Members of a Novel Kinase Family (DUF1537) Can Recycle Toxic Intermediates into an Essential Metabolite

Jennifer J. Thiaville, Jake Flood, Svetlana Yurgel, Laurence Prunetti, Mona Elbadawi-Sidhu, Geoffrey Hutinet, Farhad Forouhar, Xinshuai Zhang, Venkateswaran Ganesan, Patrick Reddy, Oliver Fiehn, J. A. Gerlt, John F. Hunt, Shelley D. Copley, Valérie De Crécy-Lagard

Research output: Contribution to journalArticle

Abstract

DUF1537 is a novel family of kinases identified by comparative genomic approaches. The family is widespread and found in all sequenced plant genomes and 16% of sequenced bacterial genomes. DUF1537 is not a monofunctional family and contains subgroups that can be separated by phylogenetic and genome neighborhood context analyses. A subset of the DUF1537 proteins is strongly associated by physical clustering and gene fusion with the PdxA2 family, demonstrated here to be a functional paralog of the 4-phosphohydroxy-l-threonine dehydrogenase enzyme (PdxA), a central enzyme in the synthesis of pyridoxal-5′-phosphate (PLP) in proteobacteria. Some members of this DUF1537 subgroup phosphorylate l-4-hydroxythreonine (4HT) into 4-phosphohydroxy-l-threonine (4PHT), the substrate of PdxA, in vitro and in vivo. This provides an alternative route to PLP from the toxic antimetabolite 4HT that can be directly generated from the toxic intermediate glycolaldehyde. Although the kinetic and physical clustering data indicate that these functions in PLP synthesis are not the main roles of the DUF1537-PdxA2 enzymes, genetic and physiological data suggest these side activities function has been maintained in diverse sets of organisms.

Original languageEnglish (US)
Pages (from-to)2304-2311
Number of pages8
JournalACS chemical biology
Volume11
Issue number8
DOIs
StatePublished - Aug 19 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Thiaville, J. J., Flood, J., Yurgel, S., Prunetti, L., Elbadawi-Sidhu, M., Hutinet, G., Forouhar, F., Zhang, X., Ganesan, V., Reddy, P., Fiehn, O., Gerlt, J. A., Hunt, J. F., Copley, S. D., & De Crécy-Lagard, V. (2016). Members of a Novel Kinase Family (DUF1537) Can Recycle Toxic Intermediates into an Essential Metabolite. ACS chemical biology, 11(8), 2304-2311. https://doi.org/10.1021/acschembio.6b00279