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A cross-kingdom Nudix enzyme that pre-empts damage in thiamin metabolism

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Abstract
  • Genes specifying the thiamin monophosphate phosphatase and adenylated thiazole diphosphatase steps in fungal and plant thiamin biosynthesis remain unknown, as do genes for thiamin diphosphate (ThDP) hydrolysis in thiamin metabolism. A distinctive Nudix domain fused to thiamin diphosphokinase (Tnr3) in Schizosaccharomyces pombe was evaluated as a candidate for these functions. Comparative genomic analysis predicted a role in thiamin metabolism, not biosynthesis, because freestanding homologues of this Nudix domain occur not only in fungi and plants, but also in proteobacteria (whose thiamin biosynthesis pathway has no adenylated thiazole or thiamin monophosphate hydrolysis steps) and animals (which do not make thiamin). Supporting this prediction, recombinant Tnr3 and its Saccharomyces cerevisiae, Arabidopsis, and maize Nudix homologues lacked thiamin monophosphate phosphatase activity but were active against ThDP, and up to 60-fold more active against diphosphates of the toxic thiamin degradation products oxy- and oxothiamin. Deleting the S. cerevisiae Nudix gene (YJR142W) lowered oxythiamin resistance, overexpressing it raised resistance, and expressing its plant or bacterial counterparts restored resistance to the YJR142W deletant. By hydrolysing the diphosphates of damaged forms of thiamin, the Tnr3 Nudix domain and its homologues can pre-empt the misincorporation of these damaged forms into ThDP-dependent enzymes, and the resulting toxicity.
  • A podcast of Aymeric Goyer discussing his work with Andrew Hanson and colleagues on the function of a group of Nudix enzymes from fungi and plants, showing that they hydrolyse oxidized forms of the enzyme cofactor thiamin diphosphate is available from the publisher at: http://www.biochemj.org/bj/podcasts/default.htm#107981264.
  • This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the authors and published by Portland Press on behalf of the Biochemical Society. The final version of record is available at: http://www.biochemj.org/bj/default.htm.
  • Keywords: Nudix hydrolase, Vitamin B₁, Metabolite proofreading, Comparative genomics, Thiamin
  • Keywords: Nudix hydrolase, Vitamin B₁, Metabolite proofreading, Comparative genomics, Thiamin
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  • Goyer, A., Hasnain, G., Frelin, O., Ralat, M. A., Gregory III, J. F., & Hanson, A. D. (2013). A cross-kingdom Nudix enzyme that pre-empts damage in thiamin metabolism. Biochemical Journal, 454(3), 533-542. doi:10.1042/BJ20130516
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  • 454
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  • 3
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  • Supported by the U.S. National Science Foundation [grant numbers IOS-1025398 and MCB- 1153413 to A.D.H.], by an endowment from the C.V. Griffin Sr. Foundation, and by a General Research Fund grant from the Oregon State University Research Office [to A.G.].
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