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Originally published In Press as doi:10.1074/jbc.M501964200 on July 28, 2005
J. Biol. Chem., Vol. 280, Issue 38, 32662-32668, September 23, 2005
A B12-responsive Internal Ribosome Entry Site (IRES) Element in Human Methionine Synthase*
Sebastian Oltean and
Ruma Banerjee1
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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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
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