期刊
ACS CHEMICAL BIOLOGY
卷 15, 期 8, 页码 2041-2047出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.0c00114
关键词
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资金
- Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (NIH) [R03HD092878, R21HD088775, R35GM124838]
- National Center for Advancing Translational Sciences, NIH [UL1TR001433]
- DOE Office of Science by Brookhaven National Laboratory [DE-SC0012704]
- NIH, National Institute of General Medical Sciences (NIGMS) through a Biomedical Technology Research Resource P41 grant [P41GM111244]
- DOE Office of Biological and Environmental Research [KP1605010]
DHTKD1 is the E1 component of the 2-oxoadipate dehydrogenase complex, which is an enzyme involved in the catabolism of (hydroxy-)lysine and tryptophan. Mutations in DHTKD1 have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease type 2Q and eosinophilic esophagitis, but the pathophysiology of these clinically distinct disorders remains elusive. Here, we report the identification of adipoylphosphonic acid and tenatoprazole as DHTKD1 inhibitors using targeted and high throughput screening, respectively. We furthermore elucidate the DHTKD1 crystal structure with thiamin diphosphate bound at 2.25 angstrom. We also report the impact of 10 disease-associated missense mutations on DHTKD1. Whereas the majority of the DHTKD1 variants displayed impaired folding or reduced thermal stability in combination with absent or reduced enzyme activity, three variants showed no abnormalities. Our work provides chemical and structural tools for further understanding of the function of DHTKD1 and its role in several human pathologies.
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