HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 36, 37445-37451, September 3, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/36/37445    most recent M404383200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, Y. Articles by Mukhopadhyay, R. Search for Related Content PubMed PubMed Citation Articles by Zhou, Y. Articles by Mukhopadhyay, R. Social Bookmarking                      What's this?

Leishmania major LmACR2 Is a Pentavalent Antimony Reductase That Confers Sensitivity to the Drug Pentostam^*

Yao Zhou, Nadine Messier, Marc Ouellette¶, Barry P. Rosen, and Rita Mukhopadhyay||

From the Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan 48201 and Centre de Recherche en Infectiologie and Département de Microbiologie, Faculté de Médecine, Université Laval, Quebec G1V 4G2, Canada

Arsenicals and antimonials are first line drugs for the treatment of trypanosomal and leishmanial diseases. To create the active form of the drug, Sb(V) must be reduced to Sb(III). Because arsenic and antimony are related metalloids, and arsenical resistant Leishmania strains are frequently cross-resistant to antimonials, we considered the possibility that Sb(V) is reduced by a leishmanial As(V) reductase. The sequence for the arsenate reductase of Saccharomyces cerevisiae, ScAcr2p, was used to clone the gene for a homologue, LmACR2, from Leishmania major. LmACR2 was able to complement the arsenate-sensitive phenotype of an arsC deletion strain of Escherichia coli or an ScACR2 deletion strain of Saccharomyces cerevisiae. Transfection of Leishmania infantum with LmACR2 augmented Pentostam sensitivity in intracellular amastigotes. LmACR2 was purified and shown to reduce both As(V) and Sb(V). This is the first report of an enzyme that confers Pentostam sensitivity in intracellular amastigotes of Leishmania. We propose that LmACR2 is responsible for reduction of the pentavalent antimony in Pentostam to the active trivalent form of the drug in Leishmania.

Received for publication, April 21, 2004 , and in revised form, June 10, 2004.

^* This work was supported by National Institutes of Health Grant GM2216-08 (to B. P. R. and R. M.), by Canadian Institutes for Health Research group and operating grants (to M. O.), and by a Wellcome Trust-Burroughs Wellcome Fund new initiative in infectious diseases program grant (to M. O. and B. P. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Burroughs Wellcome Fund Scholar in Molecular Parasitology and holds a Canada Research Chair in antimicrobial resistance.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Wayne State University, School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201. Tel.: 313-577-0618; Fax: 313-577-2765; E-mail: rmukhopa{at}med.wayne.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. K. MITTAL, S. RAI, ASHUTOSH, RAVINDER, S. GUPTA, S. SUNDAR, and N. GOYAL CHARACTERIZATION OF NATURAL ANTIMONY RESISTANCE IN LEISHMANIA DONOVANI ISOLATES Am J Trop Med Hyg, April 1, 2007; 76(4): 681 - 688. [Abstract] [Full Text] [PDF]

				A. Mukherjee, P. K. Padmanabhan, S. Singh, G. Roy, I. Girard, M. Chatterjee, M. Ouellette, and R. Madhubala Role of ABC transporter MRPA, {gamma}-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani J. Antimicrob. Chemother., February 1, 2007; 59(2): 204 - 211. [Abstract] [Full Text] [PDF]

				Ashutosh, S. Sundar, and N. Goyal Molecular mechanisms of antimony resistance in Leishmania J. Med. Microbiol., February 1, 2007; 56(2): 143 - 153. [Abstract] [Full Text] [PDF]

				O. P. Dhankher, B. P. Rosen, E. C. McKinney, and R. B. Meagher Hyperaccumulation of arsenic in the shoots of Arabidopsis silenced for arsenate reductase (ACR2) PNAS, April 4, 2006; 103(14): 5413 - 5418. [Abstract] [Full Text] [PDF]

				S. L. Croft, S. Sundar, and A. H. Fairlamb Drug Resistance in Leishmaniasis Clin. Microbiol. Rev., January 1, 2006; 19(1): 111 - 126. [Abstract] [Full Text] [PDF]

				S. Decuypere, S. Rijal, V. Yardley, S. De Doncker, T. Laurent, B. Khanal, F. Chappuis, and J.-C. Dujardin Gene Expression Analysis of the Mechanism of Natural Sb(V) Resistance in Leishmania donovani Isolates from Nepal Antimicrob. Agents Chemother., November 1, 2005; 49(11): 4616 - 4621. [Abstract] [Full Text] [PDF]

				H.-C. Yang, J. Cheng, T. M. Finan, B. P. Rosen, and H. Bhattacharjee Novel Pathway for Arsenic Detoxification in the Legume Symbiont Sinorhizobium meliloti J. Bacteriol., October 15, 2005; 187(20): 6991 - 6997. [Abstract] [Full Text] [PDF]

				K. El Fadili, N. Messier, P. Leprohon, G. Roy, C. Guimond, N. Trudel, N. G. Saravia, B. Papadopoulou, D. Legare, and M. Ouellette Role of the ABC Transporter MRPA (PGPA) in Antimony Resistance in Leishmania infantum Axenic and Intracellular Amastigotes Antimicrob. Agents Chemother., May 1, 2005; 49(5): 1988 - 1993. [Abstract] [Full Text] [PDF]