Flashcards in biochem: metabolism Deck (172):
used ATP to add a (high E) phosphate group
adds inorganic phosphate w/o ATP
removes phosphate group
catalyzes redox rxns
transfers CO2 groups w/help from biotin
relocates a fxnal group w/in a molecule
fatty acid oxidation (beta-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation, ketogenesis
glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis
mitochondrial AND cytoplasmic metabolism
HUGS take two: Heme synthesis, Urea cycle, Gluconeogenesis
glycolysis rate-limiting enzyme
+: AMP, fructose-2,6-bisphosphate. -: ATP, citrate
gluconeogenesis rate-limiting enzyme
+: ATP, acetyl-CoA. -: AMP, fructose-2.6-bisphosphate
TCA cycle rate-limiting enzyme
TCA cycle regulators
+: ADP. -: ATP, NADH
glycogenesis rate-limiting enzyme
+: G6P, insulin, cortisol. -: epinephrine, glucagon
glycogenolysis rate-limiting enzyme
+: epinephrine, glucagon, AMP. -: G6P, insulin, ATP
HMP shunt rate-limiting enzyme
HMP shunt regulators
+:NADP+. -: NADPH
de novo pyrimidine rate-limiting enzyme
carbamoyl phosphate synthetase II
de novo pyrimidine regulators
+: ATP. -: UTP
de novo purine synthesis rate-limiting enzyme
de novo purine synthesis regulators
-: AMP, inosine monophosphate (IMP), GMP
urea cycle rate-limiting enzyme
carbamoyl phosphate synthetase I
urea cycle regulators
fatty acid synthesis rate-limiting enzyme
acetyl-CoA carboxylase (ACC)
fatty acid synthesis regulators
+: insulin, citrate. -: glucagon, palmitoyl-CoA
fatty acid oxidation rate-limiting enzyme
carnitine acyltransferase I
fatty acid oxidation regulators
ketogenesis rate-limiting enzyme
cholesterol synthesis rate-limiting enzyme
cholesterol synthesis regulators
+: insulin, thyroxine. -: glucagon, cholesterol
aerobic glucose metabolism
net + 32 ATP via malate-aspartate shuttle (heart and liver), 30 net ATP via glycerol-3-phosphate shuttle (muscle)
net + 2 ATP/glucose
causes glycolysis to produce 0 net ATP. inhibits lipoic acid. -> vomiting, rice-water stools, garlic breath
activated ATP carries
activated NADH, NADPH, FADH2 carry
activated CoA, lipoamide carry
activated biotin carries
activated tetrahydrofolates carry
activated S-adenosylmethionine (SAM) carries
activated TPP carries
= product of HMP shunt. used in: anabolic processes, respiratory burst, cytochrome P-450 system, glutathione reductase
universal electron acceptors
NAD+ (from vit B3), NADP+, FAD+ (from vit B2)
NAD+ vs. NADPH
NAD+: generally catabolic, carries reducing equivalents away. NADPH: generally anabolic (e.g. steroid and fatty acid synthesis), supplies reducing equivalents
in most tissues except liver and pancreatic beta cells. low Km (high affinity), low Vmax (low capacity), not induced by insulin. + feedback inhibition by G6P.
in liver, pancreas beta cells. high Km (low affinity), high Vmax (high capacity), induced by insulin. no feedback inhibition by G6P. gene mutation associated w/maturity-onset diabetes of the young
hexokinase vs. glucokinase
both can phosphorylate glucose into G6P: 1st step of glycolysis or glycogen synthesis. low [glu], hexokinase sequesters it in tissues. high [glu], liver stores it
FBPase-2 and PFK-2 in fasting state
inc. glucagon -> inc. cAMP -> inc. PKA -> inc. FBPase-2, dec. PFK-2, less glycolysis, more gluconeogenesis
FBPase-2 and PFK-2 in fed state
inc. insulin -> dec. cAMP -> dec. PKA -> dec. FBPase-2, inc. PFK-2, more glycolysis, less gluconeogenesis
pyruvate dehydrogenase complex
mitochondrial enzyme complex linking glycolysis and TCA cycle. active in fed state. similar to alpha-detoglutarate dehydrogenase complex in TCA cycle. 3 enzymes, 5 cofactors: pyrophosphate, FAD, NAD, CoA, and lipoic acid. exercise -> inc. NAD+/NADH ratio, inc. ADP, inc. Ca 2+ -> activation of complex.
