<p>Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [<cite idref="PUB00005115"/>]:</p><p> <ul> <li>Serine/threonine-protein kinases</li><li>Tyrosine-protein kinases</li><li>Dual specific protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)</li> </ul> </p><p>Protein kinase function has been evolutionarily conserved from <taxon tax_id="562">Escherichia coli</taxon> to human [<cite idref="PUB00020114"/>]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [<cite idref="PUB00015362"/>]. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [<cite idref="PUB00034898"/>], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [<cite idref="PUB00034899"/>].</p><p> Phosphomevalonate kinase (<db_xref db="EC" dbkey="2.7.4.2"/>)catalyzes the phosphorylation of 5-phosphomevalonate into 5-diphosphomevalonate, an essential step in isoprenoid biosynthesis via the mevalonate pathway. This pathway starts with three molecules of acetyl-CoA, which, in a series of six different enzyme reactions, are converted to isopentanyl pyrophosphate (IPP), the basic C5 isoprene unit and a common intermediate for a number of pathways including isoprenoid and cholesterol biosynthesis.There are two unrelated types of PMK. The first type belongs to the GHMP kinase and includes a eukaryotic group which is typified by <taxon tax_id="4932">Saccharomyces cerevisiae</taxon> ERG8 [<cite idref="PUB00003676"/>] and a bacterial group typified by by <taxon tax_id="1313">Streptococcus pneumoniae</taxon>PMK (MvaK2) [<cite idref="PUB00015730"/>]. The second type includes animal PMKs, typified by human PMK [<cite idref="PUB00015827"/>]. PMKs of the first type are present in eubacteria, fungi, and plants, while the second type is found only in animals, indicative of a nonorthologous gene displacement early in animal evolution [<cite idref="PUB00007911"/>]. PMKs of the GHMP kinase type are closely related to mevalonate kinases. The two types of PMK have different consensus ATP-binding motifs: a protein kinase motif in the ERG8 orthologs versus a P-loop or Walker A motif in the animal orthologs. The fact that ERG8 orthologs are found in pathogenic eubacteria and fungi but not in humans makes them attractive targets for the development of antibacterial and/or antifungal drugs [<cite idref="PUB00007911"/>].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) [<cite idref="PUB00015675"/>]. 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 [<cite idref="PUB00015644"/>]. 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 [<cite idref="PUB00015644"/>]. 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 [<cite idref="PUB00015835"/>, <cite idref="PUB00015644"/>, <cite idref="PUB00015669"/>, <cite idref="PUB00015730"/>].</p> Phosphomevalonate kinase, Gram-positive