
Vitamin B9 is absorbed in the _____.
jejunum
A small reserve pool of Vitamin B9 is stored primarily in the _____.
liver
_____ causes macrocytic, megaloblastic anemia; hypersegmented polymorphonuclear cells (PMNs); glossitis; no neurologic symptoms. Labs: ↑ homocysteine, normal methylmalonic acid levels. Seen in alcoholism and pregnancy.
Vitamin B9 Deficiency
Vitamin B9 Deficiency can be caused by drugs such as _____.
Phenytoin
Sulfonamides
Methotrexate
Supplemental maternal folic acid is given at least _____ prior to conception and during early pregnancy to ↓ risk of neural tube defects.
1 month
Vitamin B12 is also called _____.
Cobalamin
_____ is a cofactor for methionine synthase (transfers CH3 groups as methylcobalamin) and methylmalonyl CoA mutase. Important for DNA synthesis.
Vitamin B12
Vitamin B12 is found in _____.
animal products
Vitamin B12 is synthesized only by _____.
microorganisms
Vitamin B12 has a very large reserve pool (several years) stored primarily in the _____.
liver
_____ causes macrocytic, megaloblastic anemia; hypersegmented PMNs; paresthesias and subacute combined degeneration (degeneration of dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts) due to abnormal myelin. Associated with ↑ serum homocysteine and methylmalonic acid levels, along with 2° folate deficiency. Prolonged deficiency → irreversible nerve damage.
Vitamin B12 Deficiency
Vitamin B12 Deficiency is caused by _____.
- malabsorption (eg. sprue, enteritis, Diphyllobothrium latum, achlorhydria, bacterial overgrowth, alcohol excess)
- lack of intrinsic factor (eg. pernicious anemia, gastric bypass surgery)
- absence of terminal ileum (surgical resection, eg. for Crohn disease)
- insufficient intake (eg. veganism)
The presence of anti-intrinsic factor antibodies is diagnostic for _____.
Pernicious Anemia
Folate supplementation can mask the hematologic symptoms of B12 deficiency, but not the _____.
neurologic symptoms
Vitamin B6 and B12 Processes
Vitamin C is also called _____.
ascorbic acid
_____ is an antioxidant that also facilitates iron absorption by reducing it to Fe2+ state. Necessary for hydroxylation of proline and lysine in collagen synthesis. Necessary for dopamine β-hydroxylase, which converts dopamine to NE.
Vitamin C
Vitamin C is found in _____.
fruits and vegetables
_____ is an ancillary treatment for methemoglobinemia by reducing Fe3+ to Fe2+.
Vitamin C
_____ causes swollen gums, bruising, petechiae, hemarthrosis, anemia, poor wound healing, perifollicular and subperiosteal hemorrhages, “corkscrew” hair and weakened immune response.
Vitamin C Deficiency
(Scurvy)
Vitamin C deficiency causes sCurvy due to a
Collagen synthesis defect.
_____ causes nausea, vomiting, diarrhea, fatigue, calcium oxalate nephrolithiasis. Can ↑ iron toxicity in predisposed individuals by increasing dietary iron absorption (ie. can worsen hereditary hemochromatosis or transfusion-related iron overload).
Vitamin C Toxicity
Vitamin D2 (ergocalciferol) comes from ingestion of _____.
- plants
- fungi
- yeasts
Vitamin D3 (cholecalciferol) comes from _____.
- exposure of skin (stratum basale) to sun
- fish
- milk
- plants
Vitamin D2 is also called _____.
Ergocalciferol
Vitamin D3 is also called _____.
Cholecalciferol
Vitamin D2 and D3 are converted to their stirage form _____ in the _____.
25-OH D3
liver
Vitamin D2 and D3 are converted to their active form, _____, in the _____.
1,25-(OH)2 D3 (calcitriol)
kidney
Functions of Vitamin D
- ↑ intestinal absorption of Ca2+ and PO43
- ↑ bone mineralization at low levels
- ↑ bone resorption at higher levels
At low levels of Vitamin D, there is _____.
↑ bone mineralization
At high levels of Vitamin D, there is _____.
↑ bone resorption
Vitamin D Regulation
- ↑ PTH, ↓ Ca2+, ↓ PO43– → ↑ 1,25-(OH)2D3 production
- 1,25-(OH)2D3 feedback inhibits its own production.
- ↑ PTH → ↑ Ca2+ reabsorption and ↓ PO43– reabsorption in the kidney.
Vitamin D Deficiency causes _____ in children (deformity, such as genu varum “bow legs”).
Rickets
Vitamin D Deficiency causes _____ in adults (bone pain and muscle weakness).
Osteomalacia
Vitamin D Deficiency causes _____.
- Rickets in children (deformity, such as genu varum “bow legs”)
- Osteomalacia in adults (bone pain and muscle weakness)
- Hypocalcemic Tetany
Vitamin D Deficiency is caused by _____.
- malabsorption
- ↓ sun exposure
- poor diet
- chronic kidney disease
Vitamin D Deficiency is exacerbated by _____.
- pigmented skin
- premature birth
Oral Vitamin D is given to _____ infants.
breastfed
_____ causes hypercalcemia, hypercalciuria, loss of appetite and stupor and is seen in granulomatous disease (↑ activation by epithelioid macrophages).
Vitamin D Toxicity
Vitamin E includes _____.
- tocopherol
- tocotrienol
_____ is an antioxidant (protects RBCs and membranes from free radical damage). High-dose supplementation may alter metabolism of vitamin K → enhanced anticoagulant effects of warfarin.
Vitamin E
_____ causes hemolytic anemia, acanthocytosis, muscle weakness, posterior column and spinocerebellar tract demyelination.
Vitamin E Deficiency
The neurologic presentation of _____ may appear similar to vitamin B12 deficiency, but without megaloblastic anemia, hypersegmented neutrophils or ↑ serum methylmalonic acid levels.
Vitamin E Deficiency
Excess vitamin E ↑ risk of _____ in infants.
enterocolitis
Vitamin K includes _____.
- phytomenadione
- phylloquinone
- phytonadione
- menaquinone
_____ is activated by epoxide reductase to the reduced form, which is a cofactor for the γ-carboxylation of glutamic acid residues on various proteins required for blood clotting. Synthesized by intestinal flora.
