Metabolism of propionic acid via propionyl-coenzyme A (CoA) integrates branched chain amino acid, odd chain fatty acid, and cholesterol metabolic pathways, as well as provides an anapleurotic reaction into the Krebs cycle. Aberrant propionyl-CoA metabolism can result in propionic acidemia (PA) which is a cause of significant morbidity and mortality in pediatric populations, despite the use of newborn screening. Recently, we discovered a 6-carbon, mono-unsaturated product of propionate metabolism, 2-methyl-2-pentenoic acid (2M2PE) which was previously not thought to occur in humans. The existence of this pathway indicates the potential for an alternative enzymatic pathway for clearance of excess propionic acid. This research will elucidate and quantify this new branch of metabolism in the following three aims;
Specific Aim 1. Characterize and quantify metabolites of propionate through 2M2PE.
Specific Aim 2. Identify cellular localization and enzymology of metabolism through 2M2PE.
Specific Aim 3. Establish and validate a quantitative method for novel propionic acid metabolites in urine, plasma, and serum.
These aims are limited in scope and focused on early-stage research meant to address gaps in knowledge necessary before studies in animal model systems and human subjects.
Propionic acidemia (PA) is the manifestation of a set of inborn errors of metabolism that still result in significant morbidity and mortality despite detection by newborn screening. The recent discovery of a metabolite of excess propionic acid indicates that biomarkers with diagnostic, prognostic, and therapeutic potential may be possible. This research will quantify and describe the metabolism of this new metabolite for further investigation in PA patients and model systems.
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