HMG-CoA reductase family explained

Symbol:HMG-CoA_red
Hydroxymethylglutaryl-coenzyme A reductase
Pfam:PF00368
Interpro:IPR002202
Prosite:PDOC00064
Scop:1qax

In molecular biology, the HMG-CoA reductase family is a family of enzymes which participate in the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids.

There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes, while class II consists of prokaryotic enzymes .[1] [2]

Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds.[2] The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids.[3] Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.

Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA.[4] Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).

Notes and References

  1. Bochar DA, Stauffacher CV, Rodwell VW . Sequence comparisons reveal two classes of 3-hydroxy-3-methylglutaryl coenzyme A reductase . Mol. Genet. Metab. . 66 . 2 . 122–7 . February 1999 . 10068515 . 10.1006/mgme.1998.2786 .
  2. Friesen JA, Rodwell VW . The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases . Genome Biol. . 5 . 11 . 248 . 2004 . 15535874 . 545772 . 10.1186/gb-2004-5-11-248 . free .
  3. Kim DY, Bochar DA, Stauffacher CV, Rodwell VW . Expression and characterization of the HMG-CoA reductase of the thermophilic archaeon Sulfolobus solfataricus . Protein Expr. Purif. . 17 . 3 . 435–42 . December 1999 . 10600463 . 10.1006/prep.1999.1147 .
  4. Hedl M, Tabernero L, Stauffacher CV, Rodwell VW . Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases . J. Bacteriol. . 186 . 7 . 1927–32 . April 2004 . 15028676 . 374403 . 10.1128/jb.186.7.1927-1932.2004.