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USMLE First AID > Biochemistry: molecular-cellular-lab-genetics-nutrition-metabolism > Flashcards

Biochemistry: molecular-cellular-lab-genetics-nutrition-metabolism Flashcards

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USMLE® Step 1 flashcards
1
Q

Chromatin structure

A
  • DNA exits int he condensed, chromatin from in order to fit into nucleus
  • negatively charged DNA loops 2x around positively charged histone octamer to form nucleosome bead
  • histones are rich in the amino acids lysine & arginine
  • H1 ties nucleosome beads together in a string
  • in mitosis, DNA condenses to form chromosomes.
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2
Q

Heterochromatin

A
  • condensed, transcriptionally inactive, sterically inaccessible
  • HeteroChromatin=Highly Condensed
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3
Q

Euchromatin

A

Less condensed, transcriptionally active, sterically accessible.
-Eu=true, truly transcribed

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4
Q

DNA methylation

A

-template strand Cytosine & Adenine are methylated in DNA replication, which allows mismatch repair enzymes to distinguish between old & new strands in prokaryotes

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5
Q

Histone methylation

A

inactivates transcription of DNA

-Methylation makes DNA Mute (M-M)

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6
Q

Histone acetylation

A

Relaxes DNA coiling, allowing for transcription

-Acetylation makes DNA Active (A_A)

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7
Q

Nucleotides

A

-PURines (A, G)-2 rings= “PUR As Gold”
-PYrimidines (CTU)- 1 ring= CUT the PY (pie)
-Guanine has a ketone. Thymine has a methyl. THYmine has a meTHYl
-Deamination of cytosine makes uracil.
-Uracil found in RNA; thymine in DNA
G-C bond (3 H bonds) stronger than A-T bond (2 H bond).
-increase G-C content= increase melting temperature
-GAG- amino acids necessary for purine synthesis
-Glycine
-Aspartate
-Glutamine
-nucleoSide=base + ribose (Sugar)
-nucleoTides=base + ribose + phosphaTe;
linked by 3’-5’ phosphodiester bond

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8
Q

De novo pyrimidine & purine synthesis

A

Purines:
-start with sugar + phosphate (PRPP)
-add base
Pyrimidines:
-make temporary base (orotic acid)
-add sugar + phosphate (PRPP)
-modify base
-ribonucleotides are synthesized first & are converted to deoxyribonucleotides by ribonucleotide reductase
-carbamoyl phosphate is involved in 2 metabolic pathways:
1. de novo pyrimidine synthesis & urea cycle
2. ornithine transcarbamoylase deficiency (OTC, key enzyme
in urea cycle).
-leads to accumulation of carbamoyl phosphate, which
is converted to orotic acid.
-various antineoplastic & antibiotic drugs function by interfering
with purine synthesis:
1. hydroxyurea inhibits ribonucleotide reductase
2. 6-mercaptopurine (6-MP) blocks de novo purine synthesis
3. 5-fluorouracil (5-FU) inhibits thymidylate synthase
(decrease deoxythymidine monophosphate [dTMP]
4. methotrexate (MTX) inhibits dihydrofolate reductase
(decrease dTMP)
5. trimethoprim (TMP) inhibits bacterial dihydrofolate reductase
(decrease dTMP)

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9
Q
  • Orotic aciduria:
  • finding:
  • treatments:
A

Orotic aciduria:
-inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) because of defect in UMP synthase (a bifunctional enzyme). -Autosomal recessive.

Finding:
-increase orotic acid in urine,
-megaloblastic anemia (does not improve with administration of vit B12 or folic acid),
failure to thrive
-no hyperammonemia (vs. OTC deficiency= increase orotic acid with hyperammonemia)

Treatments:

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10
Q

Purine Salvage Deficiencies:

-Adenosine deaminase deficiency

A
  • excess ATP & dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase—> prevents DNA synthesis & thus decrease lymphocyte count.
  • one of major causes of SCID
  • autosomal recessive
  • Severe Combined Immunodeficiency Disease (SCID) happens to KIDS
  • 1 st disease to be treated by experimental human gene therapy
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11
Q

Purine Salvage Deficiencies:

-Lesch-Nyhan syndrome

A

-defective purine salvage owing to absence of HGPRT, which converts:
hypoxanthine–> IMP &
guanine—> GMP
-result in excess uric acid production & de novo purine synthesis
-x-linked recessive

Findings:

  • retardation
  • self-mutilation
  • aggression
  • hyperuricemia
  • gout
  • choreoathetosis
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12
Q

Genetic Code Features:

  1. unambiguous:
  2. degenerate/redundant:
  3. commaless, nonoverlapping
  4. universal
A
  1. unambiguous:
    each codon specifies only one amino acid
  2. degenerate/redundant:
    -most amino acids are coded by multiple codons
    -exceptions: methione & tryptophan encoded by only 1 codon (AUG & UGG)
  3. commaless, nonoverlapping
    -read from fixed starting point as a continuous sequence of bases
    -except some viruses
  4. universal
    -genetic code is conserved throughout evolution
    -except in humans–> mitochondria
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13
Q

Genetic Code Features:

  1. unambiguous:
  2. degenerate/redundant:
  3. commaless, nonoverlapping
  4. universal
A
  1. unambiguous:
    each codon specifies only one amino acid
  2. degenerate/redundant:
    -most amino acids are coded by multiple codons
    -exceptions: methione & tryptophan encoded by only 1 codon (AUG & UGG)
  3. commaless, nonoverlapping
    -read from fixed starting point as a continuous sequence of bases
    -except some viruses
  4. universal
    -genetic code is conserved throughout evolution
    -except in humans–> mitochondria
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14
Q

Point mutations in DNA

  1. silent:
  2. missense:
  3. nonsense:
  4. frameshift:
  5. severity less–>greatest
A
  1. silent:
    - same amino acid, often base change in 3rd position of codon (tRNA wobble)
  2. missense:
    - changed amino acid (conservative-new amino acid is similar in chemical structure)
  3. nonsense:
    - change resulting in early stop codon
    - “Stop the nonsense”
  4. frameshift:
    - misreading of all nucleotides downstream
    - truncated, nonfunctional pattern
  5. silent<frameshift
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15
Q
  1. DNA Replication
  2. origin of replication
  3. replication fork
  4. helicase
  5. single-stranded binding proteins
  6. DNA topoisomerases
  7. primase
  8. DNA polymerase III
  9. DNA polymerase I
  10. DNA ligase
  11. Telomerase
A
  1. DNA Replication
    - Eukaryotic DNA replication is more complex than the prokaryotic process but uses many enzymes.
    - both prokaryotes & eukaryotes=DNA replication is semiconservative & involves both continuous & discontinuous (Okazaki fragment) synthesis
  2. origin of replication
    - particular consensus sequence of base pairs in genome where DNA replication begins.
    - may be single (prokaryotes) or multiple in eukaryotes
  3. replication fork
    - Y-shaped region along DNA template where leading & lagging strands are synthesized
  4. helicase
    - unwinds DNA template at replication fork
  5. single-stranded binding proteins
    - prevent strands from reannealing
  6. DNA topoisomerases
    - create nick in helix relieve supercoils created in replication
    - fluoroquinolones= inhibit DNA gyrase (prokaryotic topoisomerase II)
  7. primase
    - makes RNA primer on which DNA polymerase III can initiate replication
  8. DNA polymerase III
    - prokaryotes only
    - elongates leading strand adding deoxynucleotides to the 3’ end.
    - elongates lagging strand until it reaches primer of preceding fragment
    - 3’-5’ exonuclease activity “proofreads” each added nucleotide
    - DNA pol III has 5’-3’ synthesis & proofreads with 3’-5’ exonuclease
  9. DNA polymerase I
    - prokaryotes only
    - degrades RNA primer
    - replaces it with DNA
    - has same functions as DNA polymerase III but also excises RNA primer with 5’-3’ exonuclease
  10. DNA ligase
    - catalyzes formation of phosphodiesterase bond within a strand of double stranded DNA (Okazki frag)
    - seals
  11. Telomerase
    - enzyme adds DNA to 3’ end chromosomes to avoid loss genetic material with every duplication
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16
Q 
DNA repair
Single strand
1. nucleotide excision repair
2. base excision repair
3. mismatch repair
A

