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J. Biol. Chem., Vol. 281, Issue 32, 22485-22492, August 11, 2006

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Protective Mechanisms against Homocysteine Toxicity

THE ROLE OF BLEOMYCIN HYDROLASE^*

Jarosaw Zimny, Marta Sikora^¶, Andrzej Guranowski, and Hieronim Jakubowski^¶1

From the Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, International Center for Public Health, Newark, New Jersey 07101 and the Department of Biochemistry and Biotechnology, Agricultural University, 60637 Pozna, Poland, and ^¶Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61704 Pozna, Poland

Homocysteine (Hcy) editing by methionyl-tRNA synthetase results in the formation of Hcy-thiolactone and initiates a pathway that has been implicated in human disease. In addition to being cleared from the circulation by urinary excretion, Hcy-thiolactone is detoxified by the serum Hcy-thiolactonase/paraoxonase carried on high density lipoprotein. Whether Hcy-thiolactone is detoxified inside cells was unknown. Here we show that Hcy-thiolactone is hydrolyzed by an intracellular enzyme, which we have purified to homogeneity from human placenta and identified by proteomic analyses as human bleomycin hydrolase (hBLH). We have also purified an Hcy-thiolactonase from the yeast Saccharomyces cerevisiae and identified it as yeast bleomycin hydrolase (yBLH). BLH belongs to a family of evolutionarily conserved cysteine aminopeptidases, and its only known biologically relevant function was deamidation of the anticancer drug bleomycin. Recombinant hBLH or yBLH, expressed in Escherichia coli, exhibits Hcy-thiolactonase activity similar to that of the native enzymes. Active site mutations, C73A for hBLH and H369A for yBLH, inactivate Hcy-thiolactonase activities. Yeast blh1 mutants are deficient in Hcy-thiolactonase activity in vitro and in vivo, produce more Hcy-thiolactone, and exhibit greater sensitivity to Hcy toxicity than wild type yeast cells. Our data suggest that BLH protects cells against Hcy toxicity by hydrolyzing intracellular Hcy-thiolactone.

Received for publication, April 17, 2006 , and in revised form, June 8, 2006.

^* This work was supported in part by grants from the American Heart Association (to H. J.) and Committee for Scientific Research, Poland, Grant 3 P04A 00725 (to A. G. and J. Z.). Preliminary accounts of this work were published in abstract form (33, 34). 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.

¹ To whom correspondence should be addressed: Dept. of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren St., Newark, NJ 07101-1709. Tel.: 973-972-4483; Fax: 973-972-8982; E-mail: jakubows{at}umdnj.edu.

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