Vitamin K
Vitamin K is necessary for the maturation of_____.
- clotting factors II, VII, IX, X (1972)
- proteins C and S
_____ inhibits vitamin K-dependent synthesis of clotting factors and proteins.
Warfarin
_____ causes neonatal hemorrhage with ↑ PT and ↑ aPTT but normal bleeding time (neonates have sterile intestines and are unable to synthesize _____). Can also occur after prolonged use of broad-spectrum antibiotics.
Vitamin K Deficiency
_____ is not in breast milk therefore neonates are given _____ injection at birth to prevent hemorrhagic disease of the newborn.
Vitamin K
_____ is a mineral essential for the activity of 100+ enzymes. Important in the formation of _____ (transcription factor motif).
Zinc
Zinc Fingers
_____ causes delayed wound healing, suppressed immunity, hypogonadism, ↓ adult hair (axillary, facial, pubic), dysgeusia, anosmia, acrodermatitis enteropathica. May predispose to alcoholic cirrhosis.
Zinc Deficiency
_____ is protein malnutrition resulting in skin lesions, edema due to ↓ plasma oncotic pressure, liver malfunction (fatty change due to ↓ apolipoprotein synthesis). Clinical picture is small child with swollen abdomen.
Kwashiorkor
Kwashiorkor Findings
Kwashiorkor results from protein deficient MEALS:
- Malnutrition
- Edema
- Anemia
- Liver (fatty)
- Skin lesions (eg, hyperkeratosis, dyspigmentation)
_____ is malnutrition not causing edema. Diet is deficient in calories but no nutrients are entirely absent.
Marasmus
Marasmus results in Muscle wasting.
Ethanol Metabolism
_____ inhibits alcohol dehydrogenase and is an antidote for overdoses of methanol or ethylene glycol.
Fomepizole
FOMEpizole = For Overdoses of Methanol or Ethylene glycol
_____ inhibits acetaldehyde dehydrogenase (acetaldehyde accumulates, contributing to hangover symptoms), discouraging drinking.
Disulfiram
_____ is the limiting reagent in ethanol metabolism.
NAD+
Alcohol dehydrogenase operates via _____.
zero-order kinetics
Ethanol metabolism ↑ NADH/NAD+ ratio in
liver, causing:
- Pyruvate → lactate (lactic acidosis)
- Oxaloacetate → malate (prevents gluconeogenesis → fasting hypoglycemia)
- Dihydroxyacetone phosphate → glycerol-3‑phosphate (combines with fatty acids to make triglycerides → hepatosteatosis)
_____ disfavors TCA production of NADH → ↑ utilization of acetyl-CoA for ketogenesis (→ ketoacidosis) and lipogenesis (→ hepatosteatosis).
↑ NADH/NAD+ ratio
Metabolism Sites:
fatty acid oxidation (β-oxidation)
Mitochondria
Metabolism Sites:
acetyl-CoA production
Mitochondria
Metabolism Sites:
TCA cycle
Mitochondria
Metabolism Sites:
oxidative phosphorylation
Mitochondria
Metabolism Sites:
ketogenesis
Mitochondria
Metabolism Sites:
glycolysis
Cytoplasm
Metabolism Sites:
HMP shunt
Cytoplasm
Metabolism Sites:
synthesis of steroids (SER)
Cytoplasm
Metabolism Sites:
synthesis of proteins (ribosomes, RER)
Cytoplasm
Metabolism Sites:
synthesis of fatty acids
Cytoplasm
Metabolism Sites:
synthesis of cholesterol
Cytoplasm
Metabolism Sites:
synthesis of nucleotides
Cytoplasm
_____ are processes which occur in both the mitochondria and the cytoplasm.
HUGs take two (ie, both).
- Heme Synthesis
- Urea Cycle
- Gluconeogenesis.
Enzymes:
catalyzes transfer of a phosphate group from a high energy molecule (usually ATP) to a substrate (eg. phosphofructo_____)
Kinase
Enzymes:
adds inorganic phosphate onto substrate without using ATP (eg. glycogen _____)
Phosphorylase
Enzymes:
removes phosphate group from substrate (eg. fructose-1,6-bis_____)
Phosphatase
Enzymes:
catalyzes oxidation-reduction reactions (eg. pyruvate _____)
Dehydrogenase
Enzymes:
adds hydroxyl group (−OH) onto substrate (eg. tyrosine _____)
Hydroxylase
Enzymes:
transfers CO2 groups with the help of biotin (eg. pyruvate _____)
Carboxylase
Enzymes:
relocates a functional group within a molecule (eg. vitamin B12-dependent methylmalonyl-CoA _____)
Mutase
Enzymes:
joins two molecules together using a source of energy (eg. ATP, acetyl CoA, nucleotide sugar)
Synthase/Synthetase
Glycolysis:
Rate-Determining Enzyme
Phosphofructokinase-1 (PFK-1)
Glycolysis:
Regulators
- AMP ⊕, fructose-2,6-bisphosphate ⊕
- ATP ⊝, citrate ⊝
Gluconeogenesis:
Rate-Determining Enzyme
Fructose-1,6-bisphosphatase
Gluconeogenesis:
Regulators
- Citrate ⊕
- AMP ⊝, fructose-2,6-bisphosphate ⊝
TCA Cycle:
Rate-Determining Enzyme
Isocitrate Dehydrogenase
TCA Cycle:
Regulators
- ADP ⊕
- ATP ⊝, NADH ⊝
Glycogenesis:
Rate-Determining Enzyme
Glycogen Synthase
Glycogenesis:
Regulators
- Glucose-6-phosphate ⊕, insulin ⊕, cortisol ⊕
- Epinephrine ⊝, glucagon ⊝
Glycogenolysis:
Rate-Determining Enzyme
Glycogen Phosphorylase
Glycogenolysis:
Regulators
- Epinephrine ⊕, glucagon ⊕, AMP ⊕
- Glucose-6-phosphate ⊝, insulin ⊝, ATP ⊝
HMP Shunt:
Rate-Determining Enzyme
Glucose-6-Phosphate Dehydrogenase (G6PD)
HMP Shunt:
Regulators
- NADP+ ⊕
- NADPH ⊝
De novo Pyrimidine Synthesis:
Rate-Determining Enzyme
Carbamoyl Phosphate Synthetase II
De novo Pyrimidine Synthesis:
Regulators
- ATP ⊕, PRPP ⊕
- UTP ⊝
De novo Purine Synthesis:
Rate-Determining Enzyme
Glutamine-phosphoribosylpyrophosphate (PRPP) Amidotransferase
De novo Purine Synthesis:
Regulators
AMP ⊝, inosine monophosphate (IMP) ⊝, GMP ⊝
Urea Cycle:
Rate-Determining Enzyme
Carbamoyl Phosphate Synthetase I
Urea Cycle:
Regulators
N-acetylglutamate ⊕
Fatty Acid Synthesis:
Rate-Determining Enzyme
Acetyl-CoA carboxylase (ACC)
Fatty Acid Synthesis:
Regulators
- Insulin ⊕, citrate ⊕
- Glucagon ⊝, palmitoyl-CoA ⊝
Fatty Acid Oxidation:
Rate-Determining Enzyme
Carnitine Acyltransferase I
Fatty Acid Oxidation:
Regulators
Malonyl-CoA ⊝
Ketogenesis:
Rate-Determining Enzyme
HMG-CoA Synthase
Cholesterol Synthesis:
Rate-Determining Enzyme
HMG-CoA Reductase
Cholesterol Synthesis:
Regulators
- Insulin ⊕, thyroxine ⊕
- Glucagon ⊝, cholesterol ⊝
Biochemical Pathways
Aerobic metabolism of one glucose molecule produces _____ via malate-aspartate shuttle (heart and liver).