Single strand

  1. nucleotide excision repair
    - specific endonucleases release the oligonucleotide-containing damaged bases
    - DNA polymerase & ligase fill and reseal the gap.
    - repairs bulky helix distorting leions
    - mutated in xeroderma pigmentosum, which prevents repair of pyrimidine dimers because of ultraviolet light exposure
  2. base excision repair
    - specific glycosylases recognize and remove damaged bases, apurinic/apyrimidinic endonuclease cuts DNA at both apurinic and apyrimidinic sites
    - empty sugar is removed
    - gap is filled and resealed
    - important in repair of spontaneous/toxic deamination
  3. mismatch repair
    - newly synthesized strand is recognized
    - mismatched nucleotides are removed
    - gap filled and resealed
    - mutated in hereditary nonpolyposis colorectal cancer (HNPCC)
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17
Q

DNA repair
Double strand
1. nonhomologous end joining

A
  1. nonhomologous end joining
    - brings together 2 ends of DNA fragments to repair double stranded breaks.
    - no requirement for homology
    - mutated in ataxia telangiectasia
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18
Q

DNA/RNA/Protein synthesis direction

A

-DNA & RNA synthesized 5’-3’
(5’ of incoming nucleotide bears triphosphate energy source for bond)
-triphosphate bond is target of 3’ hydroxyl attack.
-drugs blocking DNA replication often have modified 3’OH, preventing addition of next nucleotide–>chain termination
-mRNA read 5’-3’
-protein synthesis is N-terminus to C-terminus

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19
Q

Types of RNA

A
  1. rRNA-most abundant type
  2. mRNA longest type
  3. tRNA smallest type

rampant, massive, tiny

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20
Q

Start & stop codons

  1. mRNA start
    a. euk
    b. prok
  2. mRNA stop
A
  1. AUG or rarely GUG (AUG in AUGurates protein synthesis)
    a.) codes for methionine, may be removed before translation is completed
    b.) codes for formylmethionine (f-met)
  2. UGA= U Go Away
    UAA= U Are Away
    UAG= U Are Gone
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21
Q

Regulation of gene expression

  1. promoter
  2. enhancer
  3. silencer
A
  1. promoter
    - site where RNA pol and multiple other transcription factors bind to DNA upstream from gene locus (AT rich upstream sequence with TATA and CAAT)
    - promoter mutation commonly results in dramatic decrease in amount of gene transcribed
  2. enhancer
    - stretch of DNA that alters gene expression by binding transcription factors
    - enhancers and silencers may be located close to, far from, or even within (in an intron) the gene whose expression it regulates
  3. silencer
    - site where negative regulators (repressors) bind
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22
Q

RNA pol

  1. Euk
  2. Prok
A
  1. Euk
    - RNA pol I: makes rRNA (most numerous RNA, rampant)
    - RNA pol II: makes mRNA (largest RNA massive
    - RNA pol III: makes tRNA (smallest RNA, tiny)
    - no proofreading function but initiate chains. RNA pol II opens DNA at promoter site
    - pol I, II, III, numbered as their products are used in protein synthesis
    - alpha-amanitin in Amanita phalloides (death cap mushrooms), inhibits RNA polymerase II.Causes severe hepatotoxicity if ingested
  2. Prok
    - 1 RNA pol (multisubunit complex) makes all 3 kinds of RNA
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23
Q

RNA processing (Euk)

A
  • initial transcript is called heterogeneous nuclear RNA (hnRNA), hnRNA destined for translation is called pre-mRNA
  • only processed RNA is transported out of nucleus
  • processing occurs in nucleus
  • after transcription:
    1. capping 5’ end (addition of 7-methylguanosine cap)
    2. polyadenylation on 3’ end (=200 A’s)
    3. splicing out of introns
  • Poly A polymerase does not require a template AAUAAA=polyadenylation signal
  • capped, tailed, spliced transcript=mRNA
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24
Q

Splicing of pre-MRNA

3 steps

A
  1. primary transcript combines with snRNPs and other proteins to form spliceosome.
  2. Lariat-shaped (looped) intermediate is generated.
  3. lariat is released to remove intron precisely and join 2 exons
    * *patients with lupus make antibodies to spliceosomal snRNPs.
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25
Q

Intron vs. Exons

A
  • exons contain the actual genetic info coding for protein
  • introns are intervening noncoding segments of DNA
  • INtrons are INtervening sequences and say IN the nucleus, whereas EXons EXit and are EXpressed.
  • different exons can be combined by alternative splicing to make unique proteins in different tissues
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26
Q

tRNA: structure

A
  • 75-90 nucleotides, secondary structure, cloverleaf form, anticodon end is opposite 3’ aminoacyl end.
  • all tRNAs both EUK & PROK, ahve CCA at 3’ end along with high percentage of chemically modified bases.
  • the amino acid is covalently bound to 3’ end of tRNA
  • *CCA: Can Carry Amino acids
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27
Q

tRNA: charging

A
  • aminoacyl-tRNA synthetase (1 per amino acid, “matchmaker” uses ATP) scrutinizes amino acid before & after it binds to tRNA.
  • if correct, bond is hydrolyzed
  • amino acid acid-tRNA bond has energy for formation of peptide bond
  • mischarged tRNA reads usual codon but inserts wrong amino acid
  • aminoacyl-tRNA synthetase and binding of charged tRNA to codon are repsonsible for accuracy of amino acid selection
  • Tetracyclines bind 30S subunit, preventing attachment of aminoacyl-tRNA
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28
Q

tRNA wobble

A

-accurate base pairing is required only in the first 2 nucleotide positions of an MRNA codon, so codons differing in the 3rd wobble position may code for same tRNA/amino acid (result from degeneracy of genetic code)

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29
Q

Protein synthesis

  1. Initiation
  2. Elongation
  3. Termination
A
  1. Initiation
    - activated by GTP hydrolysis, initation factors (EUK IFs) help assemble 40S robosomal subunit with initiator tRNA and are released when mRNA and the ribosomal subunit assemble with complex
    - Eukaryotes: 40S+60S–> 80S (Even)
    - PrOkaryotes: 30S+50S–>70S (Odd)
    - ATP-tRNA Activation (charging)
    - GTP-tRNA Gripping and Going places (translocation)
  2. Elongation
    -aminoacyl-tRNA binds to A site (except for initiator methionine)
    -ribosomal 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)
    -***think of going APE
    A site-incoming Aminoacyl tRNA
    P site- accomondates growing Peptide
    E site- holds Empty tRNA as it Exits
  3. Termination
    - stop codon recognized by release factor and completed protein is released from ribosome.
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30
Q

