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


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.


CONCLUSIONS
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.
Tang
Baiqing
B
Cancer Genetics and Signaling Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Mustafa
Aladdin
A
Gupta
Sapna
S
Melnyk
Stepan
S
James
S Jill
SJ
Kruger
Warren D
WD
D000465:Algorithms; D000818:Animals; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism*; D003677:Deficiency Diseases / Q000097:blood / Q000201:enzymology; D004032:Diet / Q000009:adverse effects*; D015536:Down-Regulation; D005260:Female; D006706:Homeostasis; D006710:Homocysteine / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008715:Methionine / Q000008:administration & dosage* / Q000097:blood / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D013997:Time Factors
D012333:RNA, Messenger; D006710:Homocysteine; D012436:S-Adenosylmethionine; D008715:Methionine; D003541:Cystathionine beta-Synthase