Table 1.

Short List of Candidates that May Replace the “Missing” Enzymes of Mevalonate Pathway in Archaea, Borrelia, and Gram-Positive Cocci

Missing function Suggested candidates Criteria for selection Comments
Phosphomevalonate kinase (archaea) Family of proteins related to uridylate and acetyl glutamate kinases 3258052_Pyrho Y044_METJA 2621082_Metth 2648231_Arcfu 5105458_AerpeLinked to mevalonate kinase in all archaea, similarly to the linkage observed between mevalonate kinase and phosphomevalonate kinase in Borellia and cocci; isolated phylogenetic position.A more likely candidate.
Family of orthologs within galactokinase superfamily 3258263_Pyrho 3024949_Metja 2621655_Metth 2648904_Arcfu 5105835_AerpeSequence similarity and isolated phylogenetic position within the superfamily.
Family of orthologs within galactokinase superfamily 2128859_Metja 2621895_Metth 2850101_Arcfu 5105835_AerpeSequence similarity and isolated phylogenetic position within the superfamily.No orthologs in two of three Pyrococcus species.
Family of orthologs within galactokinase superfamily YE27_METJA 3256616_Pyrho 3257645_Pyrho Y830_METTH YK89_ARCFU 5106179_Aerpe 5105197_AerpeSequence similarity and isolated phylogenetic position within the superfamily. P. horikoshii andAeropyrum have a set of paralogs, generally not seen for mevalonate pathway enzymes.
Family of orthologs within nucleoside monophosphate kinase superfamily 3257422_Pyrho 2128835_Metja 2621499_Metth 2649179_ArcfuSequence similarity and isolated phylogenetic position within the superfamily.Closer to CMP/UMP kinases and may be required for the nucleotide kinase function (judged from the numbers of paralogs with such specificity in bacterial genomes).
Diphosphomevalonate decarboxylase (archaea) Homologs (probably paralogs) of SAM decarboxylase from E. coli 5103467_Aerpe 2648951_Arcfu 2495908_Metja 3258436_PyrhoElimination of other decarboxylases in archaea, either as misannotations, or because they are predicted to have a clearly unrelated biological function.Related genes in some bacteria, but an internal deletion in archaeal genes suggests that the substrate in archaea may be different. No homolog in M. thermoautotrophicum.
Isopentenyl pyrophosphate delta-isomerase (archaea, Borrelia,cocci)FMN-dependent dehydrogenases, including glycolate oxidase (NCBI COG1304) 2688617_Borbu 5105455_Aerpe 2648236_Arcfu 1591547_Metja 2621084_Metth 3257619_PyrhoIn Borrelia,found within an “operon” with all other enzymes of mevalonate pathway; neighbors with relevant functions in some archaea. Consistent phyletic pattern, although paralogs are widespread.Oxidoreductase activity predicted by sequence similarity. In plants, some oxidoreductases are known to have a desaturase activity, which, in this case, could be exploited to isomerize the double bonds in IPP.
Uncharacterized family (NCBI COG1916) 2688316_Borbu 2650316_Arcfu 2129184_Metja 2622291_Metth 3257569_PyrhoExceptionally consistent phyletic pattern in microorganisms (Borrelia, Enterococcus, only one additional bacterium, Treponema, and archaea except forAeropyrum).In Enterococcus, plasmid-borne copy is involved in response to peptide pheromone, which controls conjugation. Orthologs in plants, C. elegans and humans.
Uncharacterized family (NCBI COG0327) 2688374_Borbu 2648773_Arcfu Y927_METJA 726074_Metth 3257033_PyrhoPhyletic pattern (archaea+ Borrelia), although orthologs are found in many bacteria.Presence of several invariant histidines suggests that this may be a metalloenzyme.
Uncharacterized family (NCBI COG0061) 2688218_Borbu 5104774_Aerpe 2650718_Arcfu 2621965_Metth 2826350_Metja 3257490_PyrhoPhyletic pattern (archaea+ Borrelia), although orthologs are found in many bacteria.Glycine-rich (phosphate-binding?) motif shared with diacylglycerol kinases and 6- phosphofructokinases.
Undecaprenyl diphosphate synthase (NCBI COG0020) UPPS_BORBU 5105068_Aerpe UPPS_ARCFU UPPS_METJA UPPS_PYRHOPhyletic pattern (archaea+ Bacteria except for Mycoplasmae), note that the DXPS-pathway bacteria may need such activity, too (see text).Multiple functions in the same pathway would have to be assumed; no biochemical evidence.
Missing function Suggested candidates Criteria for selection Comments
Geranylgeranyl pyrophosphate synthase beta-subunit 2688215_Borbu 5105454_Aerpe 4633648_Arcfu IDSA_METJA IDSA_METTH 3257488_Pyrho Phyletic pattern (archaea+ Bacteria except for Mycoplasmae), note that the DXPS-pathway bacteria may need such activity, too (see text).Multiple functions in the same pathway would have to be assumed; no biochemical evidence.
TPR-repeat proteins including geranylgeranyl pyrophosphate synthase alpha-subunit (large NCBI COG 0457)Phyletic pattern (archaea+ Bacteria except for Mycoplasmae), note that the DXPS-pathway bacteria may need such activity, too (see text).Multiple functions in the same pathway would have to be assumed; no biochemical evidence.