Identification of FAH Domain-containing Protein 1 (FAHD1) as Oxaloacetate Decarboxylase

Fumarylacetoacetate hydrolase (FAH) domain-containing proteins occur in both prokaryotes and eukaryotes, where they carry out diverse enzymatic reactions, probably related to structural differences in their respective FAH domains; however, the precise relationship between structure of the FAH domain and the associated enzyme function remains elusive. In mammals, three FAH domain-containing proteins, FAHD1, FAHD2A, and FAHD2B, are known; however, their enzymatic function, if any, remains to be demonstrated. In bacteria, oxaloacetate is subject to enzymatic decarboxylation; however, oxaloacetate decarboxylases (ODx) were so far not identified in eukaryotes. Based on molecular modeling and subsequent biochemical investigations, we identified FAHD1 as a eukaryotic ODx enzyme. The results presented here indicate that dedicated oxaloacetate decarboxylases exist in eukaryotes. Background: Enzymes of the FAH superfamily catalyze a multitude of diverse chemical reactions. Results: Using molecular modeling followed by biochemical investigations, FAHD1 was identified as oxaloacetate decarboxylase. Conclusion: Our findings suggest that ODx activity can be found in eukaryotic members of the FAH superfamily. Significance: Our results identify a mammalian ODx enzyme as a so far undescribed player in mitochondrial metabolism.