Disease relevance of Agxt

• Application of this procedure in a recently developed Agxt-gene-deleted mouse model of PH1 resulted in marked amelioration of hyperoxaluria [1].
• This inhibition was overridden by coapplications of ceramides (the distal SPT product), indicating that the delay in repair was not due to non-specific toxicity [2].
• Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer [3].
• Our data also suggest that hyperinsulinemia and elevated tumor necrosis factor (TNF)-alpha associated with obesity may contribute to the observed increase in adipose NSMase, ASMase, and SPT mRNA in this murine model of obesity [4].
• This study showed that children with high-grade glioma have an innate resistance to alkylating agents based on mismatch repair deficiency and high levels of alkyguanine transferase (AGT) [5].

High impact information on Agxt

• We generated a null mutant mouse by targeted mutagenesis of the homologous gene, Agxt, in embryonic stem cells [3].
• Hepatic expression of human AGT1, the protein encoded by AGXT, by adenoviral vector-mediated gene transfer in Agxt(-/-) mice normalized urinary oxalate excretion and prevented oxalate crystalluria [3].
• Expression of enzymes involved in ceramide generation (neutral sphingomyelinase [NSMase], acid sphingomyelinase [ASMase], and serine-palmitoyl-transferase [SPT]) and ceramide hydrolysis (ceramidase) are elevated in obese adipose tissues [4].
• To investigate the relationship between sphingolipid metabolism and atherosclerosis, we utilized myriocin to inhibit mouse serine palmitoyl-CoA transferase (SPT), the key enzyme for sphingolipid biosynthesis [6].
• These results indicate that, apart from cholesterol levels, sphingolipids have an effect on atherosclerotic development and that SPT has proatherogenic properties [6].

Biological context of Agxt

• The mouse alanine:glyoxylate aminotransferase gene (Agxt1): cloning, expression, and mapping to chromosome 1 [7].

Associations of Agxt with chemical compounds

• On a chow diet, myriocin treatment caused a significant decrease (50%) in liver SPT activity (p < 0.001), significant decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (54, 32, and 73%, respectively) (p < 0.0001), and a significant increase in plasma phosphatidylcholine levels (91%) (p < 0.0001) [6].
• Mice that lack AGT in all organs, O(6)-methylguanine-DNA methyltransferase gene knockout (MGMT(-/-)) mice are extremely hypersensitive to the methylating agent N-methyl-N-nitrosourea (MNU) and exhibit a 10-fold reduction in the LD(90) [8].

Analytical, diagnostic and therapeutic context of Agxt

• Thus, we have carried out the molecular cloning and analysis of the mouse Agxt1 gene, as a necessary first step towards the generation of a mouse model for PH1 [7].

References