HMG-CoA reductase pathway - Definition and Overview

The HMG-CoA reductase pathway, also known as MVA pathway or mevalonate-dependent (MAD) route, is an important cellular metabolic pathway present in virtually all organisms. It forms hydrophobic molecules for tasks as diverse as cell membrane maintenance, hormones, protein anchoring and N-glycosylation.

Reactions

• Acetyl-CoA (citric acid cycle) to acetoacetyl-CoA by thiolase;
• Acetoacetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) - by HMG-CoA synthase;
• HMG-CoA to mevalonate - by HMG-CoA reductase (target of statins);
• Mevalonate to mevalonate-5-phosphate - by mevalonate kinase;
• Mevalonate-5-phosphate to mevalonate-5-pyrophosphate - by phosphomevalonate kinase;
• Mevalonate-5-pyrophosphate to isopentenyl-5-pyrophosphate (IPP) - by mevalonate-5-pyrophosphate decarboxylase (see also HIDS);
• Isopentenyl-pyrophosphate is inter-converted to dimethylallyl-5-pyrophosphate - by isopentenyl-pyrophosphate isomerase

Prenyl transferase (also called farnesyl pyrophosphate synthase) catalyzes sequential condensation reactions: -

• Dimethylallyl-5-pyrophosphate reacts with isopentenyl-5-pyrophosphate to form geranyl pyrophosphate;
• Geranyl pyrophosphate itself reacts with isopentenyl-5-pyrophosphate to form farnesyl pyrophosphate

The bisphosphonates inhibit the enzyme prenyl transferase (and also geranylgeranyl pyrophosphate synthase).

• Two molecules of farnesyl pyrophosphate condense with reduction by NADPH to form squalene - by squalene synthase;
• Squalene is oxidized with further reduction by NADPH to 2,3-oxidosqualene - by squalene epoxidase;
• 2,3-oxidosqualene is converted to lanosterol - by squalene oxidocyclase;

19 further reaction steps convert lanosterol into cholesterol.

Regulation and feedback

Several key enzymes are activated through DNA transcriptional regulation on activation of SREBP (Sterol Regulatory Element Binding Protein 1 and 2). This intracellular sensor detects low cholesterol levels and stimulates endogenous production by the HMG-CoA reductase pathway, as well as increasing lipoprotein uptake by up-regulating the LDL receptor.

Pharmacology

A number of drugs targets the HMG-CoA reductase pathway:

• Statins (used for elevated cholesterol levels);
• Bisphosphonates (used for osteoporosis).

Alternative

Plants have two pathways to create Isoprenoids: this one and the methylerythritol phosphate (MEP) pathway (also called MVA independent pathway) in plastids.