32 net ATP
Aerobic metabolism of one glucose molecule produces _____ via glycerol-3-phosphate shuttle (muscle).
30 net ATP
Anaerobic glycolysis produces _____ per glucose molecule.
2 net ATP
_____ can be coupled to energetically unfavorable reactions.
ATP hydrolysis
Arsenic causes glycolysis to produce _____.
zero net ATP
Activated Carriers:
Phosphoryl groups
ATP
Activated Carriers:
Electrons
NADH
NADPH
FADH2
Activated Carriers:
Acyl groups
CoA
lipoamide
Activated Carriers:
CO2
Biotin
Activated Carriers:
1-carbon units
Tetrahydrofolates
Activated Carriers:
CH3 groups
S-adenosylmethionine (SAM)
Activated Carriers:
Aldehydes
TPP
Universal Electron Acceptors
- NAD+
- NADP+
- FAD+
Nicotinamides from Vitamin B3
- NAD+
- NADP+
Flavin Nucleotides from Vitamin B2
FAD+
NAD+ is generally used in _____ processes to carry reducing equivalents away as NADH.
catabolic
NADPH is used in _____ processes (eg, steroid and fatty acid synthesis) as a supply of reducing equivalents.
anabolic
NADPH is a product of the _____.
HMP shunt
NADPH is used in _____.
- Anabolic processes
- Respiratory burst
- Cytochrome P-450 system
- Glutathione reductase
Phosphorylation of glucose to yield glucose-6-phosphate is catalyzed by _____ in the liver and _____ in other tissues.
Glucokinase - liver
Hexokinase - other tissues
_____ sequesters glucose in tissues, where it is used even when glucose concentrations are low.
Hexokinase
At high glucose concentrations, _____ helps to store glucose in liver.
Glucokinase
Glucose Phosphorylation:
- found in most tissues except liver and pancreatic β cells
- Km - Lower (↑ affinity)
- Vmax - Lower (↓ capacity)
- not induced by insulin
- feedback is inhibited by glucose-6-phosphate
Hexokinase
Glucose Phosphorylation:
- found in the liver and β cells of pancreas
- Km - Higher (↓ affinity)
- Vmax - Higher (↑ capacity)
- induced by insulin
- feedback is inhibited by glucose-6-phosphate
Glucokinase
Net Glycolysis (cytoplasm)
Glucose + 2 Pi + 2 ADP + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O
Glycolysis Regulation:
Require ATP
Glycolysis Regulation:
Produce ATP
Regulation by Fructose-2,6-Bisphosphate
_____ is a mitochondrial enzyme complex linking glycolysis and TCA cycle. Differentially regulated in fed/fasting states (active in fed state).
Pyruvate Dehydrogenase Complex
Pyruvate Dehydrogenase Complex Reaction
pyruvate + NAD+ + CoA → acetyl-CoA + CO2 + NADH
The Pyruvate Dehydrogenase Complex contains 3 enzymes that require 5 cofactors:
The Lovely Co-enzymes For Nerds
- Thiamine pyrophosphate (B1)
- Lipoic acid
- CoA (B5, pantothenic acid)
- FAD (B2, riboflavin)
- NAD+ (B3, niacin)
The Pyruvate Dehydrogenase Complex is activated by:
- ↑ NAD+/NADH ratio
- ↑ ADP
- ↑ Ca2+
_____ inhibits lipoic acid. _____ poisoning clinical findings: imagine a vampire (pigmentary skin changes, skin cancer), vomiting and having diarrhea, running away from a cutie (QT prolongation) with garlic breath.
Arsenic
_____ is an X-linked disease that causes a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT).
Pyruvate Dehydrogenase Complex Deficiency
_____ causes neurologic defects, lactic acidosis, ↑ serum alanine starting in infancy.
Pyruvate Dehydrogenase Complex Deficiency
Pyruvate Dehydrogenase Complex Deficiency is treated with _____.
↑ intake of ketogenic nutrients (eg, high fat content or ↑ lysine and leucine).
Pyruvate Metabolism
- Alanine aminotransferase (B6): alanine carries amino groups to the liver from muscle
- Pyruvate carboxylase (biotin): oxaloacetate can replenish TCA cycle or be used in gluconeogenesis
- Pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid): transition from glycolysis to the TCA cycle
- Lactic acid dehydrogenase (B3): end of anaerobic glycolysis (major pathway in RBCs, WBCs, kidney medulla, lens, testes, and cornea)
TCA Cycle (Krebs Cycle)
Pyruvate → acetyl-CoA produces 1 NADH, 1 CO2
Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate.
