Biochemistry Molecular II
Cholesterol Synthesis
Copyright 1999-2008 by Joyce J. Diwan. All rights reserved.
O
OH CH2 C CH3 CH2
O C SCoA
O
C
hydroxymethylglutaryl-CoA
Hydroxymethylglutaryl-coenzyme A (HMG-CoA) is the precursor for cholesterol synthesis. HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-CoA. The enzymes for ketone body production are located in the mitochondrial matrix. HMG-CoA destined for cholesterol synthesis is made by equivalent, but different, enzymes in the cytosol.
O H2 O + O H3C SCoA HSCoA O
O
C
acetoacetyl-CoA HMG-CoA Synthase
OH O CH2 C SCoA
CH2
C
SCoA
acetyl-CoA
H3 C
C
O
C
CH2
C CH3
hydroxymethylglutaryl-CoA
HMG-CoA is formed by condensation of acetyl-CoA & acetoacetyl-CoA, catalyzed by HMG-CoA Synthase. HMG-CoA Reductase catalyzes production of mevalonate from HMG-CoA.
The carboxyl of HMG that is in ester linkage to the CoA thiol is reduced to an aldehyde, and then to an alcohol. NADPH serves as reductant in the 2-step reaction. Mevaldehyde is thought to be an active site intermediate, following the first reduction and release of CoA.
HO H2C
C
CH3 CH2 C O SCoA
O
C
O
HMG-CoA
2NADPH 2NADP+ + HSCoA HO H2C
HMG-CoA Reductase
CH3 CH2 O H2 C OH
C
O
C
mevalonate
HMG-CoA Redu...
20-cholest