Acyl‐CoA dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism

Author:

Houten Sander M.1ORCID,Dodatko Tetyana1,Dwyer William1,Violante Sara2,Chen Hongjie1,Stauffer Brandon13,DeVita Robert J.45,Vaz Frédéric M.678ORCID,Cross Justin R.2,Yu Chunli13,Leandro João1ORCID

Affiliation:

1. Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York USA

2. The Donald B. and Catherine C. Marron Cancer Metabolism Center Memorial Sloan Kettering Cancer Center New York New York USA

3. Department of Pathology, Molecular and Cell Based Medicine Icahn School of Medicine at Mount Sinai New York New York USA

4. Department of Pharmacological Sciences Icahn School of Medicine at Mount Sinai New York New York USA

5. Drug Discovery Institute, Icahn School of Medicine at Mount Sinai New York New York USA

6. Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases Amsterdam UMC Location University of Amsterdam, Emma Children's Hospital Amsterdam The Netherlands

7. Amsterdam Gastroenterology Endocrinology Metabolism Inborn Errors of Metabolism Amsterdam The Netherlands

8. Core Facility Metabolomics Amsterdam UMC Location University of Amsterdam Amsterdam The Netherlands

Abstract

AbstractToxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short‐chain enoyl‐CoA hydratase (ECHS1 or crotonase) deficiency, 3‐hydroxyisobutyryl‐CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA). Isobutyryl‐CoA dehydrogenase (ACAD8) and short/branched‐chain acyl‐CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl‐CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2‐methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl‐CoA dehydrogenase, short‐chain acyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase, but not ACAD8. MCPA treatment of wild‐type and PA HEK‐293 cells caused a pronounced decrease in C3‐carnitine. Furthermore, deletion of ACADSB in HEK‐293 cells led to an equally strong decrease in C3‐carnitine when compared to wild‐type cells. Deletion of ECHS1 in HEK‐293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK‐293 cells for the isobutyryl‐CoA substrate. Substrate promiscuity appeared less prominent for 2‐methylbutyryl‐CoA at least in HEK‐293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further.

Funder

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Propionic Acidemia Foundation

Publisher

Wiley

Subject

Genetics (clinical),Genetics

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