Steve Harvey's Black and White Biochemistry Facts Flashcards
Chromatin Structure
Negatively charged DNA loops twice around positively charged histones
Histones rich in lysine and arginine
Nucleosome core= H2A, H2B, H3, H4 (two of each)
Histone H1 binds nucleosome and stabilizes nucleosomes
Heterochromatin
Condensed, transcriptionally inactive, sterically inaccessible
Heterochromatin= highly condensed
Euchromatin
less condensed, transcriptionally active, sterically accessible
Eu=true “truly transcribed”
DNA methylation
Template strand cytosine and adenine are methylated in DNA replication, which allows mismatch repair enzymes to distinguish between old and new strands in prokaryotes.
DNA methylation at CpG islands represses transcription
“CpG Methylation Makes DNA Mute”
Histone methylation
Usually reversibly represses DNA transcription. but can activate it in some cases
“methylation=muting”
Histone acetylation
Relaxes DNA coiling, allowing for transcription.
“Acetylation=Active”
Purines
PURe As Gold
Adenine and Guanine
Pyrimidine
CUT the PY
Cytosine, Thymine, Uracil
Adenosine Deaminase Deficiency
Excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase prevents DNA synthesis and thus decrease lymphocyte count.
One of the major causes of autosomal recessive SCID
Lesch-Nyhan syndrome
HGPRT
Hyperuricemia - if guanine and hypoxanthine cannot be phosphorylated by HGPRT, they get turned into urea which causes gout (see yellow crystals in their shit).
pissed off, retardation, DysTonia
HGPRT .
(hypoxanthine to IMP and guanine to GMP)
X-linked recessive
Treatment: allopurinol or febuxostat
Patient can develop macrocytic anemia because folate and b12 can compensate to make up for lost purines
DNA replication: Helicase
Unwinds DNA template at replication fork
DNA polymerase III
prokaryotes only
Elongates leading strand by adding DNA to the 3’ end
proofreads with 3’ to 5’ exonuclease
DNA polymerase I
Prokaryotes only
Degrades RNA primer (via RNAse H), replaces it with DNA
Same as polymerase III but excises RNA primer with 5’ to 3’ exonuclease
DNA ligase
Catalyzes the formation of a phosphodiester bond within a strand of double-stranded DNA (joins okazaki fragments)
Telomerase
RNA-dependent DNA polymerase that adds DNA to 3’ ends of chromosomes to avoid loss of genetic material with every duplication
DNA mutations: Transition vs transversion
Transition- purine to purine or pyrimidine to pyrimidine
Transversion- purine to pyrimidine or vise versa
Silent mutation
nucleotide substitution but codes for same amino acid: often base change in 3rd position of codon (tRNA wobble)
Missense
Nucleotide substitution resulting in changed amino acid (called conservation if new amino acid is similar in chemical structure)
example: sickle cell disease
Nonsense
Nucleotide substitution resulting in early stop codon
“Stop the nonsense”
Frameshift
Deletion or insertion of a number of nucleotides not divisible by 3, resulting in misreading of all nucleotides downstream, usually resulting in a truncated, nonfunctional protein
Example: Duchenne muscular dystrophy
Nucleotide excision repair
specific endonucleases release the oligonucleotide containing damaged bases; DNA polymerase and ligase fill and reseal the gap, respectively. Repairs bulky helix-distorting lesions.
example: xeroderma pigmentosum, prevents repair of pyrimidine dimers because of ultraviolet light exposure
Mismatch repair
Newly synthesized strand is recognized, mismatched nucleotides are removed and the gap is filled and resealed
example: defective in hereditary nonpolyposis colorectal cancer and lynch syndrome (marshawn lynch is a mismatch or some shit)
Non homologous end joining
Brings together 2 ends of DNA fragments to repair double-stranded breaks, No requirement for homology
Mutated in ataxia telangiectasia
DNA/RNA protein synthesis direction
DNA and RNA are read in the 3’ to 5’ diraction
DNA and RNA are both synthesized 5’ to 3’
Drugs blocking DNA replication often have modified 3’ OH, preventing addition of the next nucleotide (chain termination)
mRNA start codons
AUG (or rarely GUG)
eukaryotes: codes for methionine
prokaryotes: codes for formylmethionine (f-met)
mRNA stop codons
UGA (U Go Away)
UAA (U Are Away)
UAG (U Are Gone)
RNA polymerases
Eukaryotes RNA polymerase 1: makes rRNA RNA polymerase 2: makes mRNA RNA polymerase 3: makes tRNA Prokaryotes 1 RNA polymerase makes all 3 kinds of DNA
RNA processing
initial transcript is called heterogenous nuclear RNA (hnRNA)
Processing: capping 5’ end (7-methylguanosine cap), Polyadenylation of 3’ end, splicing out of introns
Splicing of pre-mRNA
- Primary transcript combines with snRNPs and other proteins to forms spliceosome
- Lariat-shaped (looped) intermediate is generate
- Lariat is released to precisely remove intron and join 2 exons
antibodies to spliceosomal snRNPs (anti-smith antibodies) are highly specific for SLE
Anti-U1 RNP antibodies are highly associated with mixed connective tissue disease
tRNA: T-arm and D-arm
T-arm: contains the sequence for tRNA-ribosome binding
D-arm: contains dihydrouracil acid for recognition by the correct aminoacyl-tRNA synthetase
3’ CCA is the amino acid acceptor site
Golgi does what
modifies N-oligosaccharides on asparagine
adds o-oligosaccharides on serine and threonine
adds mannose-6-phosphate to proteins for trafficking to lysosomes
I-Cell disease (Inclusion cell disease)
inherited lysosomal storage disorder
defect in phosphotransferase leading to failure of the golgi to phosphrylate mannose residues on glycoproteins leading to proteins that are secreted extracellularly rather than delivered to the lysosome
coarse facial features, clouded cornea, restricted joint movement,
small, thin, lethargic, and high plasma levels of lysosomal enzymes (hydrolases and glycosylases).
Fatal in childhood
Signal Recognition Particle
Abundant cytosolic ribonucleoprotein that traffics proteins from the ribosome to the RER.
COPI
Golgi to golgi trafficking (retrograde)
Golgi to ER
COPII
Golgi to golgi trafficking (anterograde)
Er to Golgi
Clathrin
Trans-golgi to lysosome
Plasma membrane to endosomes (receptor mediated endocytosis like LDL receptor)
Proteasome
Barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins. Defects in the ubiquitin-proteasome system are implicated in Parkinson disease.
Microtubule
Cylindrical structure composed of a helical array of polymerized heterodimers of α- and β-tubulin. Each dimer has 2 GTP bound.
Incorporated into flagella, cilia, mitotic spindles. Grows slowly, collapses quickly.
Also involved in slow axoplasmic transport in neurons.
Molecular motor proteins—transport cellular cargo toward opposite ends of microtubule tracks.
Dynein—retrograde to microtubule (+ to −).
Kinesin—anterograde to microtubule (− to +).
Drugs that act on microtubules
Microtubules Get Constructed Very Poorly
mebendazole, Griseofulvin, Colchicine, Vincristine/Vinblastine, Paclitaxel
Cilia structure
9+2 arrangement of microtubules
Axonemal dynein- ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets.
Kartagener syndrome
primary ciliary dyskinesia
immotile cilia due to a dynein arm defect
results in male and female infertility due to immotile sperm and dysfunctional fallopian tube cilia, respectively; increase risk of ectopic pregnancy. Can cause bronchiectasis, recurrent sinusitis, and situs inversus
What are the stains for intermediate fillaments:
TYPE Connective tissue Muscle Epithelial cells NeuroGlia Neurons
Connective tissue: Vimentin Desmin: Muscle Cytokeratin: Epithelial cells GFAP: Neuroglia Neurofilaments: neurons
Oubain does what
inhibits Na/K channel by binding to K+ site
Type 1 Collagen
Most common
Bone (made by osteoblasts)
Skin, Tendon, dentin, fascia, cornea, late wound repair
Type I: Bone (decrease production in osteogenesis imperfecta type I);
from fibroblasts and osteoblasts
Type II Collagen
Cartilage (including hyaline), vitreous body, nucleus pulposus;
Type II: cartwolage;
Made from chondrocytes
Type III Collagen
Skin, blood vessels, uterus, fetal tissue, granulation tissue
deficient in the uncommon vascular type of ehlers danlos syndrome;
made from smooth muscle cells and endothelial cells
Type IV Collagen
Basement membrane, basal lamina, lens
Defective in Alport syndrome, targeted by autoantibodies in Goodpasture syndrome;
made from endothelial and epithelial cells
Collagen synthesis Steps
- Synthesis (RER)
- Hydroxylation (RER)- requires Vit C
- Glycosylation (RER)- Problems forming triple helix leads to osteogenesis imperfecta
- Exocytosis
- proteolytic processing
- crosslinking- problem here leads to Ehlers-Danlos
Osteogenesis Imperfecta
Genetic disorder, most commonly autosomal dominant which leads to decreased production of other wise normal type 1 collagen (won’t hydroxylate on prolines and lysines)
Blue sclera due to the translucency of the connective tissue over the choroidal veins
PROGRESSIVE hearing loss (abnormal ossicles)
dental problems due to lack of dentin
Ehlers Danlos Syndrome
Faulty collagen syntheses causing hyperextensible skin, tendency to bleed and bruise and hypermobile joints
6+types, inheritance and severity vary, autosomal dominant or recessive
Associated with joint dislocation, berry and aortic aneurysms, organ rupture
Hypermobile type: most common (lysyl hydroxylase deficiency)
classical type: mutation in type V collagen (joint and skin problems)
Vascular type: deficient type III collagen
Menkes Disease
X linked recessive defect in ATP7A gene
Connective tissue disease caused by impaired copper absorption and transport.
leads to decreased activity of lysyl oxidase (copper is cofactor)
brittle kinky hair (called kinky hair disease), growth retardation, hypotonia
Elastin
rich in proline and glycine, nonhydroxylated forms
tropoelastin with fibrillin scaffolding
cross-linking takes place extracellularly and gives elastin its elastic properties
broken dwon by elastase, which is normally inhibited by alpha 1 antitrypsin
Wrinkles in aging are due to
decrease collagen and elastin production
Emphysema and elastin
Emphysema can be caused by alpha 1 antitrypsin deficiency resulting in excess elastase
Southern blot
Works with DNA
DNA is broken up, run on gel, denatured, radiolabeled, and then anneals to its complementary strand which is visualized
Northern blot
Works with RNA;
useful in studying mRNA levels;
Take mRNA and use P-cDNA probe to label it, can tell size and abundance
Western Blot
Sample proteins are separated on gel and labeled with antibodies;
Confirmatory test for HIV after a positive ELISA;
useful for identification and sizing of protein
Southwestern Blot
Identifies DNA-binding proteins like transcription factors
uses labeled oligonucleotide probes; uses P-cDNA probes like northern blots, but is looking at DNA protein interaction.
Indirect ELISA
Use a test antigen to see if a specifc antibody is present in the sample
a secondary antibody that glows is added to detect the first antibody
Direct ELISA
uses antibody to see if a specific antigen is present in the sample
a secondary antibody is coupled to a glowing enzyme that is added to detect the antigen
examples of codominance
Blood groups
Alpha 1 antitrypsin deficiency
Pleiotropy
one gene contributes to multiple phenotypic effects
PKU manifests with light skin, intellectual disability, and musty body odor
Dominant Negative Mutation
Exerts a dominant effect. A heterozygote prodeuces a nonfunctional altered protein that also prevents the normal gene product from functioning
Linkage disequilibrium
Tendency for certain alleles at 2 linked loci to occur together more often that expected by chance.
measured in a population, not in a family, varies by population
Mosaicism
Presence of genetically distinct cell lines in the same individual
Somatic mosaicism- mutation propagates through multiple tissues and organs
Gonadal mosaicism- mutation only in egg or sperm cells
McCune-Albright syndrome- genetics
Lethal disease if the mutation is somatic, survivable if the mutation is mosaic
Locus Heterogeneity
Mutations at different loci make the same phenotype
albinism
Allelic Heterogeneity
Different mutations in the same locus produce the same phenotype
Heteroplasmy
Presence of both normal and mutated mtDNA resulting in variable expression in mitochondrial inherited disease.
