Phosphoglycerate mutase from Trypanosoma brucei is hyperactivated by cobalt in vitro, but not in vivo

Fazia Adyani Ahmad Fuad, Linda A Fothergill-Gilmore, Matthew W Nowicki, Lorna J Eades, Hugh P Morgan, Iain W McNae, Paul A M Michels, Malcolm D Walkinshaw

Research output: Contribution to journalArticlepeer-review


Production of ATP by the glycolytic pathway in the mammalian pathogenic stage of protists from the genus Trypanosoma is required for the survival of the parasites. Cofactor-independent phosphoglycerate mutase (iPGAM) is particularly attractive as a drug target because it shows no similarity to the corresponding enzyme in humans, and has also been genetically validated as a target by RNAi experiments. It has previously been shown that trypanosomatid iPGAMs require Co2+ to reach maximal activity, but the biologically relevant metal has remained unclear. In this paper the metal content in the cytosol of procyclic and bloodstream-form T. brucei (analysed by inductively coupled plasma-optical emission spectroscopy) shows that Mg2+, Zn2+ and Fe2+ were the most abundant, whereas Co2+ was below the limit of detection (<0.035 μM). The low concentration indicates that Co2+ is unlikely to be the biologically relevant metal, but that instead, Mg2+ and/or Zn2+ may assume this role. Results from metal analysis of purified Leishmania mexicana iPGAM by inductively coupled plasma-mass spectrometry also show high concentrations of Mg2+ and Zn2+, and are consistent with this proposal. Our data suggest that in vivo cellular conditions lacking Co2+ are unable to support the maximal activity of iPGAM, but instead maintain its activity at a relatively low level by using Mg2+ and/or Zn2+. The physiological significance of these observations is being pursued by structural, biochemical and biophysical studies.
Original languageEnglish
Pages (from-to)1310-1317
Number of pages8
Issue number12
Early online date13 Oct 2011
Publication statusPublished - 1 Dec 2011
EventThe Third International Symposium on Metallomics 2011 - Munster, Germany
Duration: 15 Jun 201118 Jun 2011


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