The TCA cycle produces _____.
3 NADH, 1 FADH2, 2 CO2, 1 GTP per acetyl-CoA = 10 ATP/acetyl-CoA (2× everything per glucose)
TCA Cycle reactions occur in the _____.
mitochondria
α-ketoglutarate dehydrogenase complex requires the same cofactors as the pyruvate dehydrogenase complex:
B1, B2, B3, B5, lipoic acid
Electron Transport Chain
NADH electrons from glycolysis enter mitochondria via the _____.
- malate-aspartate shuttle
- glycerol-3- phosphate shuttle
FADH2 electrons are transferred to _____ (at a lower energy level than NADH)
Complex II
The passage of electrons results in the formation of a proton gradient that, coupled to _____, drives the production of ATP.
Oxidative Phosphorylation
ATP produced via ATP Sythase
1 NADH → 2.5 ATP
1 FADH2 → 1.5 ATP
_____ directly inhibit electron transport, causing a ↓ proton gradient and block of ATP synthesis.
Electron Transport Inhibitors
Electron Transport Inhibitors:
Complex I
Rotenone
Rotenone: complex one inhibitor
Electron Transport Inhibitors:
Complex III
Antimycin A
“An-3-mycin” A: complex 3 inhibitor.
Electron Transport Inhibitors:
Complex IV
- Cyanide
- Carbon monoxide
- Azide
The -ides (4 letters) inhibit complex IV.
_____ directly inhibit mitochondrial ATP synthase, causing an ↑ proton gradient. No ATP is produced because electron transport stops.
ATP Synthase Inhibitors
Oligomycin is an _____ inhibitor.
ATP Synthase
_____ ↑ permeability of membrane, causing a ↓ proton gradient and ↑ O2 consumption. ATP synthesis stops, but electron transport continues. Produces heat.
Uncoupling Agents
Uncoupling Agents
- 2,4-Dinitrophenol (used illicitly for weight loss)
- Aspirin (fevers often occur after aspirin overdose)
- Thermogenin in brown fat (has more mitochondria than white fat)
Gluconeogenesis:
Irreversible Enzymes
Pathway Produces Fresh Glucose
- Pyruvate Carboxylase
- Phosphoenolpyruvate Carboxykinase
- Fructose-1,6-bisphosphatase
- Glucose-6-phosphatase
Gluconeogenesis:
- in mitochondria
- pyruvate → oxaloacetate
- requires biotin and ATP
- activated by acetyl-CoA
Pyruvate Carboxylase
Gluconeogenesis:
- in cytosol
- oxaloacetate → phosphoenolpyruvate
- requires GTP
Phosphoenolpyruvate Carboxykinase
Gluconeogenesis:
- in cytosol
- fructose-1,6-bisphosphate → fructose-6-phosphate
- citrate ⊕, AMP ⊝, fructose 2,6-bisphosphate ⊝
Fructose-1,6-bisphosphatase
Gluconeogenesis:
- iIn ER
- glucose-6-phosphate → glucose
Glucose-6-phosphatase
_____ occurs primarily in liver (also in the kidney and intestinal epithelium); serves to maintain euglycemia during fasting.
Gluconeogenesis
Muscle cannot participate in gluconeogenesis because it lacks _____.
Glucose-6-phosphatase
Odd-chain fatty acids yield _____ during metabolism, which can enter the TCA cycle (as succinyl-CoA), undergo gluconeogenesis, and serve as a glucose source.
1 propionyl-CoA
Even-chain fatty acids cannot produce new glucose, since they yield only _____ equivalents.
acetyl-CoA
_____ provides a source of NADPH from abundantly available glucose-6-P (NADPH is required for reductive reactions, eg, glutathione reduction inside RBCs, fatty acid and cholesterol biosynthesis).
HMP Shunt
(Pentose Phosphate Pathway)
_____ yields ribose for nucleotide synthesis and has two distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm. No ATP is used or produced.
HMP Shunt
(Pentose Phosphate Pathway)
The HMP Shunt is found in _____.
- lactating mammary glands
- liver
- adrenal cortex
- RBCs
*sites of fatty acid or steroid synthesis
HMP Shunt
(Pentose Phosphate Pathway)
_____ is necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides.
NADPH
In _____, ↓ NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (eg, fava beans, sulfonamides, nitrofurantoin, primaquine/chloroquine, antituberculosis drugs). Infection (most common cause) can also precipitate hemolysis; inflammatory response produces free radicals that diffuse into RBCs, causing oxidative damage.
Glucose-6-Phosphate Dehydrogenase Deficiency
_____ is an X-linked recessive disorder; most common human enzyme deficiency; more prevalent among African Americans. ↑ malarial resistance.
Glucose-6-Phosphate Dehydrogenase Deficiency
Glucose-6-Phosphate Dehydrogenase
_____ are denatured globin chains that precipitate within RBCs due to oxidative stress.
Heinz Bodies
_____ result from the phagocytic removal of Heinz bodies by splenic macrophages.
Bite Cells
Bite into some Heinz ketchup.
_____ is an autosomal recessive disease which involves a defect in fructokinase. It’s a benign, asymptomatic condition, since fructose is not trapped in cells. Hexokinase becomes 1° pathway for converting fructose to fructose-6-phosphate.
Essential Fructosuria
_____ presents with fructose in the blood and urine. Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose metabolism.
Essential Fructosuria
_____ is an autosomal recessive disease which causes a hereditary deficiency of aldolase B. Fructose-1-phosphate accumulates, causing a ↓ in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis. Hypoglycemia, jaundice, cirrhosis and vomiting present following consumption of fruit, juice, or honey. Urine dipstick will be ⊝ (tests for glucose only); reducing sugar can be detected in the urine (nonspecific test for inborn errors of carbohydrate metabolism).
Hereditary Fructose Intolerance
Fructose is to Aldolase B as Galactose is to UridylTransferase (FAB GUT).
Hereditary Fructose Intolerance is treated with _____.
↓ intake of both fructose and sucrose (glucose + fructose)
Fructose Metabolism
_____ is an autosomal recessive condition where galactitol accumulates if galactose is present in diet. It is a relatively mild condition where galactose appears in blood (galactosemia) and urine (galactosuria). May present as infantile cataracts. failure to track objects or to develop a social smile.
