The synthesis of cholesterol is a process that involves over 30 different steps. Which step is the rate-determining step of cholesterol synthesis?1) The conversion of mevalonic acid to isopentenyl pyrophosphate2) The conversion of squalene into squalene 2,3-epoxide by squalene monooxygenase.3) The condensation of two acetyl-CoA molecules to acetoacetyl-CoA by thiolase.4) The conversion of HMG-CoA to mevalonate by HMG-CoA reductase.

The conversion of HMG-CoA to mevalonate by HMG-CoA reductase

Explanation:

Cholesterol is one of the steroids found in the cell membranes of the eukaryotes, mainly in animal cells. It has a long fatty acid chain that is derived from the acetyl CoA. Biosynthesis of cholesterol includes four steps. The first step is the condensation reaction that forms mevalonate from the three acetate residues. The mevalonate is a six-carbon substance. It is followed by the formation of the isoprene units from the mevalonate.  

The first step of the cholesterol biosynthesis that forms mevalonate from the acetate is a rate-limiting step. First, two molecules of acetyl CoA react to form acetoacetyl-CoA. It is followed by the joining of the third acetyl CoA to form HMG-CoA, a compound with six carbon atoms. The synthesis of the HMG-CoA from acetoacetyl-CoA is catalyzed by the HMG-CoA synthase. The HMG-CoA is then reduced into mevalonate, a reaction catalyzed by HMG-CoA reductase. Here, two molecules of NADPH serve as electron donors.  

The pathway of cholesterol biosynthesis is regulated by the concentration of the cholesterol present in the cell and the pancreatic hormones. Accordingly, the expression of the gene encoding HMG-CoA reductase is regulated to determine the rate of the pathway, making this step a rate-determining step.

HMG-CoA reductase is present in two alternative forms: the phosphorylated form is the inactive form while the dephosphorylated form is the active form of the enzyme.

When the cholesterol levels are high, the hormone glucagon triggers the inactive of the enzyme by its phosphorylation. This covalent modification is reversible and the enzyme is dephosphorylated under the influence of hormone insulin when the intracellular cholesterol levels are low. In this way, covalent modification of the enzyme HMG-CoA reductase regulates the cholesterol biosynthesis.  

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