Experimental beta-alaninuria was induced in rats by injection of (aminooxy)acetate (AOA), a potent inhibitor of aminotransferases, in order to elucidate the pathogenesis of hyper-beta-alaninemia. A 27-fold increase of beta-alanine (BALA) excretion was induced by subcutaneous injection of 1 5 mg of AOA per kg of body weight. A 13-fold and a 9-fold increase of beta-aminoisobutyric acid (BAIBA) and gamma-aminobutyric acid (GABA), respectively, were also induced simultaneously by the AOA injection. Identification of BALA and BAIBA isolated from the rat urine was performed by chromatographic and mass spectrometric analyses. The effects of AOA injection on the tissue levels of these amino acids were also studied. Contents of BALA in the liver and kidney and GABA in the brain increased significantly in response to AOA injection. The present study indicates that BALA transaminase is involved in hyper-beta-alaninemia.
[Show abstract][Hide abstract] ABSTRACT: Trichloroethylene (TCE) is one of the most widespread environmental contaminants, which is metabolized to N-acetyl-S-1,2-dichlorovinyl-L-cysteine (NA-DCVC) before being excreted in the urine. Alternatively, NA-DCVC can be deacetylated by aminoacylase 3 (AA3), an enzyme that is highly expressed in the kidney, liver, and brain. NA-DCVC deacetylation initiates the transformation into toxic products that ultimately causes acute renal failure. AA3 inhibition is therefore a target of interest to prevent TCE induced nephrotoxicity. Here we report the crystal structure of recombinant mouse AA3 (mAA3) in the presence of its acetate byproduct and two substrates: N(α)-acetyl-L-tyrosine and NA-DCVC. These structures, in conjunction with biochemical data, indicated that AA3 mediates substrate specificity through van der Waals interactions providing a dynamic interaction interface, which facilitates a diverse range of substrates.
Proceedings of the National Academy of Sciences 10/2010; 107(42):17962-7. DOI:10.1073/pnas.1006687107 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: H2S (hydrogen sulfide) is a well known and pungent gas recently discovered to be synthesized enzymatically in mammalian and human tissues. In a relatively short period of time, H2S has attracted substantial interest as an endogenous gaseous mediator and potential target for pharmacological manipulation. Studies in animals and humans have shown H2S to be involved in diverse physiological and pathophysiological processes, such as learning and memory, neurodegeneration, regulation of inflammation and blood pressure, and metabolism. However, research is limited by the lack of specific analytical and pharmacological tools which has led to considerable controversy in the literature. Commonly used inhibitors of endogenous H2S synthesis have been well known for decades to interact with other metabolic pathways or even generate NO (nitric oxide). Similarly, commonly used H2S donors release H2S far too quickly to be physiologically relevant, but may have therapeutic applications. In the present review, we discuss the enzymatic synthesis of H2S and its emerging importance as a mediator in physiology and pathology. We also critically discuss the suitability of proposed 'biomarkers' of H2S synthesis and metabolism, and highlight the complexities of the currently used pharmacological H2S 'donor' molecules and 'specific' H2S synthesis inhibitors in their application to studying the role of H2S in human disease.
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