Methionine-deficient diet induces post-transcriptional downregulation of cystathionine β-synthase

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• 作者：Baiqing Tang ; Aladdin Mustafa ; Sapna Gupta ; Stepan Melnyk ; S. Jill James ; Warren D. Kruger
• 关键词：Metabolism ; Genetics ; Amino acids ; Cardiovascular disease
• 刊名：Nutrition
• 出版年：2010
• 出版时间：November-December 2010
• 年：2010
• 卷：26
• 期：11-12
• 页码：1170-1175
• 全文大小：562 K

文摘

Objective

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 β-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.