Alanine-glyoxylate aminotransferase 2 AGXT2 Polymorphisms Have Considerable Impact on Methylarginine and β-aminoisobutyrate Metabolism in Healthy VolunteersReportar como inadecuado




Alanine-glyoxylate aminotransferase 2 AGXT2 Polymorphisms Have Considerable Impact on Methylarginine and β-aminoisobutyrate Metabolism in Healthy Volunteers - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Elevated plasma concentrations of asymmetric ADMA and symmetric SDMA dimethylarginine have repeatedly been linked to adverse clinical outcomes. Both methylarginines are substrates of alanine-glyoxylate aminotransferase 2 AGXT2. It was the aim of the present study to simultaneously investigate the functional relevance and relative contributions of common AGXT2 single nucleotide polymorphisms SNPs to plasma and urinary concentrations of methylarginines as well as β-aminoisobutyrate BAIB, a prototypic substrate of AGXT2. In a cohort of 400 healthy volunteers ADMA, SDMA and BAIB concentrations were determined in plasma and urine using HPLC-MS-MS and were related to the coding AGXT2 SNPs rs37369 p.Val140Ile and rs16899974 p.Val498Leu. Volunteers heterozygous or homozygous for the AGXT2 SNP rs37369 had higher SDMA plasma concentrations by 5% and 20% p = 0.002 as well as higher BAIB concentrations by 54% and 146%, respectively, in plasma and 237% and 1661%, respectively, in urine both p<0.001. ADMA concentrations were not affected by both SNPs. A haplotype analysis revealed that the second investigated AGXT2 SNP rs16899974, which was not significantly linked to the other AGXT2 SNP, further aggravates the effect of rs37369 with respect to BAIB concentrations in plasma and urine. To investigate the impact of the amino acid exchange p.Val140Ile, we established human embryonic kidney cell lines stably overexpressing wild-type or mutant p.Val140Ile AGXT2 protein and assessed enzyme activity using BAIB and stable-isotope labeled 2H6-SDMA as substrate. In vitro, the amino acid exchange of the mutant protein resulted in a significantly lower enzyme activity compared to wild-type AGXT2 p<0.05. In silico modeling of the SNPs indicated reduced enzyme stability and substrate binding. In conclusion, SNPs of AGXT2 affect plasma as well as urinary BAIB and SDMA concentrations linking methylarginine metabolism to the common genetic trait of hyper-β-aminoisobutyric aciduria.



Autor: Anja Kittel , Fabian Müller , Jörg König, Maren Mieth, Heinrich Sticht, Oliver Zolk, Ana Kralj, Markus R. Heinrich, Martin F.

Fuente: http://plos.srce.hr/



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