pyruvate dehydrogenase complex deficiency
causes buildup of pyruvate that gets shunted to lactate via LDH and alanine via ALT. X-linked
pyruvate dehydrogenase complex deficiency: findings
neurologic defects, lactic acidosis, inc. serum alanine. starts in infancy
pyruvate dehydrogenase complex deficiency: Tx
inc. intake of ketogenic nutrients (high fat, high lysine and leucine). Lysine and Leucine - the onLy pureLy ketogenic AAs.
4 possible products of pyruvate
alanine, oxaloacetate, acetyl-CoA, lactate
pyruvate -> alanine
via alanine aminotransferase (ALT) w/B6. alanine carries amino groups to liver from muscle. in cytosol
pyruvate -> oxaloacetate
via pyruvate carboxylase (PC) w/biotin. oxaloacetate can replinish TCA cycle of be used in gluconeogenesis. requires CO2 and ATP. in mitochondria
pyruvate -> acetyl-CoA
via pyruvate dehydrogenase (PDH) w/B1, B2, B3, B5, lipoic acid. transition from glycolysis to TCA cycle. NAD+ in, NADH, H+, and CO2 out. occurs in mitochondria.
pyruvate -> lactate
= cori cycle. via LDH w/B3. end of anaerobic glycolysis, the major pathway in RBCs, WBCs, kidney medulla, lens, testes, and cornea.
krebs cycle mnemonic
Citrate Is Krebs' Starting Substrate For Making Oxaloacetate: Citrate, Isocitrate, alpha-Ketoglutarate, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate
TCA cycle produces
3 NADH, 1 FADH2, 2CO2, 1 GTP per acetyl-CoA = 10ATP/acetylCoA (2x/glucose).
e- transport chain: ox phos
NADH electrons from glycolysis enter mitochondria via shuttles to complex I. FADH2 electrons are transferred to complex II (lower E than NADH). electron transport creates a proton gradient that is coupled w/ox phos to drive ATP production
NADH -> _ATP
FADH2 -> _ATP
electron transport inhibitor poisons
rotenone, cyanide, antimycin A, CO. directly inhibit electron transport, causing a dec. proton gradient and block of ATP synthesis
ATP synthase inhibitor poisons
oligomysin. directly inhibit mitochondrial ATP synthase, causing an inc. proton gradient. no ATP is produced b/c electron transport stops
uncoupling agent poisons
2,4-dinitrophenol (illicit wt. loss drug), aspirin (OD -> fever), thermogenin in brown fat. inc. permeability of membrane causes dec. proton gradient and inc. O2 consumption. ATP synthesis stops, but electron transport continues. produces heat.
irreversible enzymes in gluconeogensis
Pathway Produces Fresh Glucose: Pyruvate carboxylase, Phosphoenolpyruvate, Fructose-1,6-bisphosphatase, Glucose-6-phosphatase.
in mitochondria. pyruvate -> oxaloacetate. requires biotin, ATP. activated by acetyl-CoA
in cytosol. oxaloacetate -> phosphoenolpyruvate. requires GTP
in cytosol. fructose-1,6-bisphosphate -> fructose-6-phosphate. +: citrate. -: 2,6-bisphosphate
in ER. G6P -> glucose
occurs primarily in liver. maintains euglycemia during fasting. enzymes are also in kidney, intestinal epithelium. enzyme deficiency -> hypoglycemia. muscle can't do it b/c it has no G6Pase. only odd-chain fatty acids can participate, even chains can't b/c they yield acetyl-CoA instead of propionyl-CoA, which enters as succinyl-CoA
provides NADPH from G6P. also makes ribose for NA synthesis and glycolytic intermediates. 2 phases: oxidative and non-oxidative. both occur in cytoplasm in lactating mammary glands, liver, adrenal cortex, RBCs. no ATP is used or made.
