cholesterol biosynthesis
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Biochemistry
- de novo synthesis of cholesterol occurs in virtually all cells, but is greatest in liver, intestine, adrenal cortex & gonads
- all of the carbon atoms in cholesterol are derived from acetate
- reducing equivalents in the form of NADPH are provided mainly by enzymes of the hexose monophosphate shunt, specifically glucose-6-phosphate dehydrogenase & 6-phosphogluconate dehydrogenase.
- the pathway of cholesterol biosynthesis occurs in the cytoplasm & on the cytoplasmic face of the smooth endoplasmic reticulum.
- the rate limiting step in the pathway is the formation of mevalonate from HMG CoA catalyzed by HMG-CoA reductase.
biosynthetic pathway
- cholesterol biosynthesis 1
- enzyme: acetoacetyl-CoA-thiolase
- substrate: 2 acetyl-CoA
- product: acetoacetyl-CoA + Coenzyme-A
- cholesterol biosynthesis 2
- enzyme: HMG-CoA-synthase
- substrate: acetyl-CoA + acetoacetyl-CoA + H2O
- product: HMG-CoA + Coenzyme-A
- cholesterol biosynthesis 3*
- enzyme: HMG-CoA-reductase
- substrate: HMG-CoA + 2 NADPH
- product: mevalonate + 2 NADP
* rate-limiting step
- cholesterol biosynthesis 4
- enzyme: mevalonate kinase
- substrate: mevalonate + ATP
- product: mevalonate-5-phosphate + ADP
- cholesterol biosynthesis 5
- enzyme: phosphomevalonate kinase
- substrate: mevalonate-5-phosphate + ATP
- product: 5-pyrophosphomevalonate + ADP
- cholesterol biosynthesis 6
- enzyme: pyrophosphomevalonate decarboxylase
- substrate: 5-pyrophosphomevalonate + ATP
- product: isopentenyl pyrophosphate + ADP + CO2 + H2PO4-
- cholesterol biosynthesis 7
- cholesterol biosynthesis 8
- enzyme: dimethylallyltransferase
- substrate: isopentenyl pyrophosphate + dimethylallyl pyrophosphate
- product: geranyl pyrophosphate + H2P2O7=
- cholesterol biosynthesis 9
- enzyme: farnesylpyrophosphate synthase
- substrate: isopentenyl pyrophosphate + geranyl pyrophosphate
- product: farnesyl pyrophosphate + H2P2O7=
- cholesterol biosynthesis 10
- enzyme: squalene synthetase
- substrate: farnesyl pyrophosphate + NADPH
- product: squalene + NAD + 2 H2P2O7=
- cholesterol biosynthesis 11
- enzyme: squalene epoxidase
- substrate: squalene + NADPH + O2
- product: squalene epoxide + NAD + H2O
- cholesterol biosynthesis 11b
- enzyme: squalene oxidocyclase
- substrate: squalene + NADPH + O2
- product: lanosterol + NAD + H2O
- cholesterol biosynthesis 12
- enzyme: lanosterol cyclase
- substrate: squalene epoxide
- product: lanosterol
- cholesterol biosynthesis 13
- enzyme: methyl sterol oxidase
- substrate: lanosterol
- product: zymosterol
- reaction occurs on cytoplasmic face of the smooth endoplasmic reticulum
- cholesterol biosynthesis 14
- enzyme: isomerase
- substrate: zymosterol
- product: cholestadienol
- reaction occurs on cytoplasmic face of the smooth endoplasmic reticulum
- cholesterol biosynthesis 15
- enzyme: 7-dehydro-cholesterol-delta-7-reductase
- substrate: cholestadienol
- product: desmosterol
- reaction occurs on cytoplasmic face of the smooth endoplasmic reticulum
- cholesterol biosynthesis 16
- enzyme: dehydrogenase
- substrate: desmosterol
- product: cholesterol
- reaction occurs on cytoplasmic face of the smooth endoplasmic reticulum