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J. Biol. Chem., Vol. 280, Issue 38, 32662-32668, September 23, 2005

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A B₁₂-responsive Internal Ribosome Entry Site (IRES) Element in Human Methionine Synthase^*

From the Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588-0664

Regulation of homocysteine, a sulfur-containing amino acid that is a risk factor for cardiovascular diseases, is poorly understood. Methionine synthase (MS) is a key enzyme that clears intracellular homocysteine, and its activity is induced by its cofactor, vitamin B₁₂, at a translational level. In this study, we demonstrate that translation of MS, which has a long and highly structured 5'-untranslated region, is initiated from an internal ribosome entry site (IRES), which is modulated by B₁₂. The minimal IRES element spans 71 bases immediately upstream of the initiation codon. Electrophoretic mobility shift analysis reveals the presence of a B₁₂ -dependent protein-RNA complex and suggests the possibility that B₁₂-dependent increase of IRES efficiency is mediated via a protein. Modulation of the IRES-dependent translation of an essential gene by the cofactor of the encoded enzyme represents a novel example of a gene-nutrient interaction.

Received for publication, February 22, 2005 , and in revised form, July 27, 2005.

^* This work was supported by Grant DK64959 from the National Institutes of Health and by a predoctoral fellowship from the Heartland Affiliate of the American Heart Association (to S. O.). 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.

The online version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed. Tel.: 402-472-2941; E-mail: rbanerjee1{at}unl.edu.

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