Cholesterol biosynthesis occurs in practically all the tissues, but it is more active in liver and in steroid producing organs, like suprarrenal cortex and gonads.
In the Cholesterol synthesis participates enzymes from the smooth endoplasmic reticulum and the cytosol.
The main “materials” required for the synthesis of cholesterol are:
a) Acetyl CoA, whose acetyl groups provide all the carbons of cholesterol.
b) ATP, as an energy source.
c) NADPH.H+ as provider of the reduction equivalents required for the synthesis.
Cholesterol biosynthesis is a very complex process that can be studied in different steps:
I.- Mevalonate synthesis
The first reactions of the synthesis of cholesterol are similar to the reactions involved in ketogenesis:
1.- Two Acetyl CoA molecules react to form acetoacetyl CoA, in a reaction catalyzed by Beta-keto-thiolase.
2.- Acetoacetyl CoA reacts then with another molecule of Acetyl CoA to form Beta-Hidroxymethyl Glutaryl Co A (HMGCoA), in a reaction catalyzed by the HMGCoA synthase (this is a cytoplasmatic enzyme with an activity similar to the mitochondrial enzyme that participates in the ketogenesis).
3.- At this point, the reactions of cholesterol and ketone bodies synthesis diverge: while in ketogenesis HMGCoA is split, during the formation of cholesterol the HMGCoA is reduced by the enzyme HMGCoA reductasa, an enzime located in the Smooth Endoplasmic Reticulum, but with the active site oriented to the cytosol.
This enzyme use NADPH.H+ as reducing agent, and it is the key enzyme in the control of cholesterol biosynthesis, since it is inhibited physiologically by cholesterol and pharmacologically by statins, as will be discussed later.
II.- Conversion of Mevalonate to active isopren units.
Three consecutive phosphorylation (catalyzed by Kinases), using ATP as (P) donor, followed by a decarboxylation and a dephosphorylation, produce the active forms of isoprene, Isopentenyl pyrophosphate and its isomer, dimethylallyl pyrophosphate:
III. – Condensation of active isoprene units and formation of Squalene.
Active isoprene units can follow different pathways in the metabolism. In humans they follow mainly the synthesis of Cholesterol and synthesis of CoQ.
For the synthesis of Cholesterol:
Dimethyl allyl (P)~(P) + isopentenyl (P)~(P)-à Geranyl (P)~(P)
Geranyl (P)~(P) +Isopentenyl (P)~(P)à Farnesyl (P)~(P)
Farnesyl Pyrophosphate can bind to proteins to anchor them to the plasma membrane (prenylation), or continue in the synthesis of Cholesterol by binding to another molecule of Farnesyl (P)~(P), in a reaction catalyzed by Squalene Synthase, that also requires NADPH.H+ as donor of reduction equivalents:
Farnesyl (P)~(P) + Farnesyl (P)~(P)+ NADPH.H+ à Squalene +NADP+ + 2 (P)~(P)
Squalene (30 C) already has all the carbon atoms required for the synthesis of Cholesterol (27 C). Next reactions will close the rings to form the Sterane system of rings that is characteristic of Cholesterol.
IV.-Squalene Cyclization and transformation in Cholesterol.
Squalene is oxidized in a reaction catalyzed by an oxido squalene cyclase enzyme and converted to the first metabolite that shows the system of rings of steroid compounds: Lanosterol. This compound, besides showing this characteristic system of rings, also present already the hydroxyl in C3 that is frequent in steroid compounds (the introduction of this hydroxyl ring requires NADPH.H+).
A sequence of around 20 reactions will convert Lanosterol to Cholesterol.
Regulation of the synthesis of Cholesterol will be considered in a specific post devoted to this topic.