Insight into the self-association of key enzymes from pathogenic species

Insight into the self-association of key enzymes from pathogenic species
Engineering Village 2
2006 Elsevier Inc.
Accession number: 9080608

Title: Insight into the self-association of key enzymes from pathogenic species

Authors: Perugini, M.A.1 ; Griffin, M.D.W.; Smith, B.J.; Webb, L.E.; Davis, A.J.; Handman, E.; Gerrard, J.A.

Author affiliation: 1 Dept. of Biochem. & Molecular Biol., Melbourne Univ., Parkville, Vic., Australia

Serial title: European Biophysics Journal

Abbreviated serial title: Eur. Biophys. J. (Germany)

Volume: 34

Issue: 5

Publication date: July 2005

Pages: 469-76

Language: English

ISSN: 0175-7571


Document type: Journal article (JA)

Publisher: Springer-Verlag

Country of publication: Germany

Material Identity Number: H883-2005-004

Abstract: Self-association of protein monomers to higher-order oligomers plays an important role in a plethora of biological phenomena. The classical biophysical technique of analytical ultracentrifugation is a key method used to measure protein oligomerisation. Recent advances in sedimentation data analysis have enabled the effects of diffusion to be deconvoluted from sample heterogeneity, permitting the direct identification of oligomeric species in self-associating systems. Two such systems are described and reviewed in this study. First, we examine the enzyme dihydrodipicolinate synthase (DHDPS), which crystallises as a tetramer. Wild-type DHDPS plays a critical role in lysine biosynthesis in microbes and is therefore an important antibiotic target. To confirm the state of association of DHDPS in solution, we employed sedimentation velocity and sedimentation equilibrium studies in an analytical ultra-centrifuge to show that DHDPS exists in a slow dimer-tetramer equilibrium with a dissociation constant of 76 nM. Second, we review works describing the hexamerisation of GDP-mannose pyrophosphorylase (GDP-MP), an enzyme that plays a critical role in mannose metabolism in Leishmania species. Although the structure of the GDP-MP hexamer has not yet been determined, we describe a three-dimensional model of the hexamer based largely on homology with the uridyltransferase enzyme, Glmu. GDP-MP is a novel drug target for the treatment of leishmaniasis, a devastating parasitic disease that infects more than 12 million people worldwide. Given that both GDP-MP and DHDPS are only active in their oligomeric states, we propose that inhibition of the self-association of critical enzymes in disease is an emerging paradigm for therapeutic intervention

Number of references: 36

Inspec controlled terms: data analysis - diseases - drugs - enzymes - microorganisms - molecular biophysics - sedimentation

Uncontrolled terms: self-association - pathogenic species - protein monomer - higher-order oligomer - plethora - biological phenomena - analytical ultracentrifugation - protein oligomerisation - sedimentation data analysis - diffusion effect - enzyme dihydrodipicolinate synthase - lysine biosynthesis - microbe - antibiotic target - sedimentation velocity - sedimentation equilibrium - dimer-tetramer equilibrium - dissociation constant - hexamerisation - GDP-mannose pyrophosphorylase - mannose metabolism - Leishmania species - homology - uridyltransferase enzyme - leishmaniasis - parasitic disease - bioinformatics - drug discovery - protein-protein interaction - structural modeling

Inspec classification codes: A8715D Physical chemistry of biomolecular solutions; condensed states - A8715B Biomolecular structure, configuration, conformation, and active sites - A8715K Biomolecular interactions, charge transfer complexes

Treatment: Experimental (EXP)

Discipline: Physics (A)

DOI: 10.1007/s00249-005-0491-y

Database: Inspec

Copyright 2006, The Institution of Engineering and Technology
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