Disease relevance of PMVK

• The first structure of a phosphomevalonate kinase from Streptococcus pneumoniae was solved recently [1].
• GHMP kinase mutations at the conserved surface residues corresponding to Ser291 and Ala293 in phosphomevalonate kinase are linked to mevalonic acid deficiency, which can lead to early fatality, and galactokinase deficiency, which causes cataracts [2].
• Enterococcus faecalis phosphomevalonate kinase [3].

High impact information on PMVK

• Phosphomevalonate kinase catalyzes an essential step in the so-called mevalonate pathway, which appears to be the sole pathway for the biosynthesis of sterols and other isoprenoids in mammals and archea [1].
• Analysis of transcripts from human lymphoblasts subcultured in lipid-depleted sera (LDS) and LDS supplemented with lovastatin indicated that PMKase gene expression is subject to regulation by sterol at the level of transcription [4].
• Southern blotting indicated that PMKase is a single copy gene covering less than 15 kb in the human genome [4].
• The human PMKase amino acid sequence contains a consensus peroxisomal targeting sequence (PTS-1), Ser-Arg-Leu, at the C terminus of the protein [4].
• PMK catalyzes a reversible reaction; kinetic constants of human PMK have been determined for both forward (formation of mevalonate 5-diphosphate) and reverse (formation of mevalonate 5-phosphate) reactions [5].

Biological context of PMVK

• To expedite functional and structural study of this enzyme, an expression plasmid encoding His-tagged human PMK has been constructed and recombinant enzyme isolated in an active, stable form [5].
• The functions of these solvent-accessible residues were assessed by determining the effects of their substitution, via mutagenesis, on the initial-rate parameters of a representative member of the GHMP kinase family, phosphomevalonate kinase from Streptococcus pneumoniae [2].
• Phosphomevalonate kinase catalyzes the phosphorylation of phosphomevalonate to diphosphomevalonate by ATP, one of the initial steps in the biosynthesis of steroids and isoprenoids [6].
• Differential deficiency of mevalonate kinase and phosphomevalonate kinase in patients with distinct defects in peroxisome biogenesis: evidence for a major role of peroxisomes in cholesterol biosynthesis [7].
• Time series of long-term annual fluxes in the streamwater of nine forest catchments from the Swedish environmental monitoring program (PMK 5) [8].

Anatomical context of PMVK

• In addition, we demonstrate that phosphomevalonate kinase is a peroxisomal protein which requires the C-terminal peroxisomal targeting signal, Ser-Arg-Leu, for localization to the organelle [9].
• We found an exclusive cytosolic localization of both endogenously expressed human phosphomevalonate kinase (in human fibroblasts, human liver, and HEK293 cells) and overexpressed human phosphomevalonate kinase (in human fibroblasts, HEK293 cells, and CV1 cells) [10].
• Taken together, our data indicate that in human liver mevalonate kinase and phosphomevalonate kinase are truly peroxisomal enzymes which strongly suggests that peroxisomes play a major role in cholesterol biosynthesis [7].
• Microplate enzyme-coupled assays of mevalonate and phosphomevalonate kinase from Catharanthus roseus suspension cultured cells [11].

Associations of PMVK with chemical compounds

• Phosphomevalonate kinase catalyzes the conversion of mevalonate-5-phosphate to mevalonate-5-diphosphate and was originally believed to be a cytosolic enzyme [9].
• The peroxisomal targeting signals for phosphomevalonate kinase and isopentenyl diphosphate isomerase have been identified [12].
• Assay for phosphomevalonate kinase activity used pyruvate kinase and lactate dehydrogenase to couple the formation of ADP to the oxidation of NADH [3].
• In our study 1-(3,4-methylenedioxyphenyl)-2-propanone (MDP-2-P or PMK) was prepared by two different routes, i.e. by oxidizing isosafrole in an acid medium and by 1-(3,4-methylenedioxyphenyl)-2-nitropropene reduction [13].

Analytical, diagnostic and therapeutic context of PMVK

• In this study, we have determined the subcellular localization of human phosphomevalonate kinase using a variety of biochemical and microscopic techniques, including conventional subcellular fractionation studies, digitonin permeabilization studies, immunofluorescence, and immunoelectron microscopy [10].

References