Glycolysis occupies a central role in cellular metabolism, and is of particular importance for the catabolic production of ATP in protozoan parasites such as Leishmania and Trypanosoma. In these organisms pyruvate kinase plays a key regulatory role, and is unique in responding to fructose 2,6-bisphosphate as allosteric activator. The determination of the crystal structure of the first eukaryotic pyruvate kinase in the T-state (the inactive or ‘tense’ conformation of allosteric enzymes) is described. A comparison of the effector sites of the Leishmania and yeast enzymes reveals the structural basis for the different effector specificity. Two loops, comprising residues 443–453 and 480–489, adopt very different conformations in the two enzymes, and Lys-453 and His-480 that are a feature of trypanosomatid enzymes provide probable ligands for the 2-phospho group of the effector molecule. These and other differences offer an opportunity for the design of drugs that would exploit regulatory differences between parasite and host.
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February 2000
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Conference Article|
February 01 2000
Leishmania pyruvate kinase: the crystal structure reveals the structural basis of its unique regulatory properties
L. A. Fothergill-Gilmore;
L. A. Fothergill-Gilmore
*Department of Biomedical Sciences, University of Edinburgh, George Square, Edinburgh EH8 9XD, U.K.
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D. J. Rigden;
D. J. Rigden
†National Centre of Genetic Resources and Biotechnology, Cenargen/Embrapa, SAIN-Parque Rural 70789-970, Brasilia, DF, Brazil
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P. A. M. Michels;
P. A. M. Michels
‡Research Unit for Tropical Diseases, Christian de Duve Institute of Cellular Pathology and Laboratory of Biochemistry, Université Catholique de Louvain, Brussels, Belgium
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S. E. V. Phillips
S. E. V. Phillips
§School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, U.K.
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Publisher: Portland Press Ltd
Received:
August 09 1999
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2000 Biochemical Society
2000
Biochem Soc Trans (2000) 28 (2): 186–190.
Article history
Received:
August 09 1999
Citation
L. A. Fothergill-Gilmore, D. J. Rigden, P. A. M. Michels, S. E. V. Phillips; Leishmania pyruvate kinase: the crystal structure reveals the structural basis of its unique regulatory properties. Biochem Soc Trans 1 February 2000; 28 (2): 186–190. doi: https://doi.org/10.1042/bst0280186
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