Galactokinase Deficiency
_____ is an autosomal recessive disease which causes the absence of galactose-1-phosphate uridyltransferase. Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye). Symptoms develop when infant begins feeding (lactose present in breast milk and routine formula) and include failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability.
Classic Galactosemia
Fructose is to Aldolase B as Galactose is to UridylTransferase (FAB GUT).
Classic Galactosemia can predispose neonates to _____ sepsis.
E. coli
Classic Galactosemia is treated with _____.
exclusion galactose and lactose (galactose + glucose) from diet
Galactose Metabolism
The more serious cases of galactosemia lead to _____.
PO43− depletion
An alternative method of trapping glucose in the cell is to convert it to its alcohol counterpart, _____, via aldose reductase.
Sorbitol
Some tissues then convert sorbitol to fructose using _____; tissues with an insufficient amount/activity of this enzyme are at risk of intracellular sorbitol accumulation, causing osmotic damage (eg, cataracts, retinopathy, and peripheral neuropathy seen with chronic hyperglycemia in diabetes).
Sorbitol Dehydrogenase
High blood levels of galactose also result in conversion to the osmotically active galactitol via _____.
Aldose Reductase
_____ have both aldose reductase and sorbitol dehydrogenase.
They LOSe sorbitol.
- Liver
- Ovaries
- Seminal vesicles
_____ has primarily aldose reductase while _____, _____, _____ have only aldose reductase.
LuRKS
- Lens
- Retina
- Kidneys
- Schwann cells
Sorbitol Metabolism
_____functions on the intestinal brush border to digest lactose (in milk and milk products) into glucose and galactose.
Lactase
Lactase Deficiency:
- age-dependent decline after childhood (absence of lactase-persistent allele)
- common in people of Asian, African, or Native American descent
Primary Lactase deficiency
Lactase Deficiency:
loss of intestinal brush border due to gastroenteritis (eg, rotavirus), autoimmune disease, etc.
Secondary Lactase Deficiency
_____ presents with bloating, cramps, flatulence, and osmotic diarrhea. Stool demonstrates ↓ pH and breath shows ↑ hydrogen content with lactose hydrogen breath test. Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.
Lactase Deficiency
Lactase Deficiency is treated with _____.
- avoidance of dairy products
- lactase pills
- lactose-free milk
Only _____ are found in proteins.
L-amino acids
Essential Amino Acids
PVT TIM HaLL
- Phenylalanine
- Valine
- Tyrosine
- Threonine
- Isoleucine
- Methionine
- Histidine
- Leucine
- Lysine
Glucogenic Amino Acids
I met his valentine, she is so sweet (glucogenic).
- Methionine
- Histidine
- Valine
Glucogenic/Ketogenic Amino Acids
- Isoleucine
- Phenylalanine
- Threonine
- Tyrosine
Ketogenic Amino Acids
The onLy pureLy ketogenic amino acids.
- Leucine
- Lysine
Acidic amino acids (aspartic acid, glutamic acid) are _____ charged at body pH.
negatively charged
Basic Amino Acids
His lys (lies) are basic.
- Histidine
- Lysine
- Arginine
_____ is the most basic amino acid.
Arginine
Histidine has _____ at body pH.
no charge
_____ are amino acids required during periods of growth.
- Arginine
- Histidine
_____ are ↑ in histones which bind negatively charged DNA.
- Arginine
- Lysine
_____ results in the formation of common metabolites (eg, pyruvate, acetyl-CoA), which serve as metabolic fuels. Excess nitrogen generated by this process is converted to urea and excreted by the kidneys.
Amino Acid Catabolism
Urea Cycle
Ordinarily, Careless Crappers Are Also Frivolous About Urination.
Transport of Ammonia by Alanine
_____ can be acquired (eg, liver disease) or hereditary (eg, urea cycle enzyme deficiencies). Excess NH3 depletes glutamate (GABA) in the CNS and α-ketoglutarate → inhibition of TCA cycle. It is treated with protein limitation in the diet.
Hyperammonemia
_____ may be given to ↓ ammonia levels.
- Lactulose to acidify the GI tract and trap NH4+ for excretion.
- Antibiotics (eg, rifaximin, neomycin) to ↓ colonic ammoniagenic bacteria.
- Benzoate, phenylacetate, or phenylbutyrate react with glycine or glutamine, forming products that are renally excreted.
_____ accumulation causes flapping tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision.
Ammonia
_____ is the most common urea cycle disorder. X-linked recessive (vs other urea cycle enzyme deficiencies, which are autosomal recessive). Interferes with the body’s ability to eliminate ammonia. Often evident in the first few days of life, but may present later. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway).
Ornithine Transcarbamylase Deficiency
_____ presents with ↑ orotic acid in blood and urine, ↓ BUN, symptoms of hyperammonemia. No megaloblastic anemia (vs orotic aciduria).
Ornithine Transcarbamylase Deficiency
Amino Acid Derivatives
Catecholamine Synthesis/Tyrosine Catabolism
_____ is due to ↓ phenylalanine hydroxylase or ↓ tetrahydrobiopterin (BH4) cofactor (malignant PKU). Tyrosine becomes essential. ↑ phenylalanine → excess phenyl ketones in urine.
Phenylketonuria
_____ is an autosomal recessive disease which causes intellectual disability, growth retardation, seizures, fair complexion, eczema, musty body odor.
Phenylketonuria
Phenylketonuria is treated with _____.
- ↓ phenylalanine and ↑ tyrosine in diet
- tetrahydrobiopterin supplementation
The incidence of phenylketonuria is _____.
1:10,000
_____ - lack of proper dietary therapy during pregnancy. Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects.
Maternal PKU
Phenylketonuria screening occurs _____ after birth (normal at birth because of maternal enzyme during fetal life).
2–3 days
Phenyl Ketones
- Phenylacetate
- Phenyllactate
- Phenylpyruvate
Phenylketonuria presents with musty body odor due to _____.
disorder of aromatic amino acid metabolism
PKU patients must avoid the artificial sweetener _____, which contains phenylalanine.
