title: Reinterpreting the mechanism of inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by D-cycloserine.
abstract: d-Cycloserine is a second-line drug approved for use in the treatment of patients infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. The unique mechanism of action of d-cycloserine, compared with those of other clinically employed antimycobacterial agents, represents an untapped and exploitable resource for future rational drug design programs. Here, we show that d-cycloserine is a slow-onset inhibitor of MtDdl and that this behavior is specific to the M. tuberculosis enzyme orthologue. Furthermore, evidence is presented that indicates d-cycloserine binds exclusively to the C-terminal d-alanine binding site, even in the absence of bound d-alanine at the N-terminal binding site. Together, these results led us to propose a new model of d-alanine:d-alanine ligase inhibition by d-cycloserine and suggest new opportunities for rational drug design against an essential, clinically validated mycobacterial target.
authors.affiliation: Mycobacterial Research Division, MRC National Institute for Medical Research , The Ridgeway, Mill Hill, London NW7 1AA, U.K.
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Prosser
authors.forename: Luiz Pedro S
authors.initials: LP
authors.lastname: de Carvalho
mesh_terms: D001665:Binding Sites; D003523:Cycloserine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D003523:Cycloserine; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):730-9
references.pmid: 16888652
references.citation: J Org Chem. 1971 Sep 10;36(18):2631-4
references.pmid: 5130583
references.citation: Biochemistry. 1964 Apr;3:471-80
references.pmid: 14188160
references.citation: Clin Infect Dis. 1993 Aug;17(2):288-9
references.pmid: 8399888
references.citation: J Biol Chem. 2004 Oct 29;279(44):46143-52
references.pmid: 15302885
references.citation: J Biol Chem. 1962 Oct;237:3128-35
references.pmid: 13938148
references.citation: J Biol Chem. 1990 Jun 5;265(16):8993-8
references.pmid: 2188969
references.citation: Biochemistry. 1991 Feb 12;30(6):1673-82
references.pmid: 1993184
references.citation: Antimicrob Agents Chemother. 2011 Jan;55(1):291-301
references.pmid: 20956591
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15178-83
references.pmid: 17015835
references.citation: J Med Chem. 1999 Jan 14;42(1):109-17
references.pmid: 9888837
references.citation: Adv Enzymol Relat Areas Mol Biol. 1988;61:201-301
references.pmid: 3281418
references.citation: Biochemistry. 1991 Feb 26;30(8):2017-21
references.pmid: 1998664
references.citation: Science. 1994 Oct 21;266(5184):439-43
references.pmid: 7939684
references.citation: Nat Rev Drug Discov. 2004 Sep;3(9):801-8
references.pmid: 15340390
references.citation: Lancet Infect Dis. 2010 Sep;10(9):621-9
references.pmid: 20797644
references.citation: ACS Chem Biol. 2009 Mar 20;4(3):221-31
references.pmid: 19206187
references.citation: FEBS J. 2013 Feb;280(4):1150-66
references.pmid: 23286234