Protein synthesis:

antibiotics act as protein synthesis inhibitors

A
  • aminoglycosides bind 30S and inhibit formation of initiation complex and cause misreading of mRNA
  • tetracyclines bind 30S and block aminoacyl tRNA from entering acceptor site
  • Chloramphenicol bind 50S inhibits peptidyl transferase
  • macrolides bind 50S and prevent release of uncharged tRNA after it has donated its amino acid
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31
Q

3 post-translational modifications

A
  1. trimming-removal of N or C terminal propeptides from zymogens to generate mature proteins
  2. covalent alterations- phosphorylation, glycosylation, hydroxylation, methylation, acetylation
  3. proteasomal degradation- attachment of ubiquitin to defective proteins to tag them for breakdown.
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32
Q

Cell cycle phase

A

checkpoints control transitions between phases of cell cylce

  • process regualted by cyclins, CDKs, tumor suppressors.
  • mitosis (shortest phase): prophase-metaphase-anaphase-telophase
  • G1 G0 are variable duration
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33
Q

Regulation of cell cycle:

  1. CDKs
  2. Cyclins
  3. Cyclin-CDk complexes
  4. Tumor suppressors
A
  1. CDKs- cyclin-dependent kinases; constitutive and inactive
  2. Cyclins= regulatory proteins that control cell cycle events; phase specific; activate CDKs
  3. Cyclin-CDk complexes- must be both activated and inactivated for cell cycle to progress
  4. Tumor suppressors- p53 and hypophosphorylated Rb normally inhibit G1-to-S progression; mutations in these genes result in unrestrained cell division
    *** G=gap or growth
    S= Synthesis
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34
Q

Cell types: 3

  1. permanent
  2. stable (quiescent)
  3. Labile
A
  1. permanent- remain in G0 regenerate from stem cells (neurons, skeletal, cardiac muscle, RBCs
  2. stable (quiescent)- enter G1 from G0 when stimulated (hepatocytes, lymphocytes)
  3. Labile- never go into G0, divide rapidly with a short G1 (bone marrow, gut epithelium, skin, hair, hair follicles, germ cells.
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35
Q

Rough Endoplasmic Reticulum

A
  • site for synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins
  • Nissl bodies (RER in neurons): synthesize enzymes (eg. ChAT [choline acetyletransferase] makes ACh) and peptide neurptransmittors
  • free ribosomes- unattached to any membrane; site of synthesis of cytosolic and organellar proteins
    • mucus-secreting goblet cells of small intestine and antibody secreting plasma cells are rich in RER
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36
Q

Smooth ER

A
  • site of steroid synthesis and detoxification of drugs and poisons
  • liver hepatocytes abd steroid hormone-producing cells of adrenal cortex are rich in SER
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37
Q

Cell trafficking
I-cell disease
Vesicular trafficking proteins

A
  • Golgi distribution center for pro and lipids from ER to vesicles and plasma membrane
  • modies N-oligosaccharides on asparagine
  • adds O-oligosaccharides on serine and threonine
  • adds mannonse-6-phosphate to pro for trafficking to lysosomes
  • endosomes are sorting centers for material from outside cell or from Golgi, sending it to lysosomes for destruction or back to membrane/Golgi for further use

I-cell disease (inclusion cell disease):

  • inherited lysosomal storage disorder
  • failure of addition of mannose-6-phosphate to lysosome proteins (enzymes are secreted outside cell instead of being targeted to lysosome)
  • result in coarse facial features, clouded corneas, restricted joint movement, high plasma levels of lysosomal enxymes. fatal during childhood

Vesicular traf pro:
-COPI: Golgi–>golgi (retrograde); Golgi–>ER
-COPII: Golgi–>Golgi (anterograde); ER–>Golgi
Clathrin: trans-Golgi–>lysosomes; plasma membrane–>endosomes (receptor mediated endocytosis)

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38
Q

Peroxisome

A

membrane-enclosed organelle involved in catabolism of very long fatty acids and amino acids

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39
Q

Proteasome

A

barrel-shaped protein complex that degrades damaged or unnecessary proteins tagged for destruction with ubiquitin

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40
Q

Microtuble

A

-cylindrical structure composed of helical array of polymerized dimers of alpha beta tubulin
-each dimer has 2 GTP bound
incorporated into flagella, cilia, mitotic spindles
-grows slowly collapses quickly
-involved in slow axoplasmic transport in neurons
-molecular motor pro: transport cellular cargo toward opposite ends of microtubule tracks
-dynein= retrograde to microtubule (+ to -)
-kinesin=antergrade to microtubule (- to +)

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41
Q

Drugs that act on microtubules

A
  1. mebendazole/thiabendazole (antihelminthic)
  2. griseofulvin (antifungal)
  3. vincristine/vinblastine (anti-cancer)
  4. paclitaxel (anti-breast cancer)
  5. colchicine (anti-gout)
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42
Q

Chediak-Higashi syndrome

A
  • mutation in the lysosomal trafficking regulator gene (LYST)
  • whose product is required for microtubule-dependent sorting of endosomal pro into late multivesicular endosomes
  • results in recurrent pyogenic infections, partial albinism, peripheral neuropathy
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43
Q

Cilia structure

A

9+2 arrangment of microtubules
-axonemal dynein-ATPase that links peripheral 9 doublets and causes bending of cilcium by differential sliding of doublets

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44
Q

Kartagener’s syndrome (primary cillary dyskinesia)

A
  • inmotile cilia due to dynein arm defect
  • result in male infertility (immotile sperm) and decrease female fertility, bronchiectasis, recurrent sinusitis (bacteria and particles not pushed out); associated with situs inversus.
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45
Q

Cytoskeletal elements:

  1. actin & myosin
  2. microtubule
  3. intermediate filaments
A
  1. actin & myosin
    - microvilli, muscle contraction, cytokinesis, adherens junctions
  2. microtubule- movement. Cilia, flagella, mitotic spindle, axonal trafficking, centrioles
  3. intermediate filaments- structure. Vimentin, desmin, cytokeratin, lamins, glial fibrilliary acid proteins (GFAP), neurofilaments
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46
Q

Plasma membrane composition

A

asymmetric lipid bilayer

contains cholesterol, phospholipids, sphingolipids, glycolipids, proteins

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47
Q

Immunohistochemical stains for intermediate filaments (stain & cell type)

A

Stain & cell type

  1. vimentin-connective tissue
  2. desmin-muscle
  3. cytokeratin-epithelial cells
  4. GFAP-NeruroGlia
  5. neurofilaments-neurons
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48
Q

Sodium-potassium pump

A
  • Na+ K+ ATPase located in plasma membrane with ATP site on cytosolic side
  • each ATP consumed, 3 Na+ go out 2 K+ comes in
  • during cycle, pump is phosphorylated.
  • Ouabain inhibits by binding to K+ site
  • cardiac glycosides (digoxin & digitoxin) directly inhibit Na+ K+ ATPase, leading to indirect inhibition of Na+/Ca2+ exchange–> increase Ca2+ phosphorylate which increase cardiac contractility
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49
Q

Collagen Type I-IV

A
  • most abundant pro in human body
  • extensively modified by posttranslational modification
  • organizes & strengthens extracellular matrix
  • *Be (So Totally) Cool, Read Books.
    1. most common (90%): Bone, Skin, Tendon, dentin, fascia, cornea, late wound repair.
  • Type I: bONE–> defective in osteogenesis imperfecta
  1. Cartilage (include hyaline), virteous body, nucleus pulposus
    - Type II: carTWOlage
  2. Reticulin-skin, blood vessels, uterus, fetal tissue, granulation tissue.
    - Type III: defective in Ehlers-Danlos (ThreE D)
  3. Basement membrane or basal lamina.
    Type IV: under the floor (basement membrane) Defective in Alport syndrome
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50
Q

Collagen synthesis & structure

Inside fibroblasts

  1. synthesis (RER)
  2. Hydroxylation (ER)
  3. Glycosylation (ER)
  4. Exocytosis
A
  1. synthesis (RER)
    - translation of collagen alpha chains (pre-procollagen) usually Gly-X-Y (X & Y are proline or lysine)
  2. Hydroxylation (ER)
    - of specific proline & lysine residues (requires Vit C; deficiency–>scurvy)
  3. Glycosylation (ER)
    - of pro-alpha chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen alpha chains)
    - problems forming triple helix–>osteogeneiss imperfecta
  4. Exocytosis
    - of procollagen into extracellular space
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51
Q

Collagen synthesis & structure

Outside fibroblasts

  1. proteolytic processing
  2. cross linking
A
  1. proteolytic processing
    - cleavage of disulfide-rich terminal regions of procollagen, transfomring it into insoluble tropocollagen
  2. cross linking
    - reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linking by Cu2+ containing lysyl oxidase to make collagen fibrils.
    - problems with cross-linking–> Ehlers-Danlos
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52
Q

osteogenesis imperfecta

A
  • genetic bone disorder (brittle bone disease) caused by variety of gene defects
  • most common form is autosomal dominant with abnormal type I collagen causing:
    1. multiple fractures with minimal trauma; may occur during birthing process
    2. blue sclerae due to translucency of connective tissue over the choroidal veins
    3. hearing loss (abnormal middle ear bones)
    4. dental imperfections due to lack of dentin
    • may be confused with child abuse, 1/10,000 incidence
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53
Q

Ehlers-Danlos syndrome

A
  • faulty collagen synthesis causing hyperextensible skin, tendency to bleed (easy bruising) and hypermobile joints.
  • 6 types
  • inheritence & severity vary.
  • can be autosomal dominant or recessive
  • may associated with joint dislocation, berry aneurysms, organ rupture
  • Type I or V collagen most frequently affected in severe classic ED syndrome.
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54
Q

Alport syndrome

A
  • due to variety of gene defects resulting in abnormal type IV collagen
  • most common form is X-linked recessive
  • characterized by progressive hereditary nephritis & deafness
  • may associate with ocular disturbances
  • Type IV collagen is an important structural component of basement membrane of the kidney, ears, eyes
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55
Q

Elastin

marfan’s syndrome
Emphysema

A

-stretchy pro within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connective vertebrae–>relaxed & stretched conformations)
-rich in proline & glycine, nonhydroxylated forms
-troppelastin with fibrillin scaffolding
-cross-linking takes places extracelluarly and gives elastin its elastic properties
-broken down by elastase, normally inhibited by alpha 1 antitrypsin
***
Marfan’s syndrome-caused by defect in fibrillin
Emphysema-can be caused by alpha 1 antitrypsin deficiency, resulting in excess elastase activity.

Wrinkles of aging are due to reduced collagen & elastin production

56
Q

Polymerase Chain reaction

A
  • molecular biology lab procedure used to amplify desired fragment of DNA
    1. denaturation- DNA by heating to generate 2 separate strands
    2. annealing-cooling, excess premade DNA primers anneal to specific sequence on each strand to be amplified
    3. elongation-heat stable DNA polymerase replicates DNA sequence following each primer

Steps are repeated multiple times for DNA sequence amplification.
Agarose gel electrophoresis used for size separation of PCR products (small travel further) compared with DNA ladder

57
Q

Blotting

  1. Southern
  2. Northern
  3. Western
  4. Southwestern
A
  1. Southern
    - DNA sample electrophoresed on gel and transfereed to filter. Filter soaked in denaurant & exposed to radiolabeled DNA probe that recognizes and anneals to its complementary strand. Result double stranded labeled piece DNA visualized when filter exposed to film
  2. Northern
    - similar to Southern except RNA sample. use to study mRNA level
  3. Western
    - sample pro separated by gel electrophoresis transferred to filter. labeled antibody used to bind relevant protein
  4. Southwestern
    - ID DNA binding proteins using labeled oligonucleotide probes (eg. transcription factors)

**SNoW DRoP
S=southern=DNA
N=northern=RNA
W-western=Protein

58
Q

Microarrays

A
  • thousands nucleic acid sequences are arranged in grids on glass or silicon
  • DNA or RNA probes hybridized to chip and scanner detects relative amounts of complementary binding
  • used profile gene expression levels of thousands of genes simultaneously to study certain diseases and treatments
  • able to detect single nucleotide polymorphisms (SNPs) for variety of applications including genotyping, forensic analysis, predisposition to disease, cancer mutations, genetic linkage analysis
59
Q

Enzyme-linked immunosorbent assay

A
  • Rapid immunologic technique testing for antigen-antibody reactivity
  • Patient blood sample is probed with either
    1. indirect ELISA- uses a test antigen to see if specific antibody is present in pt blood; secondary antibody coupled to a color-generating enzyme is added to detect 1st antibody
    2. direct ELISA- uses test antibody coupled to colorgenerating enzyme to see if specific antigen is present in pt blood
  • if target substance is presnt in sample, test solution will have intense color reaction, positive
  • used in many labs determine whether a particular antibody present in blood.
  • Sensitivity & specificty approach 100%
  • both false positive and false negative results do occur
60
Q

Fluorescene in situ hybridization (FISH)

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 anomalies (microdeletion) at molecular level (when deletion is too small to be visualized by karyotype)
  • fluorescene=gene is present; no
  • fluorescene= gene has been deleted
61
Q

Cloning methods

A

cloning is the production of a recombinant DNA molecule that is self-perpetuating.

  1. isolate eukaryotic mRNA (post-RNA processing steps) of interest
  2. expose mRNA to reverse transcriptase to produce cDNA
  3. insert cDNA fragments into bacterial plasmids containing antibiotic resistance genes
  4. surviving bacteria on antibiotic medium produce cDNA library
62
Q

gene expression modifications

A
  • transgenic strategies in mice involve
    1. random insertion of gene into mouse genome
    2. targeted insertion or deletion of gene through homologous recombination with mouse gene
  • Cre-lox system: can inducibly manipulate genes at specific developmental points using an antibiotic-controlled promoter (to study a gene whose deletion causes embryonic death)
  • RNA interference (RNAi)- 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
  • Knock-out= removing a gene, taking it out.
  • knock-in= inserting a gene
63
Q

Karyotyping

A
  • a process in which metaphase chromosomes are stained, ordered, and numbered according to morphology, size, arm-length ratio, and banding pattern.
  • can be performed on a sample of blood, bone marrow, amniotic fluid, or placental tissue.
  • used to diagnose chromosomal imbalances (autsomal trisomies, sex chromosome disorders)
64
Q

codominance

A
  • both alleles contribution to the phenotype of the heterozygotic
  • blood groups A, B, AB
65
Q

Variable expressivity

A
  • phenotype varies among individuals with same genotype

- 2 patients with neurofibromatosis type I (NF1) may have varying disease severity

66
Q

incomplete penetrance

A
  • not all individuals with a mutant genotype show the mutant phenotype
  • BRCA1 gene mutations do not always result in breast or ovarian cancer.
67
Q

Pleitropy

A
  • one gene contributes to multiple phenotypic effects.

