Question

HMG-CoA reducatse is the key regulatory enzyme in the biosynthesis of cholesterol. Outline briefly the various regulatory mechanisms involving HMG-CoA reductase in cholesterol biosynthesis.

Answer 1

Regulation of cholesterol synthesis by HMG-CoA reductase:

HMG-CoA is formed by the condensation reaction involving acetyl-CoA and acetoacetyl-CoA in the presence of HMG-CoA synthase. The enzyme HMG-CoA reductase catalyzes the mevalonate formation from the HMG-CoA and it is the rate-limiting step in cholesterol biosynthesis.

Short-term regulation of HMG-CoA reductase:

Phosphorylation of HMG-CoA reductase causes inhibition of the enzyme, this phosphorylation reaction is catalyzed by the AMP-dependent protein kinase (activated by high cellular AMP levels or low ATP levels).

Long term regulation of HMG-CoA reductase:

Long term regulation is achieved by altering the synthesis of the enzyme or its degradation.

1). Degradation of HMG-CoA reductase by proteolysis: Presence of high cholesterol levels (or high mevalonate and farnesol) stimulates the degradation of HMG-CoA reductase.

2). Transcription regulation: Sterol regulatory element binding proteins (SREBP) are a group of transcription factors that regulate fatty acids synthesis and cholesterol synthesis. SREBP-2 specifically regulates cholesterol synthesis (inhibits the HMG-CoA reductase transcription when cholesterol is high and vice versa).