Question

HMG-CoA reductase is a highly regulated enzyme. Identify three distinct mechanisms by which this enzyme is regulated. For each, describe the triggering event and its outcomes on HMGR levels or activity.

Answer 1

Three distinct mechanism for regualting the HMG-CoA reductase are:

• Transcription: The transcription og the reductase gene is enhanced the sterol regulatory element binding protein(SREBP). The protein binds at the sterol regulatory element(SRE), which is found at the 5' end of the gene after the controlled proteolytic processing. In its inactive state SREBP is bound to ER or the nuclear membrane along with another protein known as the SREBP cleavage-activating protein(SCAP). SCAP when senses low cholesterol concentration it transports SREBP to the Golgi membrane. Here after consecutive proteolysis carried out by S1P and S2P, SREBP is cleaved into an active form: nSREBP. These nSREBP's now migrate to the nucleus and activate the transcription of SRE-containing genes. nSREBP are short lived transcription factors. Once the cholestrol level rises, Insigs retains the SCAP-SREBP complex in the ER, by preventing it from incorporating in the COPII vesicles.
  
• Degradation: If the level of sterol in the body is rising, the susceptibility of reductase enzyme to ER-associated degradation and proteolysis also increases.Helixes 2 to 6 of the enzyme's transmembrane domain are considered to sense the increasing level of cholestrol. Lysine residues get ubiquinated by E3 ligases and hence its degradation follows.
  
• Phosphorylation: This is the short term pathway for the regulation of HMG-CoA reductase enzyme. It is phosphorylatyed and inactivated by the action of an AMP-activated protein kinase. Phosphorylation and inactivation of acetyl-CoA carboxylase also occurs through this protein kinase; Thus acetyl CoA is utilized in both the pathways vor lipid synthesis, when energy charge is low in cells and AMP concentration rises.