Hyperacylation of Key Enzymes in Pathways Known to Be Dysregulated In MMA (Methylmalonic Acidemia) Likely Contributes to Altered Metabolism and Identifies New Set of Targets for Therapeutic Intervention

On Day 3 (Thursday, October 29) of the American Society of Human Genetics (ASHG) 2020 Virtual Annual Meeting (https://www.ashg.org/meetings/2020meeting/), one of the multiple stimulating morning sessions was “From Genes to Therapeutic Targets and Clinical Trials” (#031). Among the six presentations given during this session was a particularly interesting one titled “Aberrant Post-Translational Modifications Contribute to MMA Pathophysiology and Identify New Targets for Therapy,” delivered by PamelaSara Head (photo), PhD, Prat Fellow, National Institute of General Medical Sciences, NIH. In the abstract for her talk, Dr. Head noted that organic acidemias (OAs), such as methylmalonic acidemia (MMA), are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino- and fatty acids. She said that OAs are difficult to treat and have multisystemic manifestations such as hyperammonemia and ketotic hyperglycinemia (KH), leading to increased morbidity and mortality. Build-up of acyl-CoA species is postulated to cause intracellular toxicity. In the work reported here, Dr. Head and colleagues explored an alternative pathophysiological consequence of impaired acyl-CoA metabolism: i.e., the accumulation of aberrant post-translational modifications (PTMs) that modify enzymes in critical intracellular pathways. Using a mouse model that recapitulates the hepatic mitochondriopathy of MMA, the group surveyed PTMs in hepatic extracts with propionyl- and malonyl-lysine antibodies. The team discovered widespread hyper-acylation in the MMA mice compared to controls, but not in animals with Acsf3 deficiency, a disorder of acyl-CoA synthesis.
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