Hydroxymethylglutaryl-coenzyme A reductase signatures and profile

Hydroxymethylglutaryl-coenzyme A reductase (EC 1.1.1.34) (HMG-CoA reductase) [1,2] catalyzes the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA. In vertebrates, HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis. In plants, mevalonate is the precursor of all isoprenoid compounds.

HMG-CoA reductase is a membrane bound enzyme. Structurally, it consists of 3 domains. An N-terminal region that contains a variable number of transmembrane segments (7 in mammals, insects and fungi; 2 in plants), a linker region and a C-terminal catalytic domain of approximately 400 amino-acid residues.

In archebacteria [3] HMG-CoA reductase, which is involved in the biosynthesis of the isoprenoids side chains of lipids, seems to be cytoplasmic and lack the N-terminal hydrophobic domain.

Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. These bacteria use an NAD-dependent HMG-CoA reductase (EC 1.1.1.88) to deacetylate mevalonate into 3-hydroxy-3-methylglutaryl-CoA [3]. The Pseudomonas enzyme is structurally related to the catalytic domain of NADP-dependent HMG-CoA reductases.

We selected three conserved regions as signature patterns for HMG-CoA reductases. The first is located in the center of the catalytic domain, the second is a glycine-rich region located in the C-terminal section of the same catalytic domain and the third is also located in the C-terminal section and contains an histidine residue that seems [4] to be implicated in the catalytic mechanism as a general base.