Abstract
Eukarya, Archaea, and some Bacteria encode all or part of the essential mevalonate (MVA) metabolic pathway clinically modulated using statins. Curiously, two components of the MVA pathway are often absent from archaeal genomes. The search for these missing elements led to the discovery of isopentenyl phosphate kinase (IPK), one of two activities necessary to furnish the universal five-carbon isoprenoid building block, isopentenyl diphosphate (IPP). Unexpectedly, we now report functional IPKs also exist in Bacteria and Eukarya. Furthermore, amongst a subset of species within the bacterial phylum Chloroflexi, we identified a new enzyme catalyzing the missing decarboxylative step of the putative alternative MVA pathway. These results demonstrate, for the first time, a functioning alternative MVA pathway. Key to this pathway is the catalytic actions of a newly uncovered enzyme, mevalonate phosphate decarboxylase (MPD) and IPK. Together, these two discoveries suggest that unforeseen variation in isoprenoid metabolism may be widespread in nature. DOI: http://dx.doi.org/10.7554/eLife.00672.001.
Highlights
Isoprenoids constitute a substantial family of primary and secondary metabolites in all three domains of life
Through biochemical characterization of the enzymes encoded by the remaining MVA pathway genes (MDD and isopentenyl phosphate kinase (IPK)) from the Chloroflexi bacterium, R. castenholzii, we unequivocally demonstrate that a functional alternative MVA pathway does exist and is encoded in a completely unexpected manner
Within IPK, we previously identified a catalytically essential active site histidine residue that is not conserved among AAK family members belonging to the amino acid kinase superfamily (Dellas and Noel, 2010)
Summary
Isoprenoids constitute a substantial family of primary and secondary metabolites in all three domains of life. To confirm the phylogenetic analyses and identification of putative IPK genes, we overexpressed, purified, and biochemically characterized seven IPK homologs selected from all three domains of life These include the previously characterized IPK from M. jannaschii (Grochowski et al, 2006; Dellas and Noel, 2010) and homologs from two other archaeal species, Methanococcus maripaludis and Sulfolobus solfataricus (one of the few archaeal species that encodes the complete classical MVA pathway), the bacterium Roseiflexus castenholzii (an organism with an annotated MDD but no obvious PMK), and three eukaryotes, Trichoplax adhaerens (early-branching metazoan), Branchiostoma floridae (chordate), and Arabidopsis thaliana (plant). These IPK-bearing organisms all appear from previous annotations to encode genes associated with the classical MVA pathway. The model described above illustrates a logical route through which atypical MDDs may have over time attenuated MVAPP (5) substrate selectivity and acquired high selectivity for MVAP (3)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
