6n10
Crystal structure of Arabidopsis thaliana mevalonate 5-diphosphate decarboxylase 1 complexed with (R)-MVAPP
Structural highlights
FunctionMVD1_ARATH Performs the first committed step in the biosynthesis of isoprene-containing compounds such as sterols and terpenoids (PubMed:10344201, PubMed:26216978). Is specific for (R)-5-diphosphomevalonate (MVAPP). The catalytic efficiency with (R)-5-phosphomevalonate (MVAP) as substrate is 10000-fold lower than for MVAPP (PubMed:26216978). Can complement a yeast mutant defective in MVD activity (PubMed:10344201).[1] [2] Publication Abstract from PubMedA bifurcation of the mevalonate (MVA) pathway was recently discovered in bacteria of the Chloroflexi phylum. In this alternative route for the biosynthesis of isopentenylpyrophosphate (IPP), the penultimate step is the decarboxylation of (R)-mevalonate 5-phosphate ((R)-MVAP) to isopentenyl phosphate (IP), which is followed by the ATP-dependent phosphorylation of IP to IPP catalyzed by isopentenyl phosphate kinase (IPK). Notably, the decarboxylation reaction is catalyzed by mevalonate 5-phosphate decarboxylase (MPD), which shares considerable sequence similarity with mevalonate diphosphate decarboxylase (MDD) of the classical MVA pathway. We show that an enzyme originally annotated as an MDD from the Chloroflexi bacterium Anaerolinea thermophila possesses equal catalytic efficiency for (R)-MVAP and (R)-mevalonate 5-diphosphate ((R)-MVAPP). Further, the molecular basis for this dual specificity is revealed by near atomic-resolution X-ray crystal structures of A. thermophila MPD/MDD bound to (R)-MVAP or (R)-MVAPP. These findings, when combined with sequence and structural comparisons of this bacterial enzyme, functional MDDs, and several putative MPDs, delineate key active-site residues that confer substrate specificity and functionally distinguish MPD and MDD enzyme-classes. Extensive sequence analyses identified functional MPDs in the halobacteria class of archaea that had been annotated as MDDs. Finally, no eukaryotic MPD candidates were identified, suggesting the absence of the alternative MVA (altMVA) pathway in all eukaryotes, including, paradoxically plants, which universally encode a structural and functional homolog of IPK. Additionally, we have developed a viable engineered strain of Saccharomyces cerevisiae as an in vivo metabolic model and a synthetic biology platform for enzyme engineering and terpene biosynthesis in which the classical MVA pathway has been replaced with the altMVA pathway. Substrate specificity and engineering of mevalonate 5-phosphate decarboxylase.,Thomas ST, Louie GV, Lubin JW, Lundblad V, Noel JP ACS Chem Biol. 2019 Jul 3. doi: 10.1021/acschembio.9b00322. PMID:31268677[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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