11.2 Synthesis of cholesterol
11.2.1 Role of the endoplasmic reticulum in the synthesis of cholesterol and of steroid hormones
11.2.2 7-Dehydrocholesterol and vitamin D3
Cholesterol occurs in animals but not in plants or fungi. These have similar sterols for similar purposes, which however cannot be converted to cholesterol. Therefore, it is essential for animals (particularly for plant-feeding ones, such as sheep, goat and vegetarians) to have a pathway for cholesterol biosynthesis. This pathway is quite complex, involving some 30 enzymes, and I don't know them all myself. We will not look at all reactions in the bisynthesis individually but only at the initial stages, up to first sterol intermediate.
The first steps of the synthesis tie in with other metabolic pathways we have seen before (Figure 11.2-1). Synthesis starts with Acetyl-CoA in the mitochondrion, which is used to synthesize hydroxymethylglutaryl-CoA (HMG-CoA). These reactions also occur in ketogenesis. However, while the entire process of ketogenesis occurs in the mitochondrion, the formation of HMG-CoA in sterol synthesis occurs in the cytosol; therefore, we have separate versions of HMG-CoA synthase in the two compartments.
All subsequent steps occur in the smooth endoplasmic reticulum. HMG-CoA reductase reduces HMG-CoA to mevalonate, which in turn is converted to various isoprene compounds. Several rounds of polymerization1 lead to the linear hydrocarbon molecule squalene, which is then converted to lanosterol. Subsequent modifications lead to cholesterol.
The reactions of the synthetic pathway are shown in Figure 11.2-2. The reaction catalyzed by HMG-CoA reductase is the first committed step, which means that from this point onwards the substrates have no2 other option than becoming a sterol. Therefore, HMG-CoA reductase is the main target of regulatory mechanisms, which in turn is being exploited in pharmacotherapy (see later).
The product of HMG-CoA reductase, mevalonate, undergoes repeated phosphorylations. One of the phosphate groups is used together with carboxylation to introduce a C=C double bond; the other ones are exploited for polymerization. The most interesting reaction is the cyclization of squalene, the final polymerization product. Following the introduction of an epoxy group, all but one of the double bonds are rearranged, resulting in the formation of the first sterol (lanosterol). Two enzymes, squalene epoxidase and squalene oxidocyclase, participate in this process.
Several more steps are required to convert lanosterol to cholesterol. The last intermediate, that is the immediate precursor of cholesterol is 7-dehydrocholesterol, which is also utilized as the precursor of cholecalciferol (see below).
1: I'm using the term loosely – the reaction mechanisms are different from typical chemical polymerization.
2: No quantitatively important one, at least. However, farnesyl-pyrophosphate is also used in the post-translational modification of membrane-associated proteins.