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Research article

Crystal structure and kinetic study of dihydrodipicolinate synthase from Mycobacterium tuberculosis

Georgia Kefala, Genevieve L. Evans, Michael D. W. Griffin, Sean R. A. Devenish, F. Grant Pearce, Matthew A. Perugini, Juliet A. Gerrard, Manfred S. Weiss, Renwick C. J. Dobson
Biochemical Journal Mar 27, 2008, 411 (2) 351-360; DOI: 10.1042/BJ20071360
Georgia Kefala
EMBL Hamburg Outstation, c/o DESY, Notkestrasse 85, D-22603 Hamburg, Germany
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Genevieve L. Evans
School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
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Michael D. W. Griffin
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, University of Melbourne, Melbourne, Victoria 3010, Australia
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Sean R. A. Devenish
School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
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F. Grant Pearce
School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
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Matthew A. Perugini
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, University of Melbourne, Melbourne, Victoria 3010, Australia
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Juliet A. Gerrard
School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
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Manfred S. Weiss
EMBL Hamburg Outstation, c/o DESY, Notkestrasse 85, D-22603 Hamburg, Germany
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  • For correspondence: msweiss@embl-hamburg.derdobson@unimelb.edu.au
Renwick C. J. Dobson
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, University of Melbourne, Melbourne, Victoria 3010, Australia
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  • For correspondence: msweiss@embl-hamburg.derdobson@unimelb.edu.au
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Abstract

The three-dimensional structure of the enzyme dihydrodipicolinate synthase (KEGG entry Rv2753c, EC 4.2.1.52) from Mycobacterium tuberculosis (Mtb-DHDPS) was determined and refined at 2.28 Å (1 Å=0.1 nm) resolution. The asymmetric unit of the crystal contains two tetramers, each of which we propose to be the functional enzyme unit. This is supported by analytical ultracentrifugation studies, which show the enzyme to be tetrameric in solution. The structure of each subunit consists of an N-terminal (β/α)8-barrel followed by a C-terminal α-helical domain. The active site comprises residues from two adjacent subunits, across an interface, and is located at the C-terminal side of the (β/α)8-barrel domain. A comparison with the other known DHDPS structures shows that the overall architecture of the active site is largely conserved, albeit the proton relay motif comprising Tyr143, Thr54 and Tyr117 appears to be disrupted. The kinetic parameters of the enzyme are reported: KMASA=0.43±0.02 mM, KMpyruvate=0.17±0.01 mM and Vmax=4.42±0.08 μmol·s−1·mg−1. Interestingly, the Vmax of Mtb-DHDPS is 6-fold higher than the corresponding value for Escherichia coli DHDPS, and the enzyme is insensitive to feedback inhibition by (S)-lysine. This can be explained by the three-dimensional structure, which shows that the (S)-lysine-binding site is not conserved in Mtb-DHDPS, when compared with DHDPS enzymes that are known to be inhibited by (S)-lysine. A selection of metabolites from the aspartate family of amino acids do not inhibit this enzyme. A comprehensive understanding of the structure and function of this important enzyme from the (S)-lysine biosynthesis pathway may provide the key for the design of new antibiotics to combat tuberculosis.

  • diaminopimelate pathway
  • dihydrodipicolinate synthase (DHDPS)
  • lysine biosynthesis
  • Mycobacterium tuberculosis
  • succinylase branch

Abbreviations: DAP, diaminopimelate; DHDPR, dihydrodipicolinate reductase; DHDPS, dihydrodipicolinate synthase; DTT, dithiothreitol; HTPA, (4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinate; Mtb, Mycobacterium tuberculosis; (S)-ASA, (S)-aspartate β-semialdehyde

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April 2008

Volume: 411 Issue: 2

Biochemical Journal: 411 (2)
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Crystal structure and kinetic study of dihydrodipicolinate synthase from Mycobacterium tuberculosis
Georgia Kefala, Genevieve L. Evans, Michael D. W. Griffin, Sean R. A. Devenish, F. Grant Pearce, Matthew A. Perugini, Juliet A. Gerrard, Manfred S. Weiss, Renwick C. J. Dobson
Biochemical Journal Apr 2008, 411 (2) 351-360; DOI: 10.1042/BJ20071360
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Crystal structure and kinetic study of dihydrodipicolinate synthase from Mycobacterium tuberculosis
Georgia Kefala, Genevieve L. Evans, Michael D. W. Griffin, Sean R. A. Devenish, F. Grant Pearce, Matthew A. Perugini, Juliet A. Gerrard, Manfred S. Weiss, Renwick C. J. Dobson
Biochemical Journal Apr 2008, 411 (2) 351-360; DOI: 10.1042/BJ20071360

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Keywords

diaminopimelate pathway
dihydrodipicolinate synthase (DHDPS)
lysine biosynthesis
Mycobacterium tuberculosis
succinylase branch

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