Aspartame
_____ is an autosomal recessive disease where there is blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to ↓ branched-chain α-ketoacid dehydrogenase (B1). Causes ↑ α-ketoacids in the blood, especially those of leucine. Causes severe CNS defects, intellectual disability, and death.
Maple Syrup Urine Disease
I Love Vermont maple syrup from maple trees (with B1ranches).
_____ presents with vomiting, poor feeding and urine that smells like maple syrup/burnt sugar.
Maple Syrup Urine Disease
Maple Syrup Urine Disease is treated with _____.
- restriction of isoleucine, leucine, valine in diet
- thiamine supplementation.
_____ is an autosomal recessive congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate → pigment-forming homogentisic acid accumulates in tissue. Usually benign.
Alkaptonuria
_____ presents with bluish-black connective tissue, ear cartilage, and sclerae (ochronosis); urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentisic acid toxic to cartilage).
Alkaptonuria
Homocystinuria Types
- Cystathionine synthase deficiency (treatment: ↓ methionine, ↑ cysteine, ↑ B6, B12, and folate in diet)
- ↓ affinity of cystathionine synthase for pyridoxal phosphate (treatment: ↑↑ B6 and ↑ cysteine in diet)
- Methionine synthase (homocysteine methyltransferase) deficiency (treatment: ↑ methionine in diet)
*all autosomal recessive
Homocystinuria Findings
HOMOCYstinuria:
- ↑↑ Homocysteine in urine
- Osteoporosis
- Marfanoid habitus,
- Ocular changes (downward and inward lens subluxation)
- Cardiovascular effects (thrombosis and atherosclerosis → stroke and MI)
- kYphosis
- intellectual disability
Homocysteine Metabolism
_____ is an autosomal recessive hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cystine, Ornithine, Lysine, and Arginine Excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones.
Cystinuria
COLA
- Cystine
- Ornithine
- Lysine
- Arginine
The incidence of Cystinuria is _____.
1:7000
_____ is diagnostic for Cystinuria.
Urinary Cyanide-Nitroprusside Test
Cystinuria is treated with _____.
- urinary alkalinization (eg, potassium citrate, acetazolamide) and chelating agents (eg, penicillamine) ↑ solubility of cystine stones
- good hydration
Cystine is made of 2 cysteines connected by a _____.
disulfide bond
Glycogen Regulation by Insulin and Glucagon/Epinephrine
Glycogen branches have _____.
α-(1,6) bonds
Glycogen linkages have _____.
α-(1,4) bonds
Glycogen Metabolism in Skeletal Muscle
Glycogen undergoes glycogenolysis → glucose-1-phosphate → glucose-6-phosphate, which is rapidly metabolized during exercise.
Glycogen Metabolism in Hepatocytes
- Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.
- Glycogen phosphorylase ④ liberates glucose-1-phosphate residues off branched glycogen until 4 glucose units remain on a branch.
- Then 4-α-d glucanotransferase (debranching enzyme ⑤) moves 3 of the 4 glucose units from the branch to the linkage.
- Then α-1,6-glucosidase (debranching enzyme ⑥) cleaves off the last residue, liberating glucose.
- “Limit dextrin” refers to the one to four residues remaining on a branch after glycogen phosphorylase has already shortened it.
At least 15 types of _____ have been identified, all resulting in abnormal glycogen metabolism and an accumulation of glycogen within cells.
Glycogen Storage Diseases
_____ identifies glycogen and is useful in identifying glycogen storage diseases.
Periodic Acid–Schiff Stain
Glycogen Storage Diseases
Very Poor Carbohydrate Metabolism
- Von Gierke disease (type I)
- Pompe disease (type II)
- Cori disease (type III)
- McArdle disease (type V)
*autosomal recessive.
Glycogen Storage Diseases:
- severe fasting hypoglycemia
- ↑↑ glycogen in liver and kidneys
- ↑ blood lactate
- ↑ triglycerides
- ↑ uric acid (gout)
- hepatomegaly
- renomegaly
- liver does not regulate blood glucose
Von Gierke disease (type I)
Von Gierke = Glycogen, Gout
Glycogen Storage Diseases:
deficient in Von Gierke disease (type I)
Glucose-6-phosphatase
Von Gierke = Glucose-6-phosphatase
Glycogen Storage Diseases:
- oral glucose/cornstarch should be given frequently
- fructose and galactose should be avoided
Von Gierke disease (type I)
Glycogen Storage Diseases:
impaired gluconeogenesis and glycogenolysis
Von Gierke disease (type I)
Glycogen Storage Diseases:
- cardiomegaly
- hypertrophic
- cardiomyopathy
- hypotonia
- exercise intolerance
- systemic findings lead to early death
Pompe disease (type II)
Pompe trashes the Pump
(heart, liver, and muscle)
Glycogen Storage Diseases:
deficient in Pompe disease (type II)
Lysosomal acid α-1,4-glucosidase with α-1,6-glucosidase activity (acid maltase)
PomPe trashes the PumP (1,4)
Glycogen Storage Diseases:
- milder form of von Gierke (type I) with normal blood lactate levels
- accumulation of limit dextrin–like structures in cytosol
Cori disease (type III)
Glycogen Storage Diseases:
deficient in Cori disease (type III)
Debranching enzyme (α-1,6-glucosidase)
Glycogen Storage Diseases:
gluconeogenesis is intact
Cori disease (type III)
Glycogen Storage Diseases:
- ↑ glycogen in muscle, but muscle cannot break it down → painful muscle cramps
- myoglobinuria (red urine) with strenuous exercise
- arrhythmia from electrolyte abnormalities
- second-wind phenomenon noted during exercise due to ↑ muscular blood flow
McArdle disease (type V)
McArdle = Muscle, Myoglobinuria
Glycogen Storage Diseases:
- deficient in McArdle disease (type V)
- hallmark is a flat venous lactate curve with normal rise in ammonia levels during exercise
Skeletal muscle glycogen phosphorylase (Myophosphorylase)
McArdle = Myophosphorylase
