bioRxiv preprint doi: https://doi.org/10.1101/645689; this version posted May 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. DHTKD1 and OGDH display in vivo substrate overlap and form a hybrid ketoacid dehydrogenase complex João Leandro1,2, Tetyana Dodatko1,2, Jan Aten3, Ronald C. Hendrickson4, Roberto Sanchez5,6, Chunli Yu1,7, Robert J. DeVita5,6, Sander M. Houten1,2,8,* 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 2Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 3Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands 4Microchemistry and Proteomics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 5Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 6Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 7Mount Sinai Genomics, Inc, New York, NY 10029, USA 8Lead Contact *Correspondence:
[email protected] bioRxiv preprint doi: https://doi.org/10.1101/645689; this version posted May 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SUMMARY Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA.