All 27 carbons from cholesterol can be traced to acetate, a two-carbon precursor.

Cholesterol biosynthesis springs from a six-carbon intermediate called mevalonate (Figure 19.18). Mevalonate arises, in turn, from linkage of two acetyl-CoAs in the mitochondrion to form acetaoacetyl-CoA (4 carbons), followed by addition of another acetyl group from a third acetyl-CoA to give 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This latter compound is reduced by HMG-CoA reductase in the endoplasmic reticulum, using two NADPHs, with coincident loss of CoASH.

HMG-CoA reductase is the major regulatory enzyme in cholesterol biosynthesis. HMG-CoA reductase is controlled hormonally by insulin and glucagon and transcription and translation of the enzyme can be suppressed by the presence of cholesterol in cells. Mevalonate is converted in the cytosol to the five carbon building blocks of isoprene synthesis-isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DPP)-in the reactions shown in Figure 19.19. Subsequently, IPP and DPP form farnesyl pyrophosphate in the cytosol (Figure 19.20)

DPP + IPP <=> Geranyl Pyrophosphate + PPi

Geranyl Pyrophosphate + IPP <=> Farnesyl Pyrophosphate + PPi

Farnesyl pyrophosphate is then converted to presqualene pyrophosphate in the membrane of the endoplasmic reticulum (Figure 19.21).

2 Farnesyl Pyrophosphate <=> Presqualene Pyrophosphate + PPi

Presqualene pyrophosphate is subsequently converted to squalene, also in the membrane of endoplasmic reticulum (Figure 19.21). Subsequent reactions occur in the endoplasmic reticulum. Squalene, for example, is cyclized there to lanosterol, which is subsequently converted to cholesterol (Figure 19.22).

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