InterPro domain: IPR005935

This group of enzymes belongs to the GHMP kinase domain superfamily. GHMP kinases are a unique class of ATP-dependent enzymes (the abbreviation of which refers to the original members: galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase) [ 1 ]. Enzymes belonging to this superfamily contain three well-conserved motifs, the second of which has the typical sequence Pro-X-X-X-Gly-Leu-X-Ser-Ser-Ala and is involved in ATP binding [ 2 ]. The phosphate binding loop in GHMP kinases is distinct from the classical P-loops found in many ATP/GTP binding proteins. The bound ADP molecule adopts a rare syn conformation and is in the opposite orientation from those bound to the P-loop-containing proteins [ 3 ]. GHMP kinases display a distinctly bilobal appearance with their N-terminal subdomains dominated by a mixed beta-sheet flanked on one side by alpha-helices and their C-terminal subdomains containing a four stranded anti-parallel beta-sheet [ 3 , 4 , 4 , 5 ].

Diphosphomevalonate decarboxylase (mevalonate pyrophosphate decarboxylase, ( 4.1.1.33 ) catalyzes the decarboxylation of mevalonate pyrophosphate to isopentyl pyrophosphate (IPP) [ 6 ], the last step in the synthesis of IPP in the mevalonate pathway. In archaea, an alternate pathway involves decarboxylation of mevalonate monophosphate instead of diphosphomevalonate [ 7 ]. Mevalonate is a key intermediate in the biosynthesis of sterols and non-sterol isoprenes in the mevalonate pathway. In mammals, the majority of mevalonate is converted into cholesterol. ATP + (R)-5-diphosphomevalonate = ADP + phosphate + isopentenyl diphosphate + CO2

The classical mevalonate (MVA) pathway involves decarboxylation of mevalonate diphosphate, while an alternate pathway involves decarboxylation of mevalonate monophosphate. The enzyme responsible is known as phosphomevalonate decarboxylase [ 8 ].

1. Convergent evolution of similar enzymatic function on different protein folds: the hexokinase, ribokinase, and galactokinase families of sugar kinases. Protein Sci. 2, 31-40
2. Structure and mechanism of homoserine kinase: prototype for the GHMP kinase superfamily. Structure 8, 1247-57
3. Molecular structure of galactokinase. J. Biol. Chem. 278, 33305-11
4. Crystal structure of 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase, an enzyme in the non-mevalonate pathway of isoprenoid synthesis. J. Biol. Chem. 278, 30022-7
5. Crystal structure of the Streptococcus pneumoniae phosphomevalonate kinase, a member of the GHMP kinase superfamily. Proteins 47, 568-71
6. Mechanism of mevalonate pyrophosphate decarboxylase: evidence for a carbocationic transition state. Biochemistry 33, 13355-62
7. Identification in Haloferax volcanii of Phosphomevalonate Decarboxylase and Isopentenyl Phosphate Kinase as Catalysts of the Terminal Enzymatic Reactions in an Archaeal Alternate Mevalonate Pathway. J. Bacteriol.