- PKU causes many seemingly unrelated symptoms, ranging from mental retardation to hair/skin changes.

68
Q

Imprinting

A
  • differences in gene expression depend on whether the mutation is of maternal or paternal origin.
  • Prader-Willi and Angelman’s syndromes
69
Q

Anticipation

A
  • increased severity or earlier onset of disease in succeeding generations
  • Huntington’s disease
70
Q

Loss of heterozygosity

A
  • if a pt inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.
  • retinoblastoma and the two-hit hypothesis
71
Q

dominant negative mutation

A
  • exerts dominant effect
  • heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
  • mutation of a transcription factor in its allosteric site.
  • nonfunctioning mutant can still bind DNA, preventing wild-type transcription factor from binding.
72
Q

Linkage disequilibrium

A
  • tendency for certain alleles at 2 linked loci to occur together more often than expected by chance.
  • measured in a population, not in a family, and often varies in different populations.
73
Q

mosaicism

A
  • occurs when cells in the body differ in genetic makeup due to postfertilization loss or change of genetic info during mitosis
  • can be germ-line mosaic (gonadal mosaicism), which may produce disease that is not carried by parent’s somatic cells.
  • mutation in the embryonic precursor of the bone marrow stem cell–> a hematologic mosaic individual
  • a chimeric individual is derived from 2 zygotes that subsequently fuse
74
Q

locus heterogeneity

A
  • Marfan’s syndrome, MEN 2B, and homocystinuria; all cause marfanoid habitus.
  • Albinism
75
Q

Heteroplasmy

A

-presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease

76
Q

uniparental disomy

A
  • offspring receives 2 copies of a chromosome from 1 parent.
  • heterodisomy (heterozygous) indicates a meiosis I error.
  • isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of pair of chromosomes, and loss of the other of the original pair
  • uniparental is eUploid (correct number of chromosome), not aneuploid.
  • most occurences of UPD–> normal phenotype
  • consider UPD in an individual manisfesting a recessive disorder when only one parent is a carrier
77
Q

Hardy-Weinberg population genetics

A
  • if population is in Hardy-Weinberg equilibrium and if p and q are the frequencies of separate alleles.
  • p2 + 2pq + q2= 1 and p + q= 1
  • p2= frequency of homozygosity for allele p
  • q2= frequency of homozygosity for allele q
  • 2pq=frquency of heterozygosity (carrier frquency, if an autosomal recessive disease)
  • the frquency of an x-linked recessive disease in males=q and in females= q2

Hardy-weinberg law assumes:

  • no mutation occuring at locus
  • no selection for any of genotypes at the locus
  • completely random mating
  • no net migration
78
Q

Imprinting

A
  • at some loci, only 1 allele is active; the other is inactive (imprinted/inactivated by methylation)
  • with 1 allele inactivated, deletion of active allel–>disease
  • both Prader-Willi and Angelman’s syndromes due to inactivation of deletion of genes on chromosome 15
  • can also occur as a result of uniparental disomy
79
Q

Prader-Willi syndrome

A

mental retardation, hyperphagia, obesity, hypogonadism, hypotonia

80
Q

AngelMan’s syndrome

A

-materna retardation, seizures, ataxia, inappropriate laughter

81
Q

Autosomal dominant

A
  • often due to defects in structural genes.
  • many generations, both XY & XX affected
  • often pleiotropic
  • family history crucial to diagnosis
82
Q

Autosomal recessive

A
  • 25% offspring from 2 carrier parents are affected
  • often due to enzyme deficiencies
  • usually seen in only 1 generation
  • commonly more severe than dominant disorders
  • often present in childhood
83
Q

X-linked recessive

A
  • sons of heterozygous mothers have 50% chance of being affected
  • no male to male transmission
  • commonly more severe in males
  • females usually must be homozygous to be affected
84
Q

x-linked dominant

A
  • transmitted through both parents
  • either male or female offspring of the affected mother may be affected, whereas all females offspring of the affected fathers are affected

Hypophosphatemic rickets

  • Vit D resistant rickets
  • inherited disorder resulting in increase phosphate wasting at proximal tubule
  • results in rickets-like presentation
85
Q

Mitochondrial inheritance

A
  • transmitted only through mother
  • all offspring of affected females may show signs of disease
  • often due to failures in oxidative phosphorylation
  • variable expression in population due to heteroplasmy

Mitochondrial myopathies

  • group of rare disorders resulting from mutations affecting mitochondrial function
  • often present with myopathy and CNS disease
  • muscle biopsy often shows “ragged red fibers”
86
Q

Achondroplasia

A
  • Autosomal-dominant diseases
  • cell-signaling defect of fibroblast growth factor (FGF) receptor 3
  • results in dwarfism, short limbs, larger head, but trunk size is normal
  • associated with advanced paternal age
87
Q

Autosomal-dominant polycystic kidney disease (ADPKD)

A
  • Autosomal-dominant diseases
  • formerly known as adult polycystic kidney disease.
  • always bilateral, massive enlargement of kidneys due to multiple large cysts.
  • patients present with flank pain, hematuria, hypertension, progressive renal failure
  • 85% of cases are due to mutation in PKD1 (chromosome 16; 16 letters in polycystic kidney).
  • associated with polycystic liver disease, berry aneurysms, mitral valve prolapse
  • infantile form is recessive
88
Q

Familial adenomatous polyposis

A
  • Autosomal-dominant diseases
  • colon becomes covered with adenomatous polyps after puberty
  • progresses to colon cancer unless colon is resected
  • mutations on chromosome 5 (APC gene); 5 letters in polyp
89
Q

Familial hypercholesterolemia (hyperlipidemia type IIA)

A
  • Autosomal-dominant diseases
  • elevated LDL due to defective or absent LDL receptor
  • Heterozygotes (1:500) have cholesterol=300 mg/dL.
  • Homozygotes (very rare) have cholesterol= 700+ mg/dL, severe atheroscerotic disease early life, and tendon xanthomas (classically in the Achilles tendon); MI may develop before age 20.
90
Q

hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

A
  • Autosomal-dominant diseases
  • inherited disorder of blood vessels
  • findings: telangiectasia, recurrent epistaxis, skin discoloration, arteriovenous malformations (AVMs)
91
Q

Hereditary spherocytosis

A
  • Autosomal-dominant diseases
  • spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia
  • increase MCHC
  • splenectomy is curative
92
Q

Huntington’s disease

A
  • Autosomal-dominant diseases
  • Findings: depression, progressive dementia, choreiform movements, caudate atrophy,
  • decrease levels of GABA & ACh in brain
  • symtptoms manifest in affected individuals btw 20-50 yo
  • gene located on chromosome 4
  • trinucleotide repeat disorder: (CAG)n
  • ** Hunting 4 food
93
Q

Marfan’s syndrome

A
  • Autosomal-dominant diseases
  • Fibrillin-1 gene mutation–>connective tissue disorder affecting skeleton, heart, and eyes
  • Findings: tall with long extremeties, pectus excavatum, hypermobile joints, long, tapering fingers and toes (arachnodactyly); cystic medial necrosis of aorta–>aortic incompetence and dissecting aortic aneurysms; floppy mitral valve
  • subluxation lenses
94
Q

