Aldehyde-mediated inhibition of asparagine biosynthesis has implications for diabetes and alcoholism
Patients with alcoholism and type 2 diabetes manifest altered metabolism, including elevated aldehyde levels and unusually low asparagine levels. We show that asparagine synthetase B (ASNS), the only human asparagine-forming enzyme, is inhibited by disease-relevant reactive aldehydes, including formaldehyde and acetaldehyde. Cellular studies show non-cytotoxic amounts of reactive aldehydes induce a decrease in asparagine levels. Biochemical analyses reveal inhibition results from reaction of the aldehydes with the catalytically important N-terminal cysteine of ASNS. The combined cellular and biochemical results suggest a possible mechanism underlying the low asparagine levels in alcoholism and diabetes. The results will stimulate research on the biological consequences of the reactions of aldehydes with nucleophilic residues.
Funding
Industrial CASE Account - University of Oxford 2017
Engineering and Physical Sciences Research Council
Find out more...Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant ref. 203141/Z/16/Z)
Cancer Research UK (C8717/A18245)
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Wellcome Trust
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Author affiliation
School of Chemistry, University of LeicesterVersion
- VoR (Version of Record)