What is the Synthesis Pathway of Cholesterol in Human Body?

Cholesterol is a key component of cell membranes and is an essential precursor for steroid hormone synthesis. It can be found in our body from two different sources: it is either synthesised de novo in our cells or is taken in the form of dietary cholesterol from different food sources.

About 80% of the total cholesterol synthesis takes place in the liver and intestines; the rest being taken place in the brain, reproductive organs and adrenal glands. This article will introduce the synthesis pathway of cholesterol.

Steps of Cholesterol Synthesis

Figure 1 Synthesis Pathway of Cholesterol.[1]

The first step begins with the condensation of two acetyl CoA molecules to form acetoacetyl CoA in the presence of thiolase.

Next, another molecule of acetyl CoA binds with acetoacetyl CoA to form 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) in the presence of HMG-CoA synthase.

In the next step, HMG-CoA is reduced to mevalonate in the presence of the enzyme HMG-CoA reductase. This is a rate-limiting step of the cholesterol synthesis pathway.

Mevalonate is then converted into two active isoprenes, namely isopentenyl-5-pyrophosphate (IPP) and dimethylallyl pyrophosphate (DPP). This step is achieved by two phosphorylation and one decarboxylation reactions. ATP is also used in this step. IPP and DPP are isomers of each other.

Three molecules of IPP undergo condensation to form farnesyl pyrophosphate in the presence of geranyl transferase.

Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of the enzyme squalene synthase in the endoplasmic reticulum. Squalene is a 30-carbon compound that serves as a precursor for the synthesis of steroid hormones.

Next, squalene is cyclised to form lanosterol in the presence of oxidosqualene cyclase.

Lanosterol, a four-ring compound, then undergoes a series of reactions to form cholesterol. Lanosterol takes the Bloch or Kandutsch-Russell pathway to form cholesterol. 

Reference

[1] Chapter 6 of Cell Biology, Genetics, and Biochemistry for Pre-Clinical Students.