@article{5c4002135f45486d8c5055ee06633b32,
title = "Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex",
abstract = "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 {\AA}. 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.",
author = "Jo{\~a}o Leandro and Susmita Khamrui and Hui Wang and Chalada Suebsuwong and Nemeria, {Natalia S.} and Khoi Huynh and Moses Moustakim and Cody Secor and May Wang and Tetyana Dodatko and Brandon Stauffer and Wilson, {Christopher G.} and Chunli Yu and Arkin, {Michelle R.} and Frank Jordan and Roberto Sanchez and Devita, {Robert J.} and Lazarus, {Michael B.} and Houten, {Sander M.}",
note = "Funding Information: Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (NIH), under Award Nos. R03HD092878 (to S.M.H.), R21HD088775 (to S.M.H. and R.J.D.), and R35GM124838 (to M.B.L.), and by the National Center for Advancing Translational Sciences, NIH, under Grant No. UL1TR001433. This research used resources of the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory, under Contract No. DE-SC0012704. The Life Science Biomedical Technology Research resource is primarily supported by the NIH, National Institute of General Medical Sciences (NIGMS) through a Biomedical Technology Research Resource P41 grant (No. P41GM111244), and by the DOE Office of Biological and Environmental Research (No. KP1605010). Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",
year = "2020",
month = aug,
day = "21",
doi = "10.1021/acschembio.0c00114",
language = "English",
volume = "15",
pages = "2041--2047",
journal = "ACS Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "8",
}