Venditti, Charles (NHGRI)
Isolated Methylmalonic Acidemia (MMA) and the related disorder Propionic Acidemia (PA) comprise a relatively common and heterogeneous group of inborn errors of metabolism. NHGRI scientist discovered that in isolated MMA, a novel inhibitory PTM, methylmalonyllysine, is generated and inactivates protein targets through the failure of SIRT-mediated deacylation, and identified a series of antibodies for PTM specificity. A novel acylation resistant SIRT5 was created that did not exhibit enzymatic inhibition after hyper-methylmalonylation and appears to be resistant to inhibition by nicotinamide, which may be a universal therapy for all forms of MMA and PA. The scientist also developed a new assay involving sirtuin modulation, for targeted therapies that might be widely applicable to all forms of MMA as well as other the larger group of organic acidemias and fatty acid oxidation disorders where acyl-CoA accretion occurs. The new assays will be useful to develop small molecules that stimulate removal of methylmalonyl- and propionyl- groups for novel therapies.
This discovery could be used to find new targets causing symptoms in MMA and PA patients, the assay used to devise a chemical screen for activators and inhibitors of activity, and perhaps most importantly, the novel SIRT5 might be delivered as a therapeutic agent for patients with MMA or PA, and perhaps other organic acidemias.
The existing approaches to treat MMA and PA rely upon delivery of the missing gene specific to the form of MMA or PA (there are 17 types) while the SIRT5 approach we describe could be used to treat all forms of MMA and PA.