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J. Biol. Chem., Vol. 278, Issue 23, 20778-20784, June 6, 2003

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Nutritional Modulation of Gene Expression and Homocysteine Utilization by Vitamin B₁₂^*

Sebastian Oltean and Ruma Banerjee 

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

Vitamins B₁₂, B₆, and folic acid converge at the homocysteine metabolic junction where they support the activities of two key enzymes involved in intracellular homocysteine management, methionine synthase (MS) and cystathionine -synthase. The molecular mechanism for the regulation of homocysteine metabolism by B₁₂ supplementation has been investigated in this study. B₁₂ supplementation does not alter mRNA or protein turnover rates but induces translational up-regulation of MS by shifting the mRNA from the ribonucleoprotein to the polysome pool. The B₁₂-responsive element has been localized by deletion analysis using a reporter gene assay to a 70-bp region located at the 3' end of the 5'-untranslated region of the MS mRNA. The cellular consequence of the B₁₂ response is a 2- and 3.5-fold increase in the flux of homocysteine through the MS-dependent transmethylation pathway in HepG2 and 293 cells, respectively. It is speculated that B₁₂-induced up-regulation of MS may have evolved as an adaptive strategy for rapidly sequestering an essential and rare nutrient whose availability may have been limited in the evolutionary history of mammals, a problem that is exacerbated by the absence of this vitamin from the plant kingdom.

Received for publication, January 27, 2003 , and in revised form, April 1, 2003.

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

An Established Investigator of the American Heart Association. To whom correspondence should be addressed. Tel.: 402-472-2941; Fax: 402-472-7842; E-mail: rbanerjee1{at}unl.edu.

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