Multiple endocrine neoplasia (MEN)

A
  • Autosomal-dominant diseases
  • several distinct syndromes (1, 2A, 2B) characterized by familial tumors of endocrine glands, including those of the pancreas, parathyroid, pituitary, thyroid, and adrenal medulla
  • MEN 2A nad 2B are associated with ret gene
95
Q

Neurofibromatosis type 1 (von Recklinghausen’s disease)

A
  • Autosomal-dominant diseases
  • Findings: cafe au lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas)
  • marked by skeletal disorders (scoliosis) and optic pathway gliomas
  • on long arm of chromosome 17; 17 letters in von Recklinghausen
96
Q

Neurofibromatosis type 2

A
  • Autosomal-dominant diseases
  • bilateral acoustic schwannomas, juvenile cataracts
  • NF2 gene on chromosome 22; type 2=22
97
Q

Tuberous sclerosis

A
  • Autosomal-dominant diseases
  • Findings: facial lesions (adenoma sebaceum), hypopigmented “ash leaf spots” on skin, cortical and retinal hamartomas, seizures, mental retardation, renal cysts and renal angiomyolipomas, cardiac rhabdomyomas, increase incidence of astrocytomas. Incomplete and variable presentation
98
Q

von Hippel-Lindau disease

A

Findings: hemangioblastomas of retina/cerebellum/medula; the majority of affected individuals develop multiple bilateral renal cell carcinomas and other tumors.

  • associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p)
  • results in constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors.
  • von Hippel-Lindau=3 words for chromosome 3
99
Q

Autosomal-recessive disease

A
  • albanism
  • ARPKD ( infantile polycystic kidney disease)
  • cyctsic fibrosis
  • glycogen storage disease
  • hemochromatosis
  • mucopolysaccharidos (except Hunter’s)
  • phenylketonuria
  • sickle cell anemias
  • sphingolipidoses (except Fabry’s)
  • thalassemias
100
Q

Cystic Fibrosis

A

Autosomal-recessive disease

  • defect in CFTR gene on chromosome 7, commonly deletion of Phe 508
  • CFTR channel actively secretes Cl- in lungs and GI tract and actively reabsorbs Cl- from sweat
  • defective Cl- channel–>secretion of abnormally thick mucus that plugs lungs, pancreas, liver–>recurrent pulmonary infections (Pseudomonas species & S. aureus)
  • chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorption & steatorrhea),
  • nasal polyps, meconium ileus in newborns
  • mutation often causes abnormal protein folding resulting in degradation of channel before reaching cell surface
  • infertility in males due to bilateral absence of vas deferns
  • fat soluble vit deficiencies (A, D, E, K)
  • can present as failure to thrive in infancy
  • most common lethal genetic disease of white population
  • increase concentration of Cl-ions in sweat test is diagnostic
  • treatment: N-acetylcystein to loosen mucous plugs (cleaves disulfide bonds within mucous glycoproteins)
101
Q

X-linked recessive disorders

A

Autosomal-recessive disease

  • Bruton’s agammaglobulinemia
  • Wiskott-Aldrich syndrome
  • Fabry’s disease
  • G6PD deficiency
  • Occular albinism
  • Lesch-Nyhan syndrome
  • Duchenne’s (and Becker’s) muscular dystrophy
  • Hunter’s syndrome
  • Hemophilia A & B
  • Ornithine transcarbamoylase deficiency
  • *Be Wise, Fool’s GOLD Heeds Silly HOpe
  • female carriers may be affected and may have less severe symptoms due to random X chromosome inactivation in each cell
102
Q

Duchenne’s

A

Muscular dystrophies
-x-linked frameshift mutation–>deletion of dystrophin gene–>accelerated muscle breakdown
-weakness begins in pelvic girdle muscles nad progresses superiorly
-Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle
-cardiac myopathy
-use of Gowers’ maneuver, requiring assistance of the upper extremities to stand up is characteristic
-onset before 5 yrs of age
Duchenne’s= Deleted Dystrophin
-Dystrophin gene (DMD) longest known human gene–> increase rate of spontaneous mutation
-dystrophin helps anchor muscle fibers, primarily in skeletal & cardiac muscle
-diagnose muscular dystrophies by increase CPK & muscle biopsy

103
Q

Fragile X syndrome

A
  • Muscular dystrophy
  • x-linked defect affecting the methylation & expression of FMRI gene
  • 2nd most common cause of genetic mental retardation (after down syndrome)
  • findings:
    1. macroorchidism (enlarged testes)
    2. long face with a large jaw
    3. large everted eyes
    4. autism
    5. mitral valve prolapse
  • trinucleotide repeat disorder (CGG)n
  • fragile X=eXtra large testes, jaw, ears
104
Q

Becker’s

A

Muscular Dystrophy

  • X-linked mutated dystrophin gene
  • less severe than Duchenne’s
  • onset in adolescence or early adulthood
105
Q

Trinucleotide repeat expansion disease

A

Muscular Dystrophy
-HUNTINGton’s disease
-MYotonic dystrophy (CTG)n
-FRIEDreich’s ataxia (GAA)n
-fragile X syndrome (CGG)n
**
TRY (tribucleotide) HUNTING for MY FRIED EGGS (X)
-X-Girlfriend’s First Aid helped Ace MY Test
-may show genetic anticipation (disease severity increase and age of onset decrease in successive generation)

106
Q 
Down syndrome (trisomy 21)
1:700
A

Autosomal trisomy

  • Findings:mental retardation, flat facies, prominent epicanthal folds, simian crease, gap btw 1st 2 toes, duodenal atresia, congenital heart disease (most commonly ostium primum-type ASD)
  • associated with increase risk of ALL & Alzheimer’s disease (>35 yo)
  • 95% of cases due to meiotic nondisjunction of homologous chromosomes (associated with advanced maternal age; from 1:1500 in women 45)
  • 4% of cases due to Robertsonian translocation
  • 1% cases due to Down mosaicism (no maternal association)
  • **Drinking age 21
  • most common viable chromosomal disorder and common cause of genetic mental retardation
  • results of pregnancy quad screen: 1.decrease alpha-fetoprotein,
    2. increase beta-hCG,
    3. decrease estriol
    4. increase inhibin A
  • ultrasound shows increase nuchal in first trimester translucency
107
Q

Edwards’ syndrome (trisomy 18)

1:8000

A

autosomal trisomy
-Findings: severe mental retardation, rocker bottom feet, micrognathia (small jaw), low set Ears, clenched hands, prominent occiput, congenital heart disease
-death usually occurs within 1 y of birth
***
Election age 19
-most common trisomy resulting in love birth after Downs
-result of pregnancy quad screen
1. decrease alpha-fetoprotein
2. decrease beta-hCG
3. decrease estriol
4. normal inhibin A

108
Q

Patau’s syndrome (trisomy 13)

1:15,000

A 
Autosomal trisomy
-Findings: severe mental retardation, rocker bottom feet, microphthalmia, microcephaly, cleft liP/Plate, holoProsencephaly, Polydactyly, congenital heart disease
-Death occurs within 1 y of birth
***
Puberty age 13
-pregancy screen 1st trimester
1. decrease free beta-hCCG
2. decrease PAPP-A
3. increase nuchal translucency
109
Q

