Year: 2020
Type: article
Abstract: DHTKD1 is the E1 component of the 2-oxoadipic acid dehydrogenase complex (OADHc), which functions in the L-lysine degradation pathway. Mutations in DHTKD1 have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease type 2Q (CMT2Q) and eosinophilic esophagitis (EoE). A crystal structure and inhibitors of DHTKD1 could improve the understanding of these clinically distinct disorders, but are currently not available. 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 2.1 Å. The protein assembles as a dimer with residues from both monomers contributing to cofactor binding. We also report the impact of ten DHTKD1 missense mutations on the encoded proteins by enzyme kinetics, thermal stability and structural modeling. Some DHTKD1 variants displayed impaired folding (S777P and S862I), whereas other substitutions rendered the enzyme inactive (L234G, R715C and R455Q) or affected the thermal stability and catalytic efficiency (V360A and P773L). Three variants (R163Q, Q305H and G729R) surprisingly showed wild type like properties. Our work provides a structural basis for further understanding of the function of DHTKD1 and a starting point for selective small molecule inhibitors of the enzyme, which could help tease apart the role of this enzyme in several human pathologies.
Source: ACS Chemical Biology
Authors: João Leandro, Susmita Khamrui, Hui Wang, Chalada Suebsuwong, Natalia S. Nemeria, Khoi Huynh, Moses Moustakim, Cody Secor, May Wang, Tetyana Dodatko, Brandon Stauffer, Christopher G. Wilson, Chunli Yu, Michelle R. Arkin, Frank Jordan, Roberto Sanchez, Robert J. DeVita, Michael B. Lazarus, Sander M. Houten
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Energy, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Center for Advancing Translational Sciences, Biological and Environmental Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Brookhaven National Laboratory
Awards: G1285306620, Genetic validation of DHTKD1 as a therapeutic target for the treatment of Glutaric Aciduria type 1, G1867732070, G1868695577, G2004402655, G241279073, G2441874946, G3067052642, G3262563802, G357145406, G3728080647, G3850097093, MSHS Translational Science Hub, G4972998915, G5417557083, G5493493709, G5633341255, G5765906131, G6059574520, Novel Treatment Options for Glutaric Aciduria, Life Science and Biomedical technology Research center at NSLS-II LSBR, G6733788163, G7463374569, G8701900045, Chemical and Structural Approaches to Study Energy Homeostasis Pathways in Cancer and Metabolic disorders
OpenAlex ID: W3041827672