Characterization, structure, and inhibition of the human succinyl-coA:glutarate-coA transferase, a putative genetic modifier of glutaric aciduria type 1 Journal Article
| Authors: | Wu, R.; Khamrui, S.; Dodatko, T.; Leandro, J.; Sabovic, A.; Violante, S.; Cross, J. R.; Marsan, E.; Kumar, K.; DeVita, R. J.; Lazarus, M. B.; Houten, S. M. |
| Article Title: | Characterization, structure, and inhibition of the human succinyl-coA:glutarate-coA transferase, a putative genetic modifier of glutaric aciduria type 1 |
| 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 nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1. © 2024 American Chemical Society. |
| Keywords: | genetics; metabolism; high throughput screening; enzymology; enzyme inhibitor; high-throughput screening assays; chemistry; enzyme inhibitors; models, molecular; crystallography, x-ray; drug therapy; x ray crystallography; catalytic domain; molecular model; enzyme active site; glutarates; valsartan; acyl coenzyme a; humans; human; losartan; metabolic encephalopathy; brain diseases, metabolic; disorders of amino acid and protein metabolism; amino acid metabolism, inborn errors; coenzyme a-transferases; glutaric acidemia i; glutaryl-coa dehydrogenase; coenzyme a transferase; glutaric acid; glutaryl coenzyme a dehydrogenase |
| Journal Title: | ACS Chemical Biology |
| Volume: | 19 |
| Issue: | 7 |
| ISSN: | 1554-8929 |
| Publisher: | American Chemical Society |
| Date Published: | 2024-07-19 |
| Start Page: | 1544 |
| End Page: | 1553 |
| Language: | English |
| DOI: | 10.1021/acschembio.4c00204 |
| PUBMED: | 38915184 |
| PROVIDER: | scopus |
| PMCID: | PMC11259535 |
| DOI/URL: | |
| Notes: | Source: Scopus |
