Reconsideration of the significance of substrate‐level phosphorylation in the citric acid cycle

For nearly 50 years, students of metabolism in animals have been taught that a substrate‐level phosphorylation in the Krebs citric acid cycle produces GTP that subsequently undergoes a transphosphorylation with ADP catalyzed by nucleoside diphosphate kinase. Research in the past decade has revealed that animals also express an ADP‐forming succinate‐CoA ligase whose activity exceeds that of the GDP‐forming enzyme in some tissues. Here I argue that the primary fate of GTP is unlikely to be transphosphorylation with ADP. Rather, two succinate‐CoA ligases with different nucleotide specificities have evolved to better integrate and regulate the central metabolic pathways that involve the citric acid cycle. The products of substrate‐level phosphorylation, ATP and/or GTP, may represent a pool of nucleotide that has a different phosphorylation potential than the ATP made by oxidative phosphorylation and may be channeled to meet specific needs within mitochondria and the cell. Further research is needed to determine the applicable mechanisms and how they vary in tissues.