Glycogen Storage Diseases:
blood glucose levels typically unaffected
McArdle disease (type V)
Lysosomal Storage Diseases
Sphingolipidoses
- Tay-Sachs disease
- Fabry disease
- Metachromatic Leukodystrophy
- Krabbe disease
- Niemann-Pick disease
Mucopolysaccharidoses
- Hurler syndrome
- Hunter syndrome
Sphingolipidoses:
- autosomal recessive
- progressive neurodegeneration,
- developmental delay
- “cherry-red” spot on macula
- lysosomes with onion skin
- no hepatosplenomegaly (vs Niemann-Pick)
Tay-Sachs disease
Sphingolipidoses:
deficient in Tay-Sachs disease
Hexosaminidase A ①
TAy-SaX = HeXosaminidase A
Sphingolipidoses:
accumulates in Tay-Sachs disease
GM2 ganglioside
Sphingolipidoses:
- X-linked recessive
- Early: triad of episodic peripheral neuropathy, angiokeratomas, hypohidrosis
- Late: progressive renal failure, cardiovascular disease
Fabry disease
Sphingolipidoses:
deficient in Fabry disease
α-galactosidase A ②
Sphingolipidoses:
accumulates in Fabry disease
Ceramide Trihexoside
Sphingolipidoses:
- autosomal recessive
- central and peripheral demyelination with ataxia
- dementia
Metachromatic Leukodystrophy
Sphingolipidoses:
deficient in Metachromatic Leukodystrophy
Arylsulfatase A ③
Sphingolipidoses:
accumulates in Metachromatic Leukodystrophy
Cerebroside Sulfate
Sphingolipidoses:
- autosomal recessive
- peripheral neuropathy
- destruction of oligodendrocytes
- developmental delay
- optic atrophy
- globoid cells
Krabbe disease
Sphingolipidoses:
deficient in Krabbe disease
Galactocerebrosidase ④
Sphingolipidoses:
accumulates in Krabbe disease
- Galactocerebroside
- Psychosine
Sphingolipidoses:
- autosomal recessive
- most common
- hepatosplenomegaly
- pancytopenia
- osteoporosis
- avascular necrosis of femur
- bone crises
- Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)
Gaucher disease
Sphingolipidoses:
deficient in Gaucher disease
Glucocerebrosidase (β-glucosidase) ⑤
Sphingolipidoses:
accumulates in Gaucher disease
Glucocerebroside
Sphingolipidoses:
- autosomal recessive
- progressive neurodegeneration
- hepatosplenomegaly
- foam cells (lipid-laden macrophages)
- “cherry-red” spot on macula
Niemann-Pick disease
Sphingolipidoses:
deficient in Niemann-Pick disease
Sphingomyelinase ⑥
No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelinase).
Sphingolipidoses:
accumulates in Niemann-Pick disease
Sphingomyelin
No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelin).
Ther is ↑ incidence of Tay-Sachs, Niemann-Pick, and some forms of Gaucher disease in _____.
Ashkenazi Jews
Mucopolysaccharidoses:
- autosomal recessive
- developmental delay
- gargoylism
- airway obstruction
- corneal clouding
- hepatosplenomegaly
Hurler syndrome
Mucopolysaccharidoses:
deficient in Hurler syndrome
α-L-iduronidase
Mucopolysaccharidoses:
accumulates in Hurler syndrome
- Heparan sulfate
- Dermatan sulfate
Mucopolysaccharidoses:
- X-linked recessive
- mild Hurler + aggressive behavior
- no corneal clouding
Hunter syndrome
Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive).
Mucopolysaccharidoses:
deficient in Hunter syndrome
Iduronate-2-sulfatase
Mucopolysaccharidoses:
accumulates in Hunter syndrome
- Heparan sulfate
- Dermatan sulfate
Fatty Acid Metabolism
Fatty acid synthesis requires transport of _____ from mitochondria to cytosol.
Citrate
“SYtrate” = SYnthesis
Fatty acid metabolism predominantly occurs in _____.
- liver
- lactating mammary glands
- adipose tissue
Long-chain fatty acid (LCFA) degradation requires _____-dependent transport into the mitochondrial matrix.
Carnitine
CARnitine = CARnage of fatty acids
_____ is an inherited defect in transport of LCFAs into the mitochondria → toxic accumulation. Causes weakness, hypotonia, and hypoketotic hypoglycemia.
Systemic 1° Carnitine Deficiency
_____ causes ↓ ability to break down fatty acids into acetyl-CoA → accumulation of fatty acyl carnitines in the blood with hypoketotic hypoglycemia. Causes vomiting, lethargy, seizures, coma, liver dysfunction, hyperammonemia. Can lead to sudden death in infants or children. Treat by avoiding fasting.
Medium-Chain Acyl-CoA Dehydrogenase Deficiency
Ketone Body Metabolism
Ketone Bodies
- Acetone
- Acetoacetate
- β-hydroxybutyrate
In the liver, fatty acids and amino acids are metabolized to _____ to be used in muscle and brain.
- Acetoacetate
- β-hydroxybutyrate
In prolonged starvation and diabetic ketoacidosis, _____ is depleted for gluconeogenesis.
Oxaloacetate
In alcoholism, excess NADH shunts oxaloacetate to _____.
Malate
In prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. In alcoholism, excess NADH shunts oxaloacetate to malate. Both processes cause a buildup of _____, which shunts glucose, amino acids, and FFAs toward the production of ketone bodies.
Acetyl-CoA
Ketone bodies make the breath smell like _____.
Acetone (fruity odor)
Urine test for ketones can detect _____, but not β-hydroxybutyrate.
Acetoacetate
RBCs cannot utilize ketones; they strictly use _____.
glucose
HMG-CoA lyase is used for _____.
ketone production
HMG-CoA reductase is used for _____.
cholesterol synthesis
Metabolic Fuel Use
1g carb/protein (eg, whey) = 4 kcal
1g alcohol = 7 kcal
1g fatty acid = 9 kcal
*# letters = # kcal
During fasting and starvation, priorities are to _____.
- supply sufficient glucose to the brain and RBCs
- preserve protein
Glycolysis and aerobic respiration occur during the _____.
Fed State (after a meal)
During the fed state (after a meal), _____ stimulates storage of lipids, proteins, and glycogen.
Insulin
Hepatic glycogenolysis (major), hepatic gluconeogenesis and adipose release of FFA (minor) occur during _____.