Uniparental disomy
Offspring receive 2 copies of a chromosome from 1 parent and 0 from the other
Heterodisomy indicates a meiosis 1 error
Isodisomy indicates a meiosis II error
Imprinting
at some loci, only one allele is active, the other is inactive. With one allele inactivated, deletion of the active allele leads to disease state
Prader-Willi Syndrome
Maternal imprinting: gene from mom is normally silent and paternal gene is deleted/mutated
Results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia
25% of cases due to paternal uniparental disomy (means two paternal genes received, both imprinted, no maternal genes)
Chromosome 15
Angelman Syndrome
Paternal imprinting: gene from dad is normally silent and maternal (chromosome 15)gene has micro deletion
results in inappropriate laughter, seizures, ataxia, severe intellectual disability
5% of cases due to paternal uniparental dismony
an angel of a man is silent
the kids are known as “happy puppets”
Autosomal dominant polycystic kidney disease
Autosomal dominant
bilateral massive enlargement of kidneys due to multiple large cysts
85% due to mutation in PKD1 (chromosome 16) (16 letters in “polycystic kidney”)
15% due to mutation in PKD2 (chromosome 4)
Familial adenomatous polyposis
Autosomal dominant
Colon becomes covered with adenomatous polyps after puberty. progresses to colon cancer if not removed
Mutation in chromosome 5 (apc gene) (polyp=5)
APC is tumor suppressor gene
fap with your hand (five fingers, chromosome 5)
Familial hypercholesterolemia
Autosomal dominant
elevated LDL due to defective or absent LDL receptor (no receptor mediated endocytosis)
leads to severe atherosclerotic disease early in life and tendon xanthomas (usually in achilles tendon)
Hereditary hemorrhagic telangiectasia
Autosomal dominant
inherited disorder of blood vessels
telangiectasia, recurrent epistaxis, skin discolorations, arteriovenous malformations, GI bleeding, hematuria
AKA Osler-Weber-Rendu syndrome
Hereditary Spherocytosis
Autosomal dominant
spheroid erythrocytes due to spectrin or ankyrin defect
hemolytic anemia, increase MCHC (mean cellular hemoglobin concentration)
treat with splenectomy
Huntingtons disease
Autosomal dominant
depression, progressive dementia, choreiform movements, caudate and putamen atrophy, and decrease levels of GABA and ACh in the brain
gene on chromosome 4, trinucleotide repeat disorder (CAG)
increase # of repeats leads to younger age of onset
Marfan syndrome
Autosomal dominant
Fibrillin-1 gene (FB1) mutation leading to connective tissue disorder affecting skeleton, heart, and eyes;
Tall, long extremities, pectus excavatum, hypermobile joints, long tapered fingers and toes, cystic medial necrosis of aorta leading to aortic incompetence and dissecting aortic aneurysms, floppy mitral valve, subluxation of the lenses
Multiple Endocrine Neoplasms (MEN)
Autosomal dominant
several distinct syndromes (1, 2A, 2B) characterized by familial tumors of endocrine glands, including pancreas, parathyroid, pituitary, thyroid, and adrenal medulla
MEN 2A and 2B are associated with ret gene - encodes receptor tyrosine kinase
RET MEN
Neurofibromatosis type 1
Neurocutaneous disorder characterized by cafe-au-lait spots and cutaneous neurofibromas
Autosomal dominant, 100% penetrance, variable expressivity, NF1 gene on chromosome 17
NF1 is a tumor suppressor gene. It normally encodes for a GAP (GTP-ase activating protein). GAPs suppresses RAS activity by making RAS hydrolyse GTP to GDP faster, reducing the amount of time RAS is in the “on” state.
Neurofibromatosis type 2
Autosomal dominant
Bilateral acoustic schwannomas, juvenile cataracts, meningiomas (meninges is dura, arachnoid, and pia mater), and ependymomas (tumor on the epithelial-like lining of the ventricular system)
NF2 gene on chromsome 22q (type 2=22)
Tuberous Sclerosis
Autosomal dominant
Neurocutaneous disorder with multi-organ involvement
numerous benign hamartomas
incomplete penetrance, variable expressivity
Von Hippel-Lindau Disease
Autosomal dominant
Disorder characterized by development of numerous tumors (cerebellar hemangioblastoma, renal cell adenoma, BILATERAL renal cell carcinoma, pheochromocytoma)
associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p) (3 letters in VHL and RCC)
VHL gene normally inhibits hypoxia inducible factor 1 alpha (HIF1alpha normally is degraded when there is oxygen present)
VHL protein is a component of ubiquitin ligase
Cystic Fibrosis-genetics
Autosomal recessive
defect in CFTR gene on chromosome 7, deletion of Phe508 most common
Cystic Fibrosis-Pathophysiology
CFTR gene encodes an ATP-gated Cl- channel that secretes Cl into lungs and GI and resorbs Cl in sweat glands
Mutation causes misfolded protein, stays in RER, decrease Cl secretion and H2O, increased Na reabsoprtion, thick mucus
Cystic Fibrosis-diagnosis
increase Cl and Na concentration in sweat is diagnostic
can have contraction alkalosis, and hypokalemia
Cystic Fibrosis- Complications
Recurrent pulmonary infections (pseudomonas)
chronic bronchitis and bronchiectasis–> reticulonodular pattern on CXR, pancreatic insufficiency, malabsorption and steatorrhea, nasal polyps, meconium ileus in newborns, infertility in males (no vas deferens or sperm)
Fat soluble vitamin deficiencies (A, D, E, K)
Cystic Fibrosis-treatment
N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins), dornase alfa (DNAse) to clear leukocytic debris
also the antidote for acetaminophen overdose
Duchenne Muscular Dystrophy
X-lined frameshift mutation–> truncated dystrophin protein –> accelerated muscle breakdown
Weakness begins in pelvic girdle muscles and progresses superiorly
Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle –> Gower maneuver
Onset before 5 years
Dilated cardiomyopathy is common cause of death
Duchenne= Deleted Dystrophin
Increased CPK, western blot and muscle biopsy diagnostic
Function of Dystrophin gene
DMD gene is longest coding region in human genome
increase chance of spontaneous mutation
dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle. connects intracellular actin to transmembrane proteins alpha and beta-dystroglycan which connect to the extracellular matrix
Becker Muscular Dystrophy
Usually X-linked point mutation in dystrophin gene without frameshift
less severe than Duchenne
onset in early adolescence or early adulthood
Deletions can cause both Becker and Duchenne
Myotonic Type 1 muscular dystrophy
CTG trinucleotide repeat expansion in the DMPK gene –> abnormal expression of myotonin protein kinase –> myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, arrhythmia
CTG repeat mutation
Fragile X syndrome
X-linked dominant defect affecting the FMR1 gene (Fragile x Mental Retardation), CGG trinucleotide repeat mutation
2nd most common intellectual disability
post-pubertal macroorchidism, long face with large jaw, large everted ears, autism, mitral valve prolapse, aortic root dilation
Xtra large testes, jaw, ears
Down syndrome
trisomy 21, nondisjunction of homologous chromosomes, huge increase if mom over 45
flat facies, intellectual disability, prominent epicanthal folds, single palmar crease, gap between 1st two toes, duodenal atresia, hirschsprung disease, congenital heart disease (atrial septal defect), Brushfield spots
Down Syndrome-Increase risk of
Increase risk of ALL, AML, alzheimer disease (>35), Atrial septal defects
Down Syndrome- findings in 1st trimester
increase nuchal translucency and hypoplastic nasal bone, serum PAPP-A is decreased, free beta-hCG is increased
Down Syndrome- Findings in 2nd trimester
quad screen shows: decrease alpha-fetoprotein, increase beta-hCG, decrease estriol, increased inhibin A
Edwards Syndrome
Trisomy 18
severe intellectual disability, rocker bottom feet, micrognathia, low set ears, clenched hands, prominent occiput, congenital heart and kidney disease.
Die in first year
Edwards findings before birth
PAPP-A and free beta-hCG are decreased in first trimester
Quad screen shows: decrease alpha-fetoprotein, decreased beta-hCG, decrease estriol, decreased or normal inhibin A
Patau Syndrome
Trisomy 13
intellectual disability, rocker bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease Death in first year