oxidative phase of HMP shunt
G6P dehydrogenase converts G6P -> ribulose-5-P, yielding CO2 and 2 NADPH. rate-limiting step. irreversible
nonoxidative phase of HMP shunt
phosphopentose isomerase and transketolases convert ribulose-5-P -> ribose-5-P, G3P and fructose-6-P. reversible. requires B1
G6P dehydrogenase deficiency
can't make NADPH, so can't keep glutathione reduced, so free radicals accumulate. In RBCs, this causes hemolytic anemia, worsened by fava beans, sufas, primaquine, TB drugs, infection, inflammation. X-linked recessive. most common in AAs - inc. malarial resistance. will see heintz bodies and bite cells
defective fructokinase. autosomal recessive. benign, asymptomatic. fructose d/os are milder than analagous galactose d/os
autosomal recessive aldolase B deficiency. fructose-1-P accumulates in cells -> dec. available phosphate -> inhibition of hlycogenolysis and gluconeogenesis. Sx present after consuming fruit, juice, or honey. Udip = neg but regucing sugar can be detected in urine. Sx: hypoglycemia, jaundice, cirrhosis, vomiting. Tx: avoid fructose and sucrose
autosomal recessive. galactitol accumulates if galactose is consumed in diet. relatively mild. Sx: galactose in blood and urine, infantile cataracts, which can present as failure of social smile or object tracking
autosomal recessive absence of galactose-1-phosphate uridyltransferase. toxic falactitol and other substances accumulate. Sx: FTT, jaundice, hepatomegaly, infantile cataracts, intellectual disability, E coli sepsis (commonly fatal). Tx: exclude falactose and lactose from diet. also causes phosphate depletion.
FAB GUT: Fructose is to Aldolase B as Galactose is to UridylTransferase
= glucose's alcohol counterpart. conversion via aldose reductase traps it inside the cell. some tissues (liver, ovaries, seminal vesicles) convert sorbitol -> fructose via sorbitol dehydrogenase. other tissues (schwann cells, retina, kidneys, lens) are at risk of accumulating sorbitol -> osmotic damage: cataracts, retinopathy, peripheral neuropathy, as seen w/chronic hyperglycemia in DM.
types of lactase deficiency
primary: common. age-dependent decline after childhood 2/2 absense of lactase-persistent allele.
secondary: los of BB 2/2 gastroenteritis (e.g. rotavirus), autoimmune dz, etc.
congenital: rare, due to defective gene
Dx: stool: low pH. breath: high hydrogen content following lactose tolerance test. intestinal Bx: normal (if congenital)
Sx: bloating, cramps, flatulence, osmotic diarrhea.
Tx: avoid dairy or take lactase pills
need to be consumed in the diet.
glucogenic: methionine, valine, histidine
glucogenic/ketogenic: isoleucine, phenylalanine, threonine, tryptophan
ketogenic: leucine and lysine
aspartic acid, glutamic acid. negatively charged at normal pH
arginine (most basic), lysine, histidine (no charge at normal pH). Arg and His are required during periods of growth. Arg and Lys are used by histones to bind - charged DNA
urea cycle mnemonic
Ordinarily, Careless Crappers Are Also Frivolous About Urination: Ornithine, Citrulline, Aspartate, Argininosuccinate, Fumarate, Arginine, Urea
AA catabolism -> formation of common metabolites (e.g. pyruvate, acetyl-CoA), which serve as fuels. this process generates excess NH3, which is converted to urea and excreted renally. substrates: NH3, CO2, ATP. products: urea, AMP, fumarate. takes place in the liver
alanine transports ammonia from muscle -> liver. alanine is converted to glucose to complete cycle.
lactate (in muscle) -> lactate (in liver) -> pyruvate -> glucose (liver -> muscle) -> pyruvate -> lactate
ammonia is carried by
glutamate (w/in cells) and alanine
can be acquired (e.g. liver dz) or hereditary (e.g. urea cycle defects). -> excess NH4+, which depletes alpha-ketoglutarate, inhibiting the TCA cycle. Tx: limit protein intake. lactulose: acidified GI tract, trapping ammonia for excretion. rifampin: dec. colonic ammoniagenic bacteria. benzoate/phenylbutyrate: bind AAs -> excretion
tremor (asterixis), speech slurring, somnolence, vomiting, cerebral edema, vision blurring
N-acetylglutamate synthase deficiency
required cofactor for carbamoyl phosphate synthetase I. absense -> hyperammonemia. presents in neonates as poorly regulated respiration and body T, poor feeding, dev. delay, intellectual disability. identical presentation to carbamoyl phosphate synthetase I deficiency
ornithine transcarbamylase deficiency
X-linked (other urea cycle defects are autosomal recessive). most common urea cycle d/o. interferes w/ammonia excretion. often presents in 1st few days of life but can be later. excess carbamoyl phosphate -> orotic acid.
findings: inc. orotic acid in blood and urine, dec. BUN, Sx of hyperammonemia. NO megaloblastic anemia (vs. orotic aciduria).
tyrosine, thyroxine, melanin, dopamine, NE, epi
niacin, 5HT, melatonin
creatine, urea, NO
deficient enzyme in PKU
phenylalanine hydroxylase (phenylalanine -> tyrosine)
deficient enzyme in albinism
tyrosinase (DOPA (dihydroxyphenylalanine) -> melanin)
deficient enzyme in alkaptonuria
homogentisate oxidase (homogentisic acid -> maleylacetoacetic acid - part of tyrosine --> fumarate -> TCA cycle)
autosomal recessive. tyrosine becomes essential. if due to missing tetrahydrobiopterin cofacter, called malignant PKU. findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty odor. Tx: dec. phenylalanine (aspartame) and inc. tyrosine in diet. supplement tetrahydrobiopterin. Aromatic AA -> odor! screening 2-3 days after birth (normal levels at birth)
lack of proper dietary therapy during pregnancy -> microcephaly, intellectual disability, growth retardation and congenital heart defects in baby
maple syrup urine dz mnemonic
I Love Vermont maple syrup (trees have branches): blocked degradation of branches AAs Isoleucine, Leucine, and Valine
maple syrup urine dz
dec. alpha-detoacid dehydrogenase (B1) -> inc. alpha-ketoacids in blood (esp. of leucine) -> severe CNS defects, intellectual disability, death. Tx: restrict isoleucine, leucine, and valine in diet, supplement thiamine
= ochronosis. autosomal recessive deficiency of homogentisate oxidase -> tissue accumulation of pigment-forming homogentisic acid. usually benign. findings: dark connective tissue, brown pigmented sclerae, urine turns black when exposed to air. can cause debilitating arthralgia b/c homogentisic acid = toxic to cartilage
3 types, all autosomal recessive:
cystathionine synthase deficinecy (Tx: dec. methionine, inc. cysteine, B12, and folate in diet)
dec. affinity of cystathionine synthase or pyridoxal phosphate (Tx: inc. B6 (lots) and cysteine in diet)
homocysteine methyltransferase (methionine synthase) deficiency (Tx: inc. methionine in diet)
-> excess homocysteine. findings: lots of homocysteine in urine, intellectual disability, osteoporosis, marganoid habitus, kyphosis, downward lens subluxation, thrombosis, atherosclerosis (stroke, MI)
autosomal recessive, common defect of renal PCT and intestinal AA transporter that prevents reabsorption of COLA: Cysteine, Ornithine, Lysine, Arginine. excess urine cystine -> recurrent hexagonal kidney stones. Tx: urinary alkalinization (potassium citrate, acetazolamine), chelating agents (e.g. penicillamine) -> inc. solubility. good hydration. Dx: urinary cyanide-nitroprusside test
2 cysteines connected by disulfide bond
glycogen regulation by insulin
insulin binds tyrosine kinase dimer receptor in liver and muslce -> + glycogen synthase (glucose -> glycogen) and protein phosphatase (+ glycogen synthase, - glycogen phosphorylase). net: more glycogen
glycogen regulation by glucagon
glucagon binds receptor in liver -> +cAMP -> +PKA -> + glucogen phosphorylase kinase -> glycogen phosphorylase (glucogen -> glucose). net: less glycogen, more glucose available
glycogen regulation by epinephrine
binds beta receptor in liver and muscle -> +cAMP -> +PKA -> + glucogen phosphorylase kinase -> glycogen phosphorylase (glucogen -> glucose).
binds alpha receptor in liver -> ER releases Ca -> + glycogen phosphorylase kinase and +Ca-calmodulin in contracting muscle -> + glycogen phosphorylase kinase
net: less glycogen, more glucose available
branches: alpha-(1,6) bonds. linkages: alpha-(1,4) bonds
glycogen in skeletal muscle
glycogenolysis -> G1P -> G6P -> fuel
glycogen in hepatocytes
stored. glycogenolysis to maintain normal blood sugar. glycogen phosphorylase frees G1Ps until 4 glucose per branch, then 4-alpha-D-glucanotransferase (debranching enzyme) moves 3 G1Ps from the branch to the linkage. then alpha-1,6-glucosidase (debranching enzyme) cleaves the last glucose - everything is free!
the 1-4 glucose residues that remain on a branch after glycogen phosphorylase has shortened it
glycogen storage dzs
12 types, all causing glycogen accumulation in cells. Very Poor Carbohydrate Metabolism: Con gierke dz (type I), Pompe dz (type II), Cori dz (type III), McArdle dz (type V)
von gierke dz
autosomal recessive. Sx: severe fasting hypoglycemia, inc. glycogen in liver, blood lactate, triglycerides, uric acid, and hepatomegaly. Tx: frequent oral glucose/cornstarch, avoid fluctose and galactose. deficient enzyme: G6Pase
autosomal recessive. Pompe trashes the Pump (heart, liver, muscle). Sx: cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, early death. deficient enzyme: lysosomal alpha-1,4-glucosidase (acid maltase)
autosomal recessive. gluconeogenesis = intact. Sx: milder type I w/normal blood lactate levels. deficient enzyme: alpha-1,6-glucosidase (debranching enzyme)
autosomal recessive. Mcardle = Muscle. normal blood glucose. Sx: inc. glycogen in muscle (which can't break it down) -> painful muscle cramps, myoglobinuria w/strenuous exercise, arrhythmia from electrolyte disturbance
XR. sphingolipidosis. Sx: peripheral neuropathy of hands/feet, angiokeratomas, CV/renal dz. deficient enzyme: alpha-galactosidase A. accumulate: ceramide trihexoside
AR. most common. Sx: HSM, pancytopenia, osteoporosis, aseptic necrosis of femur, bone crises, gaucher cells (lipid-laden macrophages that look like crumpled tissue paper). Tx: recombinant glucocerebrosidase. deficient enzyme: glucocerebrosidase (beta-glucosidase). accumulate: glucocerebroside. inc. in ashkenazi
AR. sphingolipidosis. Sx: progressive neurodegeneration, HSM, foam cells, cherry-red macula. deficient enzyme: sphingomyelinase. accumulate: sphingomyelin. inc. in ashkenazi
AR. sphingolipidosis. Sx: progressive neurodegeneration, dev. delay, cherry-red macula, lysosomes w/onion skin, NO HSM. deficient enzyme: hexosaminidase A. accumulate: GM2 ganglioside. inc. in ashkenazi
AR. sphingolipidosis. Sx: peripheral neuropathy, dev. delay, optic atrophy, globoid cells. deficient enzyme: galactocerebrosidase. accumulate: galactocerebroside, psychosine
AR. sphingolipidosis. Sx: central and peripheral demyelination w/ataxia, dementia. deficient enzyme: arylsulfatase A. accumulate: cerebroside sulfate
AR. mucopolysaccharidosis. Sx: dev. delay, gargoylism, airway obstruction, corneal clouding, HSM. deficient enzyme: alpha-L-iduronidase. accumulate: heparan sulfate, dermatan sulfate
XR. mucopolysaccharidosis. Sx: mild hurler + agressive behavior. NO corneal clouding. deficient enzyme: deparan sulfate, dermatan sulfate
lysosomal storage mnemonics
No man picks his nose w/his sphinger. tay-saX lacks heXosaminidase. hunters see clearly and aggressively aim for the X.
fatty acid synthesis
SYtrate: SYnthesis. requires citrate transport from mitochondria to cytosol. occurs mostly in liver, lactating mammary glands, and adipose tissue. biotin = cofactor.
fatty acid degradation
CARnitine: CARnage of fatty acids. long-chain FA degradation requires carnitine-dependent transport into mitochondrial matrix.
