2. Academic Validation
  3. Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1

Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1

  • bioRxiv. 2024 Feb 7:2024.02.07.578422. doi: 10.1101/2024.02.07.578422.
Susmita Khamrui 1,  Tetyana Dodatko 2,  Ruoxi Wu 1,  João Leandro 2,  Amanda Sabovic 1,  Sara Violante 3,  Justin R Cross 3,  Eric Marsan 1,  Kunal Kumar 1,  Robert J DeVita 1,  Michael B Lazarus 1,  Sander M Houten 2
Affiliations

Affiliations

  • 1 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 2 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 3 The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
PMID: 38370847 DOI: 10.1101/2024.02.07.578422
Abstract

Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or non-toxic metabolites. Here, we report a novel target, SUGCT, which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA. We report the structure of SUGCT, the first eukaryotic structure of a type III CoA transferase, develop a high-throughput enzyme assay and a cell-based assay, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme validating the screening approach. These results may form the basis for future development of new pharmacological intervention to treat GA1.

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