Structure of Leishmania major cysteine synthase

Fyfe, P.K., Westrop, G.D., Ramos, T., Muller, S., Coombs, G.H. and Hunter, W.N. (2012) Structure of Leishmania major cysteine synthase. Acta Crystallographica. Section F: Structural Biology and Crystallization Communications, 68(7), pp. 738-743. (doi: 10.1107/S1744309112019124)

Abstract

Cysteine biosynthesis is a potential target for drug development against parasitic Leishmania species; these protozoa are responsible for a range of serious diseases. To improve understanding of this aspect of Leishmania biology, a crystallographic and biochemical study of L. major cysteine synthase has been undertaken, seeking to understand its structure, enzyme activity and modes of inhibition. Active enzyme was purified, assayed and crystallized in an orthorhombic form with a dimer in the asymmetric unit. Diffraction data extending to 1.8 Å resolution were measured and the structure was solved by molecular replacement. A fragment of γ-poly-D-glutamic acid, a constituent of the crystallization mixture, was bound in the enzyme active site. Although a D-glutamate tetrapeptide had insignificant inhibitory activity, the enzyme was competitively inhibited (K(i) = 4 µM) by DYVI, a peptide based on the C-terminus of the partner serine acetyltransferase with which the enzyme forms a complex. The structure surprisingly revealed that the cofactor pyridoxal phosphate had been lost during crystallization.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Muller, Professor Sylke and Coombs, Professor Graham and Westrop, Mr Gareth
• Authors: Fyfe, P.K., Westrop, G.D., Ramos, T., Muller, S., Coombs, G.H., and Hunter, W.N.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Acta Crystallographica. Section F: Structural Biology and Crystallization Communications
• Publisher: Wiley-Blackwell Publishing, Inc.
• ISSN: 1744-3091
• Copyright Holders: Copyright © 2012 International Union of Crystallography
• First Published: First published in 2012 68(7):738-743
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher