Biochem Flashcards
AAs in histones
Lysine and arginine, positively charged to hold DNA
Histone Structure
H2A, H2B, H3, H4 (2ea) form the histone - 10nm fiber
Recall the 10nm fiber is vulnerable to endonucleases
H1s condense to 30nm
Name the purines
A, G
Name the pyrimidines
C,U,T
Lesch-Nyhan Syndrome
Defective purine salvage due to absent HGPRT
Build up of uric acid
XLR
Intellectual Disability, self-mutilation, aggression, hyperurecemia, gout, dystonia
HGPRT Function
Converts hypoxanthine to IMP, Guanine to GMP
Purine Salvage pathway
Defect of nucleotide excision repair
Xeroderma pigmentosum
no repair of pyrimidine dimers due to UV light
Defect of DNA mismatch repair
HNPCC - Chr5
Defect in phosphotranferase -> failure of Golgi to phosphorylate mannose residues
I-cell disease
Proteins are secreted rather than targeted to the lysosome
Course facial features, clouded corneas, restricted joint movement, high plasma lysosomal enzymes
Fatal in childhood
ADPKD
Bilateral, massive enlargement of the kidneys due to multiple large cysts
AD
85% mutation in PKD1 - Chr16
15% mutation in PKD2 - Chr4
Familial Adenomatous Polyposis
Colon has 1000’s of polyps -> 100% progression to colon cancer unless resected
AD
Chr5
Familial Hypercholesterolemia
Elevated LDL b/c absent LDL receptors -> severe atherosclerosis in early life, tendonous xanthomas
AD
Hereditary spherocytosis
Spheroid RBCs due to absent ankyrin or spectrin -> hemolytic anemia
AD
Treatment: splenectomy
Marfan Syndrome
Fibrillin-1 mutation -> connective tissue disorder
tall w/ long extremities, hypermobile joints, cystic medial necrosis of the aorta, dissections, floppy valves, lens subluxations
AD
NF1
Chr17
cafe-au-lait, cutaneous neurofibromas
AD, variable expression
NF2
Chr22
bilateral acoustic schwannomas, juvenile cataracts, meningiomas, ependymomas
AD, variable expression
von Hippel-Lindau
Multiple tumors, benign and malignant
VHL gene on Chr3
AD
Fragile X Syndrome
Defect in methylation and expression of FMR1 gene due to CGG repeats on X
2nd most common cause of genetic intellectual disability
enlarged testes, long face w/ large jaw, large ears, autism,
mitral valve prolapse
Trisomy 21
Down Syndrome
Flat facies, epicanthal folds, single palmar crease, gap between toes, duodenal atresia, Hirschsprung’s, ostium primum ASDs, ALL, Alzhiemer’s
Most cases due to meiotic non-disjunctions
Trisomy 18
Edwards Syndrome
severe intellectual disability, rocker bottom feet, low set ears, clenched hands
Trisomy 13
Patau Syndrome
severe intellectual disability, rocker bottom feet, cleft lip/palate, polydactyly
Biochemical action of Glucagon
Phosphorylate Stuff!!! through PKA on Ser, Thr
Biochemical action of Insulin
Dephosphorylate stuff!!! TK receptors
TLCFN
Cofactors required by PDH and alpha-ketoglutarateDH Thiamine (B1) Lipoic Acid CoA (pantothenate/B5) Flavin (Riboflavin/B2) NAD (Niacin, B3)
Inputs to TCA Cycle
1 Acetyl CoA
3 NAD+
1 FAD+
1 GDP
Outputs of TCA Cycle
2 CO2
3 NADH
1 FADH2
1 GTP
Citrate Function, outside of TCA
used in FA synthesis, inhibits glycolysis
Succinyl-CoA Sources
VOMIT
Valine, Oddchain FA, Met, Iso, Thr
Requires B12
In excess energy states (high ATP), goes to heme synthesis
Required cofactor of transaminases?
B6 / pyridoxine
Malate shuttle
Used to get NADH into the mitochondria for ETC
Get 2.5-3 ATP per NADH (3 H+ pumps)
G3P shuttle
Used to get NADH into ETC via FADH2 (1.5-2 ATPs, uses 2 H+ pumps)
Rotenone
Blocks Complex 1 of ETC
Decreases proton gradient and ATP synthesis
Barbiturates also block Complex 1
Antimycin A
Inhibits Complex III of ETC
blocks ATP synthesis
Cyanine, CO
Block Complex IV of ETC
Decreased ATP synthesis
House fires, ‘almond breath’ for cyanide
Oligomycin
Inhibits ATP synthase, F0 subunit (channel)
No ATP production
Name some ETC uncoupling agents and explain the mechanism
2,4 DNP, high dose aspirin, thermogenin (in brown fat)
leaky membrane causes decreased H+ gradient and increased metabolism -> heat, increased O2 usage
Sources of pyruvate for gluconeogenesis
Alanine via ALT [B6]
all aa’s except leucine and lysine can eventually make pyruvate
Lactate via LDH (uses NAD+, produces NADH)
DHAP can come from FA and make glucose also
Name the enzymes unique to gluconeogenesis
Pyruvate carboxylase: in mito, pyr -> OAA
PEP carboxylase: in cyto, OAA -> PEP (induced by cortisol, leading to hyperglycemia in Cushing’s)
F1,6bisphosphatase: cyto, inhibited by F2,6BP, F16BP->F6P
G6phosphatase: cyto, G6P -> glucose, only in the liver
Aldolase B Deficiency
Fructose intolerance, AR
accumulation of F6P, causing a decrease in available phosphate -> inhibition of glycogenolysis and gluconeogenesis
hypoglycemia, jaundice, cirrhosis, vomiting after ingestion of juice, fruit, honey…
‘reducing sugar in the urine’- non-specific
Tx; avoid fructose and sucrose in the diet
Galactokinase Deficiency
Relatively mild, AR
Build up of Galactitol (via aldose reductase) -> infantile cataracts, failure to track, failure to develop social smile, galactose in blood and urine
Galactose-1-phosphate uridyltransferase deficiency
Classic Galactosemia, AR
accumulation of back-products (Galactitol) causes damage
FtT, jaundine, hepatomegaly, infantile cataracts, intellecetual disability
associated with Ecoli sepsis in neonates
Glucose-6-Phosphatase deficiency
Von Gierke’s, AR
severe fasting hypoglycemia, excess glycogen in liver (megaly), lactic acidosis
Normal glycogen
Tx: frequent oral glucose/cornstarch
Lysosomal alpha1,4-glucosidase (acid maltase) deficiency
Pompe Disease, AR
cardiomyopathy and systemic findings lead to early death
normal glycogen
Tx: ERT
Debranching enzyme (alpha16glusidase) deficiency
Cori Disease, AR
Mild hypoglycemia, nml blood lactate
short (1 residue) branches in glycogen
Skeletal muscle glycogen phosphorylase deficiency
McArdle Disease, AR
increased glycogen in muscle, but can’t break it down
painful muscle cramps, myoglobinuria
What are the essential FAs?
Linoleic (w6) and Linolenic (3) acids
Linoleic is the precursor to arachidonic acid (w6)
ApoE
Mediates remnant uptake by the liver
donated to VLDL, chylomicron by HDL
ApoA1
Activates LCAT, allows HDL to pick up peripheral cholesterol
ApoCII
Activates lipoprotein lipase
donated to VLDL, chylomicron from HDL
ApoB48
In chylomicrons from the gut
ApoB100
Binds LDL receptors
Chylomicrons
ApoB48. Gets E and CII from HDL; E allows uptake by the liver and CII activates LPL for TGs drop-off. Delivers dietary TGs to peripheral tissues, then (as a chylo remnant) delivers cholesterol to the liver
VLDL
ApoB100. Gets E and CII from HDL; E allows uptake by the liver and CII activates LPL for TGs drop-off. Delivers hepatic TGs to peripheral tissues.
IDL
Formed from degradation of VLDL (by LPL). Can deliver TGs and cholesterol to the liver or progress to LDL.
LDL
Delivers hepatic cholesterol to peripheral tissues. Formed from IDL via hepatic lipase (HL). ApoB100.
HDL
Picks up peripheral cholesterol (in vessels) and returns to the liver. Donates CII and E to chylo’s and VLDL.
Effects of increased liver cholesterol
downregulates LDL receptors leading to increased LDL in the blood
Statins work by decreasing denovo synthesis of liver cholesterol, thus increasing the number of LDL receptors and clearing LDL from the blood
Fatty Streak Formation Basics
LDL + O2 (oxidized) -> cholesterol deposits in the vessels
enhanced by O2 and turbulence: arteries > veins
also enhanced by gravity: AA at the iliac bifurcation
Smith-Lemli-Optiz Syndrome (SLO)
Mutation in DHCR7 (last step in cholesterol synthesis)
decreased cholesterol for development -> FtT, int. disability, decreased steroid hormones, problems with myelination, problems with SSH processing
Tx: high dietary cholesterol and HMG-CoA reductase inhibitors
Type I Familial Dyslipidemia - Hyperchylomicronemia
AR LPL or CII deficiency -> increased chylo’s, TGs in the blood; saturated excretion via bile leads to gallstones and recurrent pancreatitis; xanthomas
Type II Familial Dyslipidemia - Famial Hypercholesterolemia
AD absent or defective LDL receptors
accelerated atherosclerosis, tendon xanthomas, corneal arcus
Abetalipoproteinemia
no ApoB100 or ApoB48
cant absorb dietary fat: DKEA deficiencies (poor night vision, acanthocytes), steatorhea, no lineoleic acid -> no arachodonic acid products
markedly decreased TGs and cholesterol
Name the amino acids which are strictly ketogenic
leucine and lysine
Name the amino acids which can be glucogenic or ketogenic
Tyr, Trp, Phe, Ile, Thr
Symptoms of hyperammonemia?
asterixis tremor, CNS/ mental status changes, blurred vision
Increased orotic acid in the urine, decreased BUN, hyperammonemia
Ornithine transcarbamylase deficiency
ornithine + carbamoyl phosphate -> citrulline in the urea cycle
buildup of carbamoyl phasphate leads to increased orotic acid
Derivatives of Phenylalanine
Tyrosine –> Thyroxine
Tyrosine -> dopa -> melanin and dopamine
dopamine -> NE and epi
Derivatives of Tryptophan
Niacin -> NAD/NADP
Serotonin -> Melatonin
Peripheral burning neuropathy, angiokeratomas, CV/renal disease
Fabry’s; XLR
deficient in alpha-galactosidase A, build up of ceramide trihexoside
Bone marrow issues causing fractures and pancytopenia, hepatosplenomegaly
Gaucher Disease, AR
Deficient in glucocerebrosidase (beta-glucosidase)
Build up of Glucocerebroside
Neurodegeneration, cherry red spot on the macula, with hepatosplenomegaly
Niemann-Pick Disease, AR
Deficient in Sphingomylinase
Build up of sphingomyelin
Neurodegeneration, developmental delay, cherry red spot on the macula without hepatosplenomegaly
Tay-Sachs, AR in Ashkenazi Jews
Deficient in Hexosaminidase A
Build up of GM2 ganglioside
Peripheral neuropathy with optic atrophy and globoid cells
Krabbe Disease, AR
deficiency of galactocerebrosidase
build up of galactocerebroside, psychosine
central and peripheral demylination with ataxia and dementia
Metachromatic leukodystrophy, AR
Deficiency of arylsulfatase A
build up of cerebroside sulfate
developmental delay, gargoylism, airway obstruction, corneal clouding and hepatosplenomegaly
Hurler syndrome
deficiency of alpha-L-iduronidase
build up of heparan sulfate and dermatan sulfate
mild Hurler symptoms with aggressive behavior, no clouding
Hunter syndrome ‘hunters need to see’
deficiency of iduronate sulfatase
build up of heparan sulfate and dermatan sulfate
alpha-galactosidase A deficiency
Fabry’s; ceramide trihexoside
glucocerebrosidase (beta-glucosidase) deficiency
Gaucher’s Disease; glucerebroside
sphingomyelinase deficiency
Niemann-Pick; sphingomyelin
hexosaminidase A deficiency
Tay-Sachs; GM2 ganglioside
galactocerebrosidase deficiency
Krabbe; galactocerebroside, psychosine
arylsulfatase A deficiency
Metachromatic leukodystrophy; cerebroside sulfate
alpha-L-iduronidase deficiency
Hurler; heparan sulfate, dermatan sulfate
iduronate sulfatase deficiency
Hunter; heparan sulfate, dermatan sulfate