Fasting (between meals)
During fasting (between meals), _____ stimulate use of fuel reserves.
- Glucagon
- Epinephrine
During starvation (days 1–3), blood glucose levels aremaintained by:
- Hepatic glycogenolysis
- Adipose release of FFA
- Muscle and liver, which shift fuel use from glucose to FFA
- Hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl-CoA (from odd-chain FFA—the only triacylglycerol components that contribute to gluconeogenesis)
During starvation (after day 3), _____ are used and _____ become the main source of energy for the brain. After these are depleted, vital protein degradation accelerates, leading to organ failure and death. Amount of excess stores determines survival time.
adipose stores
ketone bodies
Glycogen reserves are depleted after _____ of starvation.
day 1
RBCs lack _____ and therefore cannot use ketones.
mitochondria
Energy Use in Starvation
Lipid Transport
_____ mediates transfer of cholesterol esters to other lipoprotein particles.
Cholesterol Ester Transfer Protein
Lipid Transport
Key Enzymes in Lipid Transport
- Hepatic Lipase
- Hormone-Sensitive Lipase
- Lecithin-Cholesterol Acyltransferase
- Lipoprotein Lipase
- Pancreatic Lipase
Key Enzymes in Lipid Transport:
degrades TGs remaining in IDL
Hepatic Lipase
Key Enzymes in Lipid Transport:
degrades TGs stored in adipocytes
Hormone-Sensitive Lipase
Key Enzymes in Lipid Transport:
catalyzes esterification of 2⁄3 of plasma cholesterol
Lecithin-Cholesterol Acyltransferase
Key Enzymes in Lipid Transport:
- degrades TGs circulating chylomicrons and VLDLs
- found on vascular endothelial surface
Lipoprotein Lipase
Key Enzymes in Lipid Transport:
degrades dietary TGs in small intestine
Pancreatic Lipase
Major Apolipoproteins
Apolipoproteins:
mediates remnant uptake
E
Everything Except LDL
Apolipoproteins:
activates LCAT
A-I
Activate
Apolipoproteins:
lipoprotein lipase cofactor that catalyzes cleavage
C-II
Cofactor that Catalyzes Cleavage
Apolipoproteins:
- mediates chylomicron secretion into lymphatics
- only on particles originating from the intestines
B-48
Apolipoproteins:
- binds LDL receptor
- only on particles originating from the liver
B-100
Lipoproteins are composed of varying proportions of _____.
- cholesterol
- TGs
- phospholipids
_____ carry the most cholesterol.
LDL, HDL
_____ transports cholesterol from liver to tissues.
LDL
_____ transports cholesterol from periphery to liver.
HDL
_____ is needed to maintain cell membrane integrity and synthesize bile acid, steroids, and vitamin D.
Cholesterol
_____ deliver dietary TGs to peripheral tissues. The also deliver cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their TGs. They are secreted by intestinal epithelial cells.
Chylomicrons
_____ delivers hepatic TGs to peripheral tissue. It is secreted by liver.
VLDL
_____ is formed in the degradation of VLDL. It delivers TGs and cholesterol to liver.
IDL
_____ delivers hepatic cholesterol to peripheral tissues. It is formed by hepatic lipase modification of IDL in the liver and peripheral tissue. It is taken up by target cells via receptor-mediated endocytosis.
LDL
_____ mediates reverse cholesterol transport from periphery to liver. It acts as a repository for apolipoproteins C and E (which are needed for chylomicron and VLDL metabolism). It is secreted from both liver and intestine. Alcohol ↑ synthesis.
HDL
_____ is an autosomal recessive disease where chylomicrons, VLDL, and LDL are absent. There is a deficiency in ApoB-48, ApoB-100. Affected infants present with severe fat malabsorption, steatorrhea, and failure to thrive. Later manifestations include retinitis pigmentosa, spinocerebellar degeneration due to vitamin E deficiency, progressive ataxia, and acanthocytosis.
Abetalipoproteinemia
Abetalipoproteinemia is treated with _____.
- restriction of long-chain fatty acids
- large doses of oral vitamin E
Familial Dyslipidemias
- I—Hyperchylomicronemia
- II—Familial hypercholesterolemia
- III—Dysbetalipoproteinemia
- IV—Hypertriglyceridemia
Familial Dyslipidemias:
- autosomal recessive
- lipoprotein lipase or apolipoprotein C-II deficiency
I—Hyperchylomicronemia
Familial Dyslipidemias:
↑ chylomicrons, TG, and cholesterol
I—Hyperchylomicronemia
Familial Dyslipidemias:
- pancreatitis
- hepatosplenomegaly
- eruptive/pruritic xanthomas
- no ↑ risk for atherosclerosis
- creamy layer in supernatant
I—Hyperchylomicronemia
Familial Dyslipidemias:
- autosomal dominant
- absent or defective LDL receptors
- defective ApoB-100
II—Familial hypercholesterolemia
Familial Dyslipidemias:
↑ LDL, cholesterol, and VLDL
II—Familial hypercholesterolemia
IIa: LDL, cholesterol
IIb: LDL, cholesterol, VLDL
Familial Dyslipidemias:
- heterozygotes (1:500) have cholesterol ≈ 300mg/dL
- homozygotes (very rare) have cholesterol ≈ 700+ mg/dL.
- accelerated atherosclerosis (may
have MI before age 20) - tendon (Achilles) xanthomas
- corneal arcus
II—Familial hypercholesterolemia
Familial Dyslipidemias:
- autosomal recessive
- defective ApoE
III—Dysbetalipoproteinemia
Familial Dyslipidemias:
↑ chylomicrons and VLDL
III—Dysbetalipoproteinemia
Familial Dyslipidemias:
- premature atherosclerosis
- tuberoeruptive xanthomas
- palmar xanthomas
III—Dysbetalipoproteinemia
Familial Dyslipidemias:
- autosomal dominant
- hepatic overproduction of VLDL
IV—Hypertriglyceridemia
Familial Dyslipidemias:
↑ VLD and TG
IV—Hypertriglyceridemia
Familial Dyslipidemias:
- hypertriglyceridemia (> 1000 mg/dL) can cause acute pancreatitis
- related to insulin resistance
IV—Hypertriglyceridemia