Robertsonian translocation

A

autosomal trisomy

  • nonreciprocal chromosomal translocation commonly involves chromosome pairs 13, 14, 15, 21, 22
  • one of most common types of translocation
  • occurs when long arms of 2 acrocentric chromosome (chromoseome with centromeres near their end) fuse at the centromere and the 2 short arms are lost
  • balanced translocations can result in miscarriage, stillbirth, chromosomal imbalance
110
Q

Cri-du-chat syndrome

A
  • autosomal trisomy
  • congenital microdeletion of short arm of chromosome 5 (46, XX or XY, 5p-)
  • Findings: microcephaly, moderate to severe mental retardation, high-pitched cyring/mewing, epicanthal folds, cardiac abnormalities (VSD)
111
Q

Williams syndrome

A

autosomal trisomy

  • congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)
  • Findings: distinctive “elfin”facies, intellectual disability, hypercalcemia (increase sensitivity to vit D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problem
112
Q

22q11 deletion syndromes

A

-variable presentation, including Cleft palate, Abnormal facies, Thymic aplasia–> T cell deficiency
-Cardiac defects, Hypocalcemia secondary to parathyroid aplasia, due to microdeletion at chromosome 22q11
-DiGeorge syndrome: thymic, parathyroid, and cardiac defects
-Velocardiofacial syndrome: palate, facial, and cardiac defects
***
CATCH 22
-Due to aberrant development of 3rd 4th branchial pouches

113
Q

Fat soluble Vit

A

A, D, E, K

  • absorption dependent on gut (ileum) and pancreas
  • toxicity more common than for water-soluble vitamins because these accumulate in fat
  • malabsorption syndromes (steatorrhea) such as cystic fibrosis and sprue, or mineral oil intake can cause fat-sol vit deficiencies
114
Q

water sol vit

A 
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)
-all wash out easily from body except B12 & folate (stored in liver)
-B-complex deficiencies often result in dermatitis, glossitis, diarrhea
115
Q

Vit A (retinol)

A

Function:
-antioxidant
-constituent of visual pigments (retinal)
-essential for normal differenitation of epithelial cells into specializing tissue (pancreas cells, mucus-secreting cells
-prevents squamous metaplasia
-used to treat measles and AML, subtype M3
-Retinol is vit A (retin-A) used for wrinkles & acne
-found in liver & leafy vegetables
Deficiency:
-night blindness, dry skin
Excess:
-arthralgias, fatigue, H/A, skin changes, sore throat, alopecia
-tetratogenic (cleft palate, cardiac abnormalities),
-negative pregnancy test and reliable contraception are needed before isotretinoin is prescribed for severe acne

116
Q

Vit B1 (thiamine)

A

Function
-in thiamine pyrophosphate (TPP) a cofactor for several enzymes in decarboxylation reactions:
1. pyruvate dehydrogenase (links glycolysis to TCA cycle)
2. alpha-ketoglutarate dehydrogenase (TCA cycle)
3. transketolase (HMP shunt)
4. branched-cahin amino acid dehydrogenase
**all above required for ATP synthesis
Deficiency
-impaired glucose breakdown–>ATP depletion worsened by glucose infusion; highly aerobic tissues (brain & heart) are affected first
-Wernicke-Korsakoff syndrome and beriberi
-seen in malnutrition as well as alcoholism (secondary to malnutrition and malabsorption)

Wernicke-Korsakoff

  • confusion, ophthalmoplegia, ataxia (classic triad) + confabulation, personality change, memory loss (permanent)
  • damage to medial dorsal nucleus of thalamus, mammillary bodies

Dry beriberi
-polyneuritis, symmetrical muscle wasting

Wet Beriberi
-high output cardiac failure (dilated cardiomyopathy), edema

117
Q

Vit B2 (riboflavin)

A 
Function
-cofactor in oxidation & reduction
Deficiency
-Cheilosis (inflammation of lips, scaling and fissures at corner of mouth)
-Corneal vascularization
***
FAD nad FMN are dervied from riboFlavin
-B2=2ATP
-The 2 C's of B2
118
Q

Vit B3 (niacin)

A 
Function
-constituent of NAD+, NADP+ (used in redox reaction)
-derived from trytophan
-synthesis requires vit B6
*** NAD dervied from Niacin
B3=3 ATP

Deficiency

  • Glossitis
  • severe deficiency leads to pellagra, which can be caused by Hartnup disease (decrease tryptophan absorption), malignant carcinoid syndrome (increase tryptophan metabolism), and INH (decrease vit B6)
  • symptoms of pellagra: Diarrhea, Dementia, Dermatitis
  • *3 D’s of B3

Excess
-facial flushing (due to pharmacologic doses for treatment of hyperlipedemia)

119
Q

Vit B5 (pantothenate)

A

Function
-essential component of CoA (a cofactor for acyltransfers) and fatty acid synthase
B5 is pento-thenate

Deficiency
-Dermatitis, enteritis, alopecia, adrenal insufficiency

120
Q

Vit B6 (pyridoxine)

A

Function

  • converted to pyridoxal phosphate, a cofactor used in transamination, decarboxylation reactions, glycogen phosphorylase
  • synthesis of cystathionine, heme, niacin, histamine, neurotransmitters including serontonin, epinephrine, norepinephrine, GABA

Deficiency

  • convulsions, hyperirritibility, peripheral neuropathy (deficiency inducible by INH and oral contraceptive)
  • sideroblastic anemias due to impaired hemoglobin synthesis and iron excess
121
Q

Vit B7 (biotin)

A

Function

  • Cofactor for carboxylation enzymes (which add a 1-carbon group):
    1. pyruvate carboxylase: pyruvate (3C)–> oxaloacetate (4C)
    2. acetyl-CoA carboxylase: acetyl-CoA (2C)–>malanyl-CoA (3C)
    3. propionyl-CoA carboxylase: propionyl-CoA (3C)–> methylmalonyl-CoA (4C)

***AVIDin in egg whites AVIDly binds biotin
Deficiency
-relatively rare
-dermatitis, alopecia, enteritis
-caused by antiobic use or excessive ingestion of raw egg

122
Q

Vit B9 (folic acid)

A

Function

  • converted to tetrahydrofolate (THF) a coenzyme for 1-carbon transfer/methylation reactions
  • important for synthesis of nitrogenous bases in DNA & RNA
  • found in leafy green veg. Folate from foliage
  • small reserve pool stored primarily in the liver

Deficiency

  • macrocytic, megaloblastic anemia
  • no neurologic symptoms (as opposed to vit B12 deficiency)
  • most common vit deficiency in US
  • seen in alcholism & pregnancy
  • deficiency caused by drugs= phenytoin, sulfonamides, MTX
  • supplemental folic acid in early pregnancy reduced neural tube defeccts
123
Q

Vit B12 (cobalamin)

A

Function

  • cofactor for homocysteine methyltransferase (transfers CH3 groups as methylcobalamin) and methylmalonyl-CoA mutase
  • found in animal products
  • synthesized only by microorganisms
  • very large reserve pool (several yrs) stored primarily in liver
  • deficiency is usually caused by malabsorption (sprue, enteritis, Diphyllobothrium latum), lack of intrinsic factor (pernicious anemia, gastric bypass surgery), or absence of terminal ileum (crohn’s dx)
  • use Schilling test to detect the etiology of the deficiency
124
Q

