Cholesterol Biosynthesis Flashcards
Cholesteryl ester
cholesterol + fatty acid (hydrophobic)
LIver and cholesterol
Sources: chylomicron remnants; cholesterol syntesized in extrahepatic tissues (HDL); de novo syntiesis
How it leaves: free cholesterol in bile, VLDLs, Bile salts/acids
Cholesterol
4 rings, 27 carbons, amphipathic (barely, enough to be in membrane)
Requirements of cholesterol synthesis
Ac-CoA, NADPH, ATP
Rate limiting step of cholestrol synthesis
HMG CoA reductase
Thynthesis of HMG-CoA
Thiolase
2 Ac-CoA ———–>Acetoacetyl-CoA
HMG-CoA synthase Acetoacyl-CoA + Ac-CoA------------->HMG-CoA
Thiolase
aka Ac-CoA acyltransferase
2 Ac-CoA–>acetoacetyl CoA + CoA
HMG-CoA synthase
Acetoacy-CoA + Ac-CoA—->2-hydroxy-3-methylglutaryl-CoA (HMG CoA) + CoA
HMG CoA reductase
HMG-CoA + 2 NADPH–>Mevalonate + 2 NADP+
(carbonyl–>alcohol)
Inhibited: Cholesterol, Glucagon (PKA phosphorylates), statins (competitive inhibition, over long term leads to upregulation due to low cholesterol levels), mevalonate (product inhibition), AMP kinase (high [AMP] stimulates)
Activated: Insulin
Cholesterol regulates: using product inhibition, modulating gene expression, promoting degredation
2nd Part of cholesterold biosynthesis
mevalonate + 2 ATP –>–> 5-pyrophosphomevalonate + ATP –>IPP —>DPP
Decarboxylase isomerization
Transferase
DPP + IPP-->GPP +PPi
Transferase
GPP + IPP --> FPP
Squalene synthase
2 FPP + NADPH------->Squalene
Squalene + NADPH + O2—->Lanosterol + H2O+NADP+ cyclization
Lanosterol–>–>–>Cholesterol
Also:
FPP and IPP–>dolichol or ubiquinone
FPP and GPP–>protein prenylation
All intermediates in cholesterol synthsis
Ac-CoA (2C) –>Acetoacyl-CoA (4C) –>HMG-CoA (6C) –>Mevalonate (6C) –> Pyrophosphomevalonate (6C)f–>isopentylpyrophosphate (IPP, 5C) –> 3,3-dimethylallylphyrophosphate (DPP, 5C) –> geranylpyrophosphate (10C, GPP) –> Farnsylpyrophosphate (FPP, 15C) –> Squalene (30C) –> Lanosterol (30C) –> Cholesterol (27C)
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SREBP
Sterol regulatory element binding protein:
released from ER in response to low [cholesterol]
binds to Sterol responsive element (SRE, enhancer) upregulates transcription of hmg coA reductase
SCAP
SREBP cleavage-activating protein
inhibits SREBP and therefore hmg coa reductase
LDL
in plasma: highest amount of cholesterol of any lipoprotein
taken up by endocytosis after binding LDL receptor in liver
Long term effects of statins
increased transcription/translation of hmg-CoA reductase
Upregulation of LDL receptor
increase in uptake of LDL
recudtion in serum cholesterol
ACAT
acyl-CoA:cholesterol acetyl transferase, upregulated by intracellular cholesterol
creates cholesteryl esters that are stored
SLOS
Smith-Lemli-Opitz Syndrome
7-dehydrocholesterol reductase partial deficiency (needed for forming dbl bond in ring B)
microencephaly (IQ 20-40)
Characteristic dysmorphic faces Microcephaly Syndactyly (most commonly of the second and third toes) Polydactyly Growth retardation Intellectual disability Cleft palate Hypospadias (males)
Degredation of Cholesterol
Doesn’t happen in humans
Excreted as bile salts in feces or as cholestanol or coprostanol (modified by intestinal flora)
7-alpha-hydroxylase
Rate limiting step in bile acid synthesis (adds OH to carbon 7)
Activated: cholesterol
Inhibited: cholic acid
Bile salts
Cholic acid and chenodeoxycholic acid conjugated with glycine or taurine to form:
glyco… or tauro…
bacteria remove hydroxyl groups to form:
deoxycholic acid, and lithocholic acid
Cholelithiasis
Bile salt deficiency-deficiency of letithin or bile saltes causes cholesterol to precipitate in gall bladder