systemic primary carnitine deficiency
inherited defect in LCFA transport into mitochondria -> toxic accumulations -> weakness, hypotonia, kypoketotic hypoglycemia
medium-chain acyl-CoA dehydrogenase deficiency
AR d/o of fatty acid oxidation -> dec. ability to break down FA -> acetyl-CoA -> accumulation of 8-10C fatty acyl carnitines in blood and hypoketotic hypoglycemia. presents in infancy or early childhood w/vomiting, lethargy, seizures, coma, and liver dysfxn. minor illness can -> sudden death so don't fast!
liver metabolizes FAs and AAs -> acetoacetate and beta-hydroxybutyrate to fuel muscle and brain. in starvation and DKA, oxaloacetate is depleted for gluconeogenesis. in alcoholism, excess NADH shunts oxaloacetate -> malate. both -> ateyl-CoA buildup, shunting glucose and FFAs -> ketone production. urine test for ketones doesn't detect beta-hydroxybutyrate
supply glucose to the brain and RBCs, preserve protein
glycolysis and aerobic respiration. insulin stimulates storage of lipids, proteins, and glycogen
hepatic glycogenolysis (major); hepatic gluconeogenesis, adipose release of FFAs (minor. glucagon and epinephrine stimulate use of fuel reserves
starvation days 1-3
blood glucose maintained by: hepatic glycogenolysis, adipose release of FFAs, muscle and liver shift fuel use from glucose to FFA, hepatic gluconeogenesis for peripheral tissue lactate and alanine and propionyl-CoA (from odd chain FAs). glycogen reserves only last 1 day. RBCs have no mitochondria - can't use ketones.
starvation days 3+
adipose stores (ketones become main fuel for brain). after these are depleted, vital protein degradation accelerates -> organ failure + death. amount stored determines survival time.
needed to maintain cell membrane integrity and to synthesize bile acid, steroids, and vit D
rate-limiting step is catalyzed by HMG-CoA reductase (induced by insulin), which converts HMG-CoA -> mevalonate. 2/3 of plasma cholesterol = esterified by lecithin-cholesterol acyltransferase (LCAT)
competitively and reversibly inhibit HMG-CoA reductase
degradation of dietary TGs in small intestine
lipoprotein lipase (LPL)
degradation of TGs circulating in chylomicrons and VLDLs. found on vascular endothelial surface
hepatic TG lipase (HL)
degradation of TGs remaining in IDL
degradation of TGs stored in adipocytes
catalyzes cholesterol esterification
cholesterol ester transfer protein (CETP)
mediates transfer of cholesterol esters to other lipoprotein particles
mediates remnant uptake. used by chylomicrons, chylomicron remnants, VLDL, IDL, and HDL (not LDL)
activates LCAT. used by chylomicrons and HDL
lipoprotein lipase cofactor. used by chylomicrons and VLDL
mediates chylomicron secretion. used by chylomicrons and chylomicron remnants
binds LDL receptor. used by VLDL, IDL, and LDL
composed of varying proportions of cholesterol, TGs, and phospholipids. LDL and HDL carry the most cholesterol. LDL transports cholesterol from liver -> tissues. HDL transports cholesterol from periphery to liver.
delivers dietary TGs to peripheral tissue. delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their TGs. secreted by intestinal epithelial cells.
delivers hepatic TGs to peripheral tissue. secreted by liver.
formed in the degradation of VLDL. delivers TGs and cholesterol to liver
delivers hepatic cholesterol to peripheral tissues. formed by hepatic lipase modification of IDL in peripheral tissue. taken up by target cells via receptor-medicated endocytosis.
mediates reverse cholesterol transport from periphery to liver. acts as a repository for apolipoproteins C and E (which are needed for chylomicron and VLDL metabolism). secreted from both liver and intestine. EtOH -> inc. synthesis.
AR. lipoprotein lipase deficiency or altered apolipoprotein C-II -> increased chylomicrons, TGs, and cholesterol in the blood -> pancreatitis, HSM, eruptive/pruritic xanthomas. NO inc. risk of atherosclerosis. creamy layer in supernatant.
IIa: familial hypercholesterolemia
AD. absent or defective LDL receptors -> inc. LDL and cholesterol in blood -> accelerated atherosclerosis (may have MI before 20), tendon xanthomas, and corneal arcus. heterozygotes (1:500) have cholesterol ~300. homozygotes (very rare) have cholesterol ~700.