Regulation of pyruvate metabolism and human disease

Lawrence R. Gray 0 Sean C. Tompkins 0 Eric B. Taylor 0 0 L. R. Gray S. C. Tompkins e. B. Taylor ( 1 ) Department of Biochemistry, Fraternal Order of the eagles Diabetes Research Center, and Franois M. Abboud Cardiovascular Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , 51 Newton Rd, 4-403 BSB, Iowa City, IA 52242, USA Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria as a master fuel input undergirding citric acid cycle carbon flux. In mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, including the recently discovered mitochondria pyruvate carrier, pyruvate dehydrogenase, and pyruvate carboxylase, to modulate overall pyruvate carbon flux. Mutations in any of the genes encoding for proteins regulating pyruvate metabolism may lead to disease. Numerous cases have been described. Aberrant pyruvate metabolism plays an especially prominent role in cancer, heart failure, and neurodegeneration. Because most major diseases involve aberrant metabolism, understanding and exploiting pyruvate carbon flux may yield novel treatments that enhance human health. ADP Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is Fig. 1 enzymes involved in proximal pyruvate metabolism. Pyruvate plays an essential role in central carbon metabolism. Pyruvate is generated from several sources, including the oxidation of lactate, the transamination of alanine, or as the terminal product of glycolysis. entry of pyruvate into the mitochondrial matrix is mediated by the MPC. Once in the matrix, pyruvate can be converted to acetyl-CoA or oxaloacetate. Oxaloacetate can enter the citric acid cycle to replenish intermediates, or be converted to phosphoenolpyruvate as part of the gluconeogenic pathway. Phosphoenolpyruvate can be formed from oxaloacetate by PePCK within the mitochondria or within the cytoplasm. The molecular structures of pyruvate and related metabolites, as well the names of the enzymes involved in their catalysis, are shown. PK pyruvate kinase, LDH lactate dehydrogenase, ALT alanine aminotransferase, MPC mitochondrial pyruvate carrier, PDH pyruvate dehydrogenase, CoA Coenzyme A, IMS mitochondrial inner membrane space, PEPCK phosphoenolpyruvate carboxykinase the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria where it is the master fuel input undergirding citric acid cycle carbon flux (Fig. 1). Accordingly, pyruvate is critical for mitochondrial ATP generation and for driving several major biosynthetic pathways intersecting the citric acid cycle (Fig. 2). Disruption in pyruvate metabolism, depending on the location or severity of the mutation, causes mild to severe disease (Table 1). Tissues with a high demand for ATP are most affected, with the nervous system being particularly vulnerable because of its predominate reliance on carbohydrate metabolism for ATP generation. Aberrant pyruvate metabolism may arise from mutations in any of the many genes coding for enzymes that regulate it. Most of these enzymes have been well studied for decades, yet additional critical aspects of pyruvate metabolism are just beginning to be understood. The mitochondrial pyruvate carrier (MPC), which serves as a highly critical link between cytosolic and mitochondrial pyruvate metabolism, was only recently identified [1, 2]. This review will discuss the enzymes regulating major aspects of pyruvate metabolism, their structures, and the biochemical bases for the reactions they catalyze, the roles dysfunctional forms play in causing human disease, and major diseases for which aberrant pyruvate metabolism is a prominent characteristic. Cytosolic pyruvate metabolism Cytosolic pyruvate originates from several sources (Fