week one Flashcards
How to measure stability of a protein; calculated Kf and delta G
Kf=equilibrium constant, concentration (folded)/concentration (unfolded); delta G= -RTln(Kf)
Protein Misfolding diseases: Alzheimers, DM, Parkinson’s
amyloid diseases; mutation causes aggregation of Beta sheets stabilized by Phe to form a cross beta structure (amyloid fibers) that precipitates
Prion Diseases
progressive dementia, cognitive impairment, impaired muscle movements; Mad Cow, Creutzfeldt-Jacob; prion-infectious agent is misfolded protein- key change of Prion alpha helix to beta sheets that form insoluble amyloid cross linked Beta structure that is resistant to proteases (can’t be broken down)- recruits our own beta rich proteins and results in oligomerization
Lamin Associated Diseases (Laminopathies)
ex. Hutchinson Gifford Progeria Syndrome- see pre-mature aging and early death (usually by mid-teens)
mutation in Lamin A-Lamin A is always farnesylated- causes permanent attachment to nuclear membrane; integrity of nucleus is compromised and disrupted attachment of chromatin to lamina
cyclin D1b mutation
affects its NES, usually cyclin D is shuttled out of nucleus at end of S phase to make sure DNA replication isn’t repeated; can’t get out of nucleus-leading to cancer
Mutation in RB
brake between G1 and S; normally cyclin-CDK complex phosphorylates to inactive it; mutations in cancer can remove this regulation and delete the RB brake- cell will progress through cell cycle even without signal
Lysosomal storage diseases
Tay Sachs, Gaucher; deficiency in a lysosomal enzyme causes cellular debri to accumulate to toxic levels and affects cell functioning-leading to cell death
Topoisomerase drugs
antibacterials (quinolones) target bacterial topoisomerase- leads to death of bacterial cells; chemotherapy drugs (etoposide) inhibit topoisomerase- cut DNA can’t be ligated back together leading to cell death; cancer cells are replicating more so you see more cancer cell death than normal cell death, but you are killing a portion of your own cells as well
telomerase inhibitor
treatments aimed at reducing telomerase activity which is often over-expressed in cancer cells, tying in to their immortality; targeting telomerase could lead to cancer cell death (but also normal cell death)
Sickle cell disease
anemia due to loss/impaired hemoglobin in RBCs; missense mutation in the beta-globin gene replaces Glu (acidic) with Val (hydrophobic) which causes clumping/polymerization of deoxygenated Hb molecules- sickled shape can occlude capillaries and produce pain
Thalassemia syndromes
complete absence of alpha and beta hemoglobin or reduced amounts of normally functioning Hb proteins due to nonsense mutation- truncated protein has zero function-normal Hb quaternary structure not made-SEVERE anemia-small, misshapen RBCs, life threatening
Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer)- HNPCC
form of colon cancer due to DNA mismatch repair gene defect in the MSH or MLH gene; autosomal dominant- one mutant copy enough for disease phenotype; if you don’t have machinery to fix mismatch, then mutations will remain and could get mutation in cell division regulatory gene- leads to cancer; colon tissue has high cellular renewal rate meaning lots of cell division and more room to make errors
Cisplatin (CDDP)-DNA cross linking agent
damages DNA by causing DNA strand breaks during replication; used to treat many cancers, chemotherapy drug that causes DNA damage on purpose, targeted more at the rapidly dividing tumor cells
Xeroderma Pigmentosum
mutation in enzymes involved in nucleotide excision repair; unable to repair DNA damage caused by sun/radiation- leads to early onset of skin damage and skin cancer
genetic anticipation
disease shows up progressively earlier and increased severity as it is passed from generation to generation as a result of triplet repeats building up; when the trinucleotide repeats invade the protein coding region, can have adverse effects/change the protein that is produced; ex. Huntington’s disease
Edwards Syndrome
trisomy 18; fatal condition with many side effects- cleft palate, microcephaly, severe developmental delays; usually die within the first year or so of life
Pellagra
lack of niacin-obtain from diet, used to make NAD/NADH; if diet is deficient or take a TB drug that blocks niacin production, get the 4 D’s: dermititis, diarrhea, dementia, death
Essential Fructosuria
defect in fructokinase means that fructose won’t be phosphorylated and is able to diffuse out of the cell (no neg. charge) and leave the body through the urine; benign condition
Hereditary Fructose Intolerance
defect in aldolase B leads to accumulated of F1P, which is now stuck in the liver because the phosphorylation gives it a negative charge; fructokinase reaction is very fast so F1P accumulates rapidly; F1P inhibits glycogen degredation- all Pi is trapped in the F1P molecule meaning other enzymes that require P to work aren’t functioning—non-functioning aldolase impairs gluconeogenesis leading to hypoglycemia; lactic acidosis due to blocked gluconeogenesis (lactate can’t be converted back to glucose) and high AMP leads to uric acid production (purine degradation) which blocks lactate release from blood into kidney
Classical Galactosemia
defect in Galactose-1-P Uridyl Transferase means you get buildup of Gal1P, which is toxic and leads to irreversible mental disability; buildup up galactose is converted to galactisol which accumulates in eye and causes water to flow in, leading to cataracts; hypoglycemia results due to inhibition of Gal1P on phosphoglucomutase (major enzyme in glycogen degradation); treatment is avoiding lactose
Non-classical galactosemia
defect in galactokinase leads to buildup of galactose and its alcohol product galactitol, which leads to cataract formation; no G1P buildup so no hypoglycemia or mental impairment; treatment is avoiding lactose
GLUT1 deficiency
Glucose transporter for RBCs and to cross the BBB; lack of GLUT1 means that not enough blood is able to get into the brain; leads to nervous system and movement problems (seizures, developmental delay, etc); autosomal dominant- meaning you need two good copies of gene to have enough GLUT1; treat with high fatty acid diet (ketogenic) so you are forcing brain to use ketone bodies as fuel
Cholera toxin
use NAD+ to ADP-ribosylate the G protein target, Arg residue accepts this ribosylation; for Gs protein, this ribosylation blocks GTPase activity, meaning the alpha G protein subunit remains active (attached to GTP) and adenyl cyclase also activated–> PKA active–>Cystic Fibrosis Membrane Regulator–> influx of ions and water into lumen of intestines–> diarrhea
Pertussis toxin
like cholera, G protein is ADP-ribosylated, which for the Gi protein blocks GTP displacement of GDP, meaning that Gi is never activated and adenyl cyclase is never inhibited
