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Cited by 7 publications
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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 GDPforming 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.Keywords: Substrate-level phosphorylation, succinate-CoA ligase, citric acid cycle, GTP, mitochondrial bioenergetics. EARLY VERSIONS OF THE CITRIC ACID CYCLE AND THE DISCOVERY OF GDP-FORMING SUCCINATE-COA LIGASEAn important step in scientific research is the proposal of a model that explains and rationalizes a body of factual knowledge. A good model leads to further experimentation that often results in an improved model. Even the best of models may go through several iterations.The citric acid cycle (CAC), 1 as conceptualized by Krebs and subsequently modified, has been a highly successful model. This likely was the basis for Scheffler [1] rhetorically asking in 1999: "Is there anything left to discover about the citric acid cycle?" Most would agree that the answer is "no" with regard to carbon intermediates of the cycle. However, regulation of the cycle, its integration into anabolic and catabolic pathways, and the characteristics of the genes and enzymes involved in the cycle continue to be active areas of research.Here we will explore the possible significance of animal species (metazoans) expressing two succinate-CoA ligases 2 (SUCLs) with different nucleotide specificities. Both ligases are located in the matrix of mitochondria, where they could participate in the oxidative direction of the cycle. Key questions center on the roles of the two ligases and the extent to which GTP produced by G-SUCL undergoes transphosphorylation with ADP, as has been described in textbooks for nearly 50 years.The citric acid cycle proposed by Johnson and Krebs in 1937 [2, 3] fostered a mode of thinking that led to the elucidation of other cycles and pathways of intermediary metabolism. Krebs stated that the concept of the cycle, as shown in Fig. 1, evolved slowly over a 5-year period [3]. Its purpose was to explain how several plant dicarboxylic acids catalytically stimulate the oxidative metabolism of pyruvate in tissue preparations from animals. The 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 GDPforming 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.Keywords: Substrate-level phosphorylation, succinate-CoA ligase, citric acid cycle, GTP, mitochondrial bioenergetics. EARLY VERSIONS OF THE CITRIC ACID CYCLE AND THE DISCOVERY OF GDP-FORMING SUCCINATE-COA LIGASEAn important step in scientific research is the proposal of a model that explains and rationalizes a body of factual knowledge. A good model leads to further experimentation that often results in an improved model. Even the best of models may go through several iterations.The citric acid cycle (CAC), 1 as conceptualized by Krebs and subsequently modified, has been a highly successful model. This likely was the basis for Scheffler [1] rhetorically asking in 1999: "Is there anything left to discover about the citric acid cycle?" Most would agree that the answer is "no" with regard to carbon intermediates of the cycle. However, regulation of the cycle, its integration into anabolic and catabolic pathways, and the characteristics of the genes and enzymes involved in the cycle continue to be active areas of research.Here we will explore the possible significance of animal species (metazoans) expressing two succinate-CoA ligases 2 (SUCLs) with different nucleotide specificities. Both ligases are located in the matrix of mitochondria, where they could participate in the oxidative direction of the cycle. Key questions center on the roles of the two ligases and the extent to which GTP produced by G-SUCL undergoes transphosphorylation with ADP, as has been described in textbooks for nearly 50 years.The citric acid cycle proposed by Johnson and Krebs in 1937 [2, 3] fostered a mode of thinking that led to the elucidation of other cycles and pathways of intermediary metabolism. Krebs stated that the concept of the cycle, as shown in Fig. 1, evolved slowly over a 5-year period [3]. Its purpose was to explain how several plant dicarboxylic acids catalytically stimulate the oxidative metabolism of pyruvate in tissue preparations from animals. The cycle
The Odyssey of a Young Gene: Structure–Function Studies in Human Glutamate Dehydrogenases Reveal Evolutionary-Acquired Complex Allosteric Regulation Mechanisms
Mammalian glutamate dehydrogenase (GDH) catalyzes the reversible inter-conversion of glutamate to α-ketoglutarate and ammonia, interconnecting carbon skeleton and nitrogen metabolism. In addition, it functions as an energy switch by its ability to fuel the Krebs cycle depending on the energy status of the cell. As GDH lies at the intersection of several metabolic pathways, its activity is tightly regulated by several allosteric compounds that are metabolic intermediates. In contrast to other mammals that have a single GDH-encoding gene, humans and great apes possess two isoforms of GDH (hGDH1 and hGDH2, encoded by the GLUD1 and GLUD2 genes, respectively) with distinct regulation pattern, but remarkable sequence similarity (they differ, in their mature form, in only 15 of their 505 amino-acids). The GLUD2 gene is considered a very young gene, emerging from the GLUD1 gene through retro-position only recently (<23 million years ago). The new hGDH2 iso-enzyme, through random mutations and natural selection, is thought to have conferred an evolutionary advantage that helped its persistence through primate evolution. The properties of the two highly homologous human GDHs have been studied using purified recombinant hGDH1 and hGDH2 proteins obtained by expression of the corresponding cDNAs in Sf21 cells. According to these studies, in contrast to hGDH1 that maintains basal activity at 35-40 % of its maximal, hGDH2 displays low basal activity that is highly responsive to activation by rising levels of ADP and/or L-leucine which can also act synergistically. While hGDH1 is inhibited potently by GTP, hGDH2 shows remarkable GTP resistance. Furthermore, the two iso-enzymes are differentially inhibited by estrogens, polyamines and neuroleptics, and also differ in heat-lability. To elucidate the molecular mechanisms that underlie these different regulation patterns of the two iso-enzymes (and consequently the evolutionary adaptation of hGDH2 to a new functional role), we have performed mutagenesis at sites of difference in their amino acid sequence. Results showed that the low basal activity, heat-lability and estrogen sensitivity of hGDH2 could be, at least partially, ascribed to the Arg443Ser evolutionary change, whereas resistance to GTP inhibition has been attributed to the Gly456Ala change. Other amino acid substitutions studied thus far cannot explain all the remaining functional differences between the two iso-enzymes. Also, the Arg443Ser/Gly456Ala double mutation in hGDH1 approached the properties of wild-type hGDH2, without being identical to it. The insights into the structural mechanism of enzymatic regulation and the implications in cell biology provided by these findings are discussed.
We suggest that both succinyl-CoA synthetases catalyze the reverse reaction in the citric acid cycle in which the ADP-forming enzyme augments ATP production, whereas the GDP-forming enzyme supports GTPdependent anabolic processes. Widely accepted shuttle mechanisms are invoked to explain how transport of P-enolpyruvate across mitochondrial membranes can transfer high energy phosphate between the cytosol and mitochondrial matrix.
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