InterPro domain: IPR009029

There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes ( 1.1.1.34 ), while class II consists of prokaryotic enzymes ( 1.1.1.88 ) [ 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 [ 3 ]. 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).

This superfamily represents the substrate-binding L-domain found in class I and II enzymes. The L-domain has the same structural fold in both classes of enzymes, and is unique to HMG-CoA reductases. Its topology resembles a prism, with a central alpha helix surrounded by three alpha/beta subdomains forming three roughly triangular walls [ 5 , 6 ].

1. Sequence comparisons reveal two classes of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mol. Genet. Metab. 66, 122-7
2. The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Genome Biol. 5, 248
3. Expression and characterization of the HMG-CoA reductase of the thermophilic archaeon Sulfolobus solfataricus. Protein Expr. Purif. 17, 435-42
4. Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases. J. Bacteriol. 186, 1927-32
5. Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. EMBO J. 19, 819-30
6. Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl-CoA reductase. Proc. Natl. Acad. Sci. U.S.A. 96, 7167-71