Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/35415
Title: Structure and proposed mechanism of l -α-glycerophosphate oxidase from Mycoplasma pneumoniae
Authors: Callia K. Elkhal
Kelsey M. Kean
Derek Parsonage
Somchart Maenpuen
Pimchai Chaiyen
Al Claiborne
P. Andrew Karplus
Oregon State University
Wake Forest University School of Medicine
Burapha University
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Aug-2015
Citation: FEBS Journal. Vol.282, No.16 (2015), 3030-3042
Abstract: © 2015 FEBS. The formation of H2O2by the FAD-dependent l-α-glycerophosphate oxidase (GlpO) is important for the pathogenesis of Streptococcus pneumoniae and Mycoplasma pneumoniae. The structurally known GlpO from Streptococcus sp. (SspGlpO) is similar to the pneumococcal protein (SpGlpO) and provides a guide for drug design against that target. However, M. pneumoniae GlpO (MpGlpO), having < 20% sequence identity with structurally known GlpOs, appears to represent a second type of GlpO that we designate as type II GlpOs. In the present study, the recombinant His-tagged MpGlpO structure is described at an approximate resolution of 2.5 Å, solved by molecular replacement using, as a search model, the Bordetella pertussis protein 3253 (Bp3253), comprising a protein of unknown function solved by structural genomics efforts. Recombinant MpGlpO is an active oxidase with a turnover number of approximately 580 min-1, whereas Bp3253 showed no GlpO activity. No substantial differences exist between the oxidized and dithionite-reduced MpGlpO structures. Although, no liganded structures were determined, a comparison with the tartrate-bound Bp3253 structure and consideration of residue conservation patterns guided the construction of a model for l-α-glycerophosphate (Glp) recognition and turnover by MpGlpO. The predicted binding mode also appears relevant for the type I GlpOs (such as SspGlpO) despite differences in substrate recognition residues, and it implicates a histidine conserved in type I and II Glp oxidases and dehydrogenases as the catalytic acid/base. The present study provides a solid foundation for guiding further studies of the mitochondrial Glp dehydrogenases, as well as for continued studies of M. pneumoniae and S. pneumoniae glycerol metabolism and the development of novel therapeutics targeting MpGlpO and SpGlpO. Database Structural data have been deposited in the Protein Data Bank under accession numbers 4X9M (oxidized) and 4X9N (reduced). The glycerol oxidases/dehydrogenases (GlpO/DHs) family includes a key mitochondrial enzyme and bacterial pathogenicity factors. Solving the crystal structure of Mycoplasma pneumoniae GlpO has allowed us to recognize that two types of GlpO/DHs exist (Type I and II), and to propose a substrate binding mode and mechanism that appears relevant for both types and can serve to guide drug design efforts.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84939267140&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/35415
ISSN: 17424658
1742464X
Appears in Collections:Scopus 2011-2015

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