2. Academic Validation
  3. Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex

Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex

  • ACS Chem Biol. 2020 Aug 21;15(8):2041-2047. doi: 10.1021/acschembio.0c00114.
João Leandro 1 2,  Susmita Khamrui 3,  Hui Wang 3 4,  Chalada Suebsuwong 3 4,  Natalia S Nemeria 5,  Khoi Huynh 3 4,  Moses Moustakim 3 4,  Cody Secor 3,  May Wang 1 2,  Tetyana Dodatko 1 2,  Brandon Stauffer 6,  Christopher G Wilson 7,  Chunli Yu 1 6,  Michelle R Arkin 7,  Frank Jordan 5,  Roberto Sanchez 3 4,  Robert J DeVita 3 4,  Michael B Lazarus 3,  Sander M Houten 1 2
Affiliations

Affiliations

  • 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 2 Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 3 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 4 Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 5 Department of Chemistry, Rutgers, The State University of New Jersey, Newark, New Jersey 07102, United States.
  • 6 Mount Sinai Genomics, Inc, Stamford, Connecticut 06902, United States.
  • 7 Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United States.
PMID: 32633484 DOI: 10.1021/acschembio.0c00114
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 Å. 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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