Lec. 1. Cholesterol chemistry and biosynthesis.

Intro.

Cholesterol is a very hydrophobic compound with 27 carbons arranged in a steroid ring + a hydrocarbon tail with an -OH on C3. It can be found in an esterified form where the -OH on C3 is replaced with a FA. Cholesterol functions:

1. Enters in the structure animal cell membranes.
2. Used to synthesize steroid hormones, bile salts, vit. D₃.

Synthesis.

~50% of the cholesterol of the body comes from from synthesis. The rest comes from the diet.

1. HMG-CoA synthesis: Two molecules of Acetyl-CoA are joined together using HMG-CoA-Synthase, and another Acetyl-CoA is added, resulting in HMG-CoA.
2. Mevalonate synthesis: HMG-CoA is reduced using HMG-CoA-Reductase to yield Mevalonate.

HMG-CoA-Reductase is the rate limiting enzyme and the major control point for cholesterol synthesis. It levels are controlled by:

1. Genetic expression.
   • Expression of HMG-CoA-Reductase is controlled by the binding of the Sterol-Regulatory-Element-Binding-Protein-2 (SREBP-2) to the Sterol Regulatory Element of the enzyme.
2. Covalent modification.
   • HMG-CoA-Reductase is active in its dephosphorylated form which results from dephosphorylation by protein phosphatase enzyme and inactive in its phosphorylated form which results from ATP-activated protein kinases.
3. Hormonal regulation.
   • Expression of HMG-CoA-Reductase can be hormonally increased by insulin and thyroxine, and decreased by glucagon and glucocorticoids.
4. Inhibition by drugs. ⭐
   • Statins are structural analogs of HMG-CoA and act as competitive inhibitors of HMG-CoA-Reductase.