S-adenosyl-methionine-

A
  • ATP + methionine –>SAM
  • SAM transfers methyl units
  • regeneration of methionine (and thus SAM) is dependent on vit B12 and folate
  • SAM the methyl donor man
  • required for the conversion of NE to epinephrine
125
Q

Vit C (ascorbic acid)

A

Function

  • antioxidant
  • also facilitates iron absorption by keeping iron in Fe2+ reduced state
  • necessary for hydroxylation of proline & lysine in collagen synthesis
  • necessary for dopamine beta-hydroxylase, which converts dopamine to NE
  • found in fruits n veg
  • pronounce absorbic acid

Deficiency

  • Scurvy
  • swollen gums, bruising, hemarthrosis, anemia, poor wound healing, weakened immune response
  • vit C def causes scurcy due to a collagen synthesis defect

Excess

  • nausea, vomiting, diarrhea, fatigue, sleep problems
  • can increase risk of iron toxicity in predisposed individuals
126
Q

Vit D

A

D2=ergo calciferol: ingested from plants
D3= cholecalciferol: consumed in milk, formed in sun exposed skin
25-OH D3= storage form
1,25-(Oh)2D3 (calcitriol)=active form
-drinking milk fortified with vit D is good for bones

Function
-increase intestinal absorption of calcium and phosphate, increase bone mineralization

Deficiency

  • rickets in children (bone pain & deformity), osteomalacia in adults (bone pain & muscle weakness), hypocalcemic tetany
  • breast milk has decrease vit D (supplement in dark skinned pt)

Excess

  • hypercalcemia, hypercalciuria, loss of appetite, stupor
  • seen in sarcoidosis (increase activation of vit D by epitheloid macrophages)
127
Q

vit E

A

Function
-antioxidant (protect erythrocytes and membranes from free-radical damage

deficiency

  • increase fragility of erythrocytes (hemolytic anemia), muscle weakness, posterior coumn and spinocerebellar tract demyelination
  • E is for Erythrocytes
128
Q

Vit K

A

Function

  • catalyzes gamma-carboxylation of glutamic acid residues on various proteins concerned with blood clotting
  • synthesized by intestinal flora
  • K is for Koagulation. Necessary for the synthesis of clotting factors II, VII, IX, X, and proteins C & S. Warfarin-vit K antagonist

deficiency

  • neonatal hemoorage with increase PT & aPTT but normal bleeding time (neonates have sterile intestines and are unable to synthesize vit K). can also occur after prolonged use of broad-spectrum antibiotics
  • not in breast milk, neonates are given vit K injection at birth to prevent hemorrage
129
Q

zinc

A

Function
-essential for the activity of 100 + enzymes. important in the formation of zinc finger (transcription factor motif)
Defciency
-delayed wound healing, hypogonadism, decrease adult hair (axillary, facial, pubic), dysgeusia, anosmia. May predispose to alcoholism cirrhosis

130
Q

Ethanol metabolism

A
  • NAD+ is the limiting reagent
  • alcohol dehydrogenase operates via zero-order kinetics
  • fomepizole-inhibits alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoning
  • disulfiram (antabuse) inhibits acetaldehyde dehydrogenase (acetaldehyde accumulates contributing to hangover symptoms)
131
Q

ethanol hypoglycemia

A
  • ehtanol metabolism increase NADH/NAD+ raio in liver, causing diversion of pyruvate to lactate and OAA to malate, thereby inhibiting glucogenesis and stimulating fatty acid synthesis
  • hypoglycemia and hepatic fatty change (hepatocellular steatosis) seen in chronic alcoholics
  • overproduction of lactate–> aciposis
  • depletion of oxaloacetate shuts down TCA cycle, shunting acetyl-CoA into ketone production
  • breakdown of excess malate increase NADPH and thus fatty acid synthesis
132
Q

Kwashiorkor

A
  • protein malnutrition resulting in skin lesions, edema, liver malfunction (fatty change due to decrease apolipoprotein synthesis)
  • clinical picture is small child with swollen belly
  • result from protein deficient MEAL
    1. malnutrition
    2. edema
    3. anemia
    4. liver (fatty)
133
Q

Marasmus

A
  • energy malnutrition resulting in tissue and muscle wasting
  • loss of subcutaneous fat and variable edema
  • Marasmus=muscle wasting
134
Q

Metabolism sites

A

mitochondria
-fatty acid oxidation (beta-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation

Cytoplasm
-glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis
BOTH
-Heme synthesis, Urea cycle, Gluconeogenesis= HUGs take two (both)

135
Q

Enzyme terms

  1. kinase
  2. phosphorylase
  3. phosphatase
  4. dehydrogenase
  5. carboxylase
A

enzyme’s name describes its function. glucokinase is an enxyme that catalyzes the phorphorylation of glucose using a molecule ATP.

  1. kinase- uses ATP to add high energy phosphate group to substrate
  2. phosphorylase- adds inorganic phosphate onto substrate without using ATP
  3. phosphatase- removes phosphate group from substrate
  4. dehydrogenase- catalyzes oxidation-reduction reactions
  5. carboxylase- transfers CO2 groups with the help of biotin
136
Q

ATP production

A

-Aerobic metabolism of glucose produces 32 ATP via malate-aspartate shuttle (heart & liver)
-30 ATP via glycerol-3-phosphate shuttle (muscle)
-

136
Q

Rate determing enzymes of metabolic processes

Process——Enzyme——-Regulators

  1. glycolysis
  2. gluconeogenesis
  3. TCA cycle
  4. Glycogen synthesis
  5. Glycogenolysis
  6. HMP shunt
  7. De novo pyrimidine synthesis
  8. De novo purine synthesis
  9. Urea cycle
  10. Fatty acid synthesis
  11. Fatty acid oxidation
  12. Ketogenesis
  13. Cholesterol synthesis
A

Process——Enzyme——-Regulators

  1. glycolysis/ phosphofructokinase-1 (PFK-1)/ AMP+; fructose-2,6-BP+; ATP-; citrate-
  2. gluconeogenesis/ fructose-1,6-bisphosphatase/ ATP+; AMP-; fructose-2,6-BP-
  3. TCA cycle/ isocitrate dehydrogenase/ ADP+; ATP-; NADH-
  4. Glycogen synthesis/ glyogen synthase/ glucose+; insulin+; epinephrine-; glucagon-
  5. Glycogenolysis/ glycogen phosphorylase/ AMP+, epinenephrine+; glucagon+; insulin-; ATP-
  6. HMP shunt/ glucose-6-phosphate dehydrogenase (G6PD)/ NADP+; NADPH-
  7. De novo pyrimidine synthesis/ carbamoyl phosphate synthetase II/
  8. De novo purine synthesis/ glutamine-PRPP amidotransferase/ AMP-; IMP-; GMP-
  9. Urea cycle/ carbamoyl phosphate synthetase I/ N-acetylglutamate+
  10. Fatty acid synthesis/ acetyl-CoA carboxylase (ACC); insulin+; citrate+; glucagon-; palmitoyl-CoA-
  11. Fatty acid oxidation/ carnitine acyltransferase I/ Malonyl-CoA-
  12. Ketogenesis/ HMG-CoA synthase/
  13. Cholesterol synthesis/ HMG-CoA reductase/ insulin+; thyroxine+; glucagon-; cholesterol-

USMLE First AID (9 decks)

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