Test I Flashcards
Albinism
Defective melanin synthesis - lack of pigmentation, white hair, pink skin
Homocystinuria
Defective methionine degradation - faulty bone development, mental retardation
Branched-chain ketoaciduria (Maple syrup urine disease)
Defective isoleucine, leucine, valine degradation - vomiting, convulsions, mental retardation, early death
PKU (phenylketonuria)
Defective conversion of phenylalanine to tyrosine - vomiting, mental retardation, seizures
Aspartame ingestion restricted
Typical (defective phenylalanine hydroxylase) and Atypical (defective dihydrobiopterin reductase) - atypical treated by Sapropterin (Kuvan)
Tyrosine-derived biomolecules
thyroid hormones, catecholamines, melanin, fumarate+acetoacetate
Sapropterin (Kuvan)
treats atypical PKU (caused by dihydrobiopterin reductase deficiency) - tetrahydrobiopterin analog, pushes phenylalanine hydroxylase reaction forward to convert more phenylalanine to tyrosine
Translation inhibitors of prok & euk, prok only, euk only
p+e: puromycin
p: streptomycin, tetracycline and chloro-/erythro-mycin
e: cycloheximide and diptheria toxin
Tetracycline
translation inhibitor of prokaryotes but not eukaryotes, blocks binding of aa-tRNA to A site of ribosome
Streptomycin
translation inhibitor of prokaryotes but not eukaryotes, prevents translation initiation complex from forming causes miscoding
Cycloheximide
translation inhibitor of eukaryotes by not prokaryotes, blocks translocation on ribosome
Puromycin
translation inhibitor of prokaryotes and eukaryotes, adds to polypeptide and can’t be extended, causing premature ejaculation of polypeptide fro ribosome
Diptheria toxin
kills cells - blocks eukaryotic translation, blocks translocation on ribosome by adding ADP-ribosyl to EF2, causes cell death
Polio virus mechanism
causes proteolysis of cap binding protein (eIF4E) for host mRNA, allowing its own mRNA to be translated by host machinery
Diseases from premature termination of translation
CF (CFTR - Cystic Fibrosis Transport Regulator), beta-thalassemia (beta globin), DMD (Duchene Muscular Dystrophy - dystrophin), Hurler Syndrome
miRNAs
21-25 nts long, affect expression of 60% of protein encoding genes, often bind 3’UTR of mRNAs (though can affect RNAs involved at any point), usually act by degrading mRNA - though some cases of activating translation have been reported
CF
most common cause: deletion of F508 in CFTR - gets marked for degradation by proteosome via ERAD even though protein is often still functional -> possible treatment: inhibit Aha1 to prveent ERAD & save some CFTR
vCJD
variant Creutzfeld-Jakob Disease - psychiatric problems, behavioral changes, painful sensations - prion disease, bovine spongiform encephalopathy (BSE / madcow)-like prions - alpha to beta reversible interconversion normally, and in disease a beta crystal induces other alpha helices to convert to beta sheets & beta aggregates form
hemophilia A
congenital bleeding disorder of varying severity - deficient or defective Factor VIII in clotting
ALS - Amyotrophic Lateral Sclerosis (Lou Gherig’s Disease)
muscle weakness, spasms, difficulty speaking, eventually death - mutated SOD1 (Cu/Zn superoxide dismutase), functional dimers don’t form, leading to aggregation
M2-PK / Warburg effect
M2PK converted in cancers to two dimers instead of normal tetramer, preventing PEP->pyruvate, allowing redirection to pentose phosphate pathway
Prader-Willi Syndrome
intellectual impairment, behavior/eating disorders, delayed/incomplete puberty - Maternal imprinting, deletion on portion of paternal chromosome 15
Angelman Syndrome
excitable, ataxia, hyperactive, delayed development, mentally retarded, speech impairment, microcephaly - Paternal imprinting, deletion on portion of maternal chromosome 15
I-cell disease
coarse facial features, skeletal abnormalities, mentally retarded - cannot mark proteins w/ M6P for lysosomal degredation due to defect in GlcNAc phosphotransferase
Kennedy’s Disease (Spinal and Bulbar Muscular Atrophy)
twitching, infertility, throat problems, muscle weakness - aggregation of protein w/ polyQ expansion androgen receptor (AR) in cytoplasm since nuclear importin (RAN) can’t bind -> no transcription of genes responsive to androgen hormones, X-linked neurodegenerative disorder
Penetrance and Frequency (High and Low) Examples:
HP/LF: HNPCC(colon cancer), BRCA 1 & 2 (breast cancer), MODY 1,2,3 (diabetes), α-synuclein (parkinsons disease)
LP/HF: APC I1307K (cancer), ApoE (alzheimers), Factor V Leiden(thromboembolic events/stroke), CCR5 (HIV)
Alcohol flush reaction
red flush, caused by accumulation of acetaldehyde due to point mutation in aldehyde dehydrogenase (increased Km, slower binding)
HGPS (Hutchinson-Guillford progeria syndrome)
rapid aging, stunted growth, full body hair loss - due to extra splicing inclusion (or incomplete lipidation) in lamin A
ALL (Acute Lymphoblastic Leukemia )
cancer in precursor of T/B cells, 9q/22q philadelphia chromosome rearrangement, Abl kinase gene overexpressed - treated by Imatinib (Gleevec) which inhibits Abl kinase, only long term treatment a bone marrow transplant
Holoprosencephaly
developmental abnormalities (e.g., cyclopsia), due to mutation in SHH pathway, can be caused by lack of proper cholesterol synthesis/modification (precursor to SHH)
Hurler Syndrome
skeletal abnormalities, mental retardation, heart disease - nonsense mutation in alpha iduronase, lysosomal storage disease, aggregation of GAGs/mucopolysaccharides
Beta Thalassemia
fatigue, SOB, slow growth - nonsense mutation of beta globin
Duchenne Muscular Dystrophy (DMD)
loss of muscle - nonsense mutation in dystrophin
Sickle cell anemia
fatigue, pain, frequent infections - glu-val mutation in beta chains, proteins aggregate
Bcl-xl
allows cancer cells to avoid apoptosis - changed 5’ splice site, larger protein, prevents apoptosis
BRCA1
breast and ovarian cancer - exon skipped due to mutation in ESE (exon splicing enhancer) binding site
Spinal Muscular Atrophy
neurodegeneration - introduction of hnRNP prevents inclusion of an exon, shortened protein is dysfunctional
46BR Patient
hypersensitivity to DNA-damaging agents, genome instability - defective DNA ligase I
Fanconi anemia Groups A-G
congenital abnormalities, leukemia, genome instability - impaired DNA interstrand crosslink repair
Bloom Syndrome
stunted growth, various cancers, genome instability - accessory DNA helicase affected
Werner Syndrome
premature aging, various cancers, genome instability - accessory 3’ exonuclease & DNA helicase affected
AT (Ataxia Telangiectasia)
leukemia, lymphoma, gamma ray sensitibvity, genome instability - ATM (protein kinase) affected
BRCA2
breast, ovarian and prostate cancer - homologous repair affected
XP (xeroderma pigmentosum) variant
UV sensitivity, skin cancer - translesion synthesis by DNA polymerase eta affected
XP (xeroderma pigmentosum) groups A-G
UV sensitivity, skin cancers, neurological abnormalities - NER (nucleotide excision repair) affected
MSH 2,3,6; MLH1; PMS2
colon cancer- mismatch repair affected
Tay-Sachs
mental deterioration starting @ 6 months, blindness, paralysis, death by age 4 - mutation in HEXA gene on chromosome 15, dysfunctional hexosaminidase lysosomal protein, buildup of lipids in brain
Zellweger Syndrome
death in first decade, dysfunctional peroxisomes
Cholera
diarrhea, dehydration - causes CFTR to transport lots of Cl- into intestine, Na+ and water follow - treated by isotonic saline and glucose
Marfan Syndrome
Tall, long limbs, mitral valve prolapse, aortic dissection - due to mutated fibrillin-1 protein
Primary Cilia Dyskinesia
chronic respiratory problems, otitis, infertility, ectopic pregnancy, hydrocephalus - dysfunction of cilia / flagella
EDS (Ehlers-Danlos Syndrome)
hyper-flexible skin w/ no tensile strength - due to mutations in collagen types I and III
MERRF (Myoclonic Epilepsy w/ Ragged Red Fibers)
epilepsy, ataxia, weakness, dementia - mitochondrial disorder, mutation in mitochondrial lysine tRNA prevents ATP production
LHON (Leber’s Hereditary Optic Neuropathy)
degeneration of retinal ganglion cells, predominantly in young males - mitochondrial disorder
Azidothymidine (AZT)
deoxythimidine analog, toxic but taken up by HIV 100 times faster - NRTI
Methotrexate
inhibits DNA synthesis (anti-cancer drug) - dihydrofolate reductase inhibitor, folic acid analog, blocks dTMP synthesis from dUMP - directly inhibits pyrimidine synthesis, indirectly inhibits purine synthesis
MG98
DNMT1 inhibitor - cancer treatment
Decitabine
global DNMT inhibitor - cancer treatment
Azacitidine
global DNMT inhibitor - cancer treatment
Rapamycin
activates autophagy
Aspirin
irreversible inhibitor of COX-1 - NSAID
Penicillin
irreversible inhibitor of bacterial transpeptidase (enzyme that forms crosslinks in bacterial cell wall) - a beta-lactam antibiotic
Fluorouracil
irreversible “suicide” inhibitor of thimidylate synthase, uracil analog, inhibits thymidine synthesis and thus DNA replication - cancer therapy drug
Allopurinol
inhibits xanthine oxidase, analog of hypoxanthine, reduces uric acid production - treatment for Gout
Dexrazoxone
Topo-II inhibitor, prevents it from detaching from dsDNA
Camptothecin
Topo-I inhibitor, leads to apoptosis
Cisplatins
covalently binds DNA, intra-/inter-/protein-crosslinks (G-G crosslinks and kinks stall DNA repair), causes apoptosis - cancer treatment
Bleomycins
ss and ds DNA breaks in presence of O2 and Fe(II)
Phenoxazone Ring (e.g. Dactinomycin)
inhibits (stalls) DNA transcription, planar rings intercalate, side chains bind minor groove
Kartagener’s Syndrom
absence of dynein arms - type of PCD (primary ciliary dyskisesia)
Young’s Syndrome
malformation of radial spikes and dynein arms - type of PCD (primary ciliary dyskinesia)
Anthracyclins (e.g., Doxorubicin)
block DNA replication - inhibits Topo-II, histone eviction
Gentamicin
stop codon bypass - inhibits release factor @ stop codon in translation - treats Duchenne Muscular Dystrophy (nonsense mutation in dystrophin gene)
Classify these proteases: Chymotrypsin, HIV protease, Thermolysin, Trypsin, Renin, Papain.
[What is the role of the main functional piece of each type of protease?]
Serine: Trypsin and Chymotrypsin [Ser = catalytic and covalent]
Cysteine: Papain [Cys = cat. and cov.]
Aspartyl: HIV protease and Renin [Asp = cat. only]
Metallo: Thermolysin [ion = cat. only]
HIV protease inhibitors, Statins and Methotrexate are what type of inhibitors?
Tight binding
5-Fluorouracil, Penicillin & Aspirin are what type of inhibitors?
Irreversible
The 4 places proteins can go from free ribosomes in cytosol:
Nucleus, ER, Mitochondria, Cytosol
Alzheimer’s, Parkinson’s, Huntington’s, ALS, CJD, SSA cardiomyopathy, Type II Diabetes can all be caused by:
Protein Aggregation
CF, Marfan syndrome, Fabry disease, Gaucher’s disease, Retinitis pigmentosa, Cancer can all be caused by:
Protein Misfolding (CFTR, Fibrillin-1, alpha galactosidase, beta-glucocerebrosidase, rhodopsin, p53)
Mediates entry of proteins from cytosol into mitochondrial matrix
TIM/TOM complex (proteins have N-terminal amphipathic helix, + charge on one end, hydrophobic on the other)
HGPS, SMA, Cancer (CD44, BRCA1, & Bcl-xl) can all be caused by:
mutations producing incorrect splicing (BRCA1->breast & ovarian cancer, Bcl-xl->melanoma & SCLC)
where protein glycosylation occurs
ER
Colchicine, Vinblastine, Vincristine and Nocodazole
tubulin polymerization inhibitors
Taxole
microtubuledepolymerization inhibitor
Bortezomib
proteasome inhibitor, binds catalytic site of 26S core
Chloramphenicol
prokaryotic translation inhibitor - binds 50S subunit & blocks peptidyltransferase activity
Cindamycin
prokaryotic translation inhibitor - binds 50S subunit & blocks translocation
Tamiflu
neuraminidase inhibitor - prevents influenza virus from infecting other cells
SAHA (Vorinostat)
HDAT inhibitor - increases transcription of targeted genes
