S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice
Elevated 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 involvin...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-06-01
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| Series: | Molecular Genetics and Metabolism Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426918300028 |
| _version_ | 1818439367111213056 |
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| author | Hyung-Ok Lee Liqun Wang Yin-Ming Kuo Andrew J. Andrews Sapna Gupta Warren D. Kruger |
| author_facet | Hyung-Ok Lee Liqun Wang Yin-Ming Kuo Andrew J. Andrews Sapna Gupta Warren D. Kruger |
| author_sort | Hyung-Ok Lee |
| collection | DOAJ |
| description | Elevated 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 β-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. Keywords: Metabolism, Methionine, Transgenic |
| first_indexed | 2024-12-14T17:55:20Z |
| format | Article |
| id | doaj.art-e9d92253faa54cf4bcbe3f111c3f2047 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-12-14T17:55:20Z |
| publishDate | 2018-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-e9d92253faa54cf4bcbe3f111c3f20472022-12-21T22:52:33ZengElsevierMolecular Genetics and Metabolism Reports2214-42692018-06-01151521S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient miceHyung-Ok Lee0Liqun Wang1Yin-Ming Kuo2Andrew J. Andrews3Sapna Gupta4Warren D. Kruger5Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USACancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, USACancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA; Corresponding author at: Cancer Biology Program, Fox Chase Cancer Program, 333 Cottman Avenue, Philadelphia, PA 19111, USA.Elevated 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 β-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. Keywords: Metabolism, Methionine, Transgenichttp://www.sciencedirect.com/science/article/pii/S2214426918300028 |
| spellingShingle | Hyung-Ok Lee Liqun Wang Yin-Ming Kuo Andrew J. Andrews Sapna Gupta Warren D. Kruger S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice Molecular Genetics and Metabolism Reports |
| title | S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice |
| title_full | S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice |
| title_fullStr | S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice |
| title_full_unstemmed | S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice |
| title_short | S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice |
| title_sort | s adenosylhomocysteine hydrolase over expression does not alter s adenosylmethionine or s adenosylhomocysteine levels in cbs deficient mice |
| url | http://www.sciencedirect.com/science/article/pii/S2214426918300028 |
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