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Tang BQ , Mustafa A , Gupta S , Melnyk S , James SJ , Kruger WD
Methionine-deficient diet induces post-transcriptional downregulation of cystathionine beta-synthase
Nutrition. 2010 Nov-Dec;26(11-12) :1170-1175
AbstractObjective: Elevated plasma total homocysteine (tHcy) is a risk factor for a variety of human diseases. Homocysteine is formed from methionine and has two primary metabolic fates: remethylation to form methionine or commitment to the transsulfuration pathway by the action of cystathionine beta-synthase (CBS). We have examined the metabolic response in mice of a shift from a methionine-replete to a methionine-free diet. Methods and results: We found that shifting 3-mo-old C57BL6 mice to a methionine-free diet caused a transient increase in tHcy and an increase in the tHcy/methionine ratio. Because CBS is a key regulator of tHcy, we examined CBS protein levels and found that within 3 d on the methionine-deficient diet, animals had a 50% reduction in the levels of liver CBS protein and enzyme activity. Examination of CBS mRNA and studies of transgenic animals that express CBS from a heterologous promoter indicated that this reduction is occurring post-transcriptionally. Loss of CBS protein was unrelated to intracellular levels of S-adenosylmethionine, a known regulator of CBS activity and stability. Conclusion: Our results imply that methionine deprivation induces a metabolic state in which methionine is effectively conserved in tissue by shutdown of the transsulfuration pathway by an S-adenosylmethionine-independent mechanism that signals a rapid downregulation of CBS protein. (C) 2010 Elsevier Inc. All rights reserved.
NotesTang, Baiqing Mustafa, Aladdin Gupta, Sapna Melnyk, Stepan James, S. Jill Kruger, Warren D. Elsevier science inc New york 672fu