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S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice
Mol Genet Metab Rep. 2018 Jun;15 :15-21
PMID: 30023284 PMCID: PMC6047060
AbstractElevated plasma total homocysteine (tHcy) is associated with a number of human diseases including coronary artery disease, stroke, osteoporosis and dementia. It is highly correlated with intracellular S-adenosylhomocysteine (SAH). Since SAH is a strong inhibitor of methyl-transfer reactions involving the methyl-donor S-adenosylmethionine (SAM), elevation in SAH could be an explanation for the wide association of tHcy and human disease. Here, we have created a transgenic mouse (Tg-hAHCY) that expresses human S-adenosylhomocysteine hydrolase (AHCY) from a zinc-inducible promoter in the liver and kidney. Protein analysis shows that human AHCY is expressed well in both liver and kidney, but elevated AHCY enzyme activity (131% increase) is only detected in the kidney due to the high levels of endogenous mouse AHCY expression in liver. Tg-hAHCY mice were crossed with mice lacking cystathionine beta-synthase activity (Tg-I278T Cbs(-/-) ) to explore the effect to AHCY overexpression in the context of elevated serum tHcy and elevated tissue SAM and SAH. Overexpression of AHCY had no significant effect on the phenotypes of Tg-I278T Cbs(-/-) mice or any effect on the steady state concentrations of methionine, total homocysteine, SAM, SAH, and SAM/SAH ratio in the liver and kidney. Furthermore, enhanced AHCY activity did not lower serum and tissue tHcy or methionine levels. Our data suggests that enhancing AHCY activity does not alter the distribution of methionine recycling metabolites, even when they are greatly elevated by Cbs mutations.
NotesLee, Hyung-Ok Wang, Liqun Kuo, Yin-Ming Andrews, Andrew J Gupta, Sapna Kruger, Warren D Journal Article United States Mol Genet Metab Rep. 2018 Jan 12;15:15-21. doi: 10.1016/j.ymgmr.2018.01.002. eCollection 2018 Jun.