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J. Biol. Chem., Vol. 283, Issue 14, 8939-8945, April 4, 2008

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Betaine-Homocysteine S-Methyltransferase-2 Is an S-Methylmethionine-Homocysteine Methyltransferase^*

Sandra S. Szegedi, Carmen C. Castro¹, Markos Koutmos^¶, and Timothy A. Garrow^||2

From the Departments of Animal Science and ^||Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, the Area de Fisiologia, Facultad de Medicina, Universidad de Cádiz, 11003 Cádiz, Spain, and the ^¶Biophysics Research Division, University of Michigan, Ann Arbor, Michigan 48109

We demonstrate that purified recombinant human betainehomocysteine methyltransferase-2 (BHMT-2) is a zinc metalloenzyme that uses S-methylmethionine (SMM) as a methyl donor for the methylation of homocysteine. Unlike the highly homologous betaine-homocysteine methyltransferase (BHMT), BHMT-2 cannot use betaine. The K_m of BHMT-2 for SMM was determined to be 0.94 mM, and it has a turnover number similar to BHMT. Several compounds were tested as inhibitors of recombinant human BHMT and BHMT-2. The SMM-specific methyltransferase activity of BHMT-2 is not inhibited by dimethylglycine and betaine, whereas the former is a potent inhibitor of BHMT. Methionine is a stronger inhibitor of BHMT-2 than BHMT, and S-adenosylmethionine does not inhibit BHMT but is a weak inhibitor of BHMT-2. BHMT can use SMM as a methyl donor with a k_cat/K_m that is 5-fold lower than the k_cat/K_m for betaine. However, SMM does not inhibit BHMT activity when it is presented to the enzyme at concentrations that are 10-fold greater than the subsaturating amounts of betaine used in the assay. Based on these data, it is our current hypothesis that in vivo most if not all of the SMM-dependent methylation of homocysteine occurs via BHMT-2.

Received for publication, December 21, 2007 , and in revised form, January 28, 2008.

^* This work was supported by National Institutes of Health Grants DK52501 (to T. A. G.) and GM48533 (to M. L. Ludwig and J. L. Smith), and Illinois Agricultural Experiment Station Project ILLU-698-352. 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 Currently a researcher of the Ramón y Cajal Program from the Spanish Ministerio de Educación y Ciencia.

² To whom correspondence should be addressed: 1201 W. Gregory Dr., 359 ERML, Urbana, IL 61801. Fax: 217-265-0925; E-mail: tagarrow{at}uiuc.edu.

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