HMG-CoA reductase pathway
The HMG-CoA reductase pathway 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.
Pharmacology
A number of drugs targets the HMG-CoA reductase pathway:
- Statins (used for elevated cholesterol levels);
- Bisphosphonates (used for osteoporosis).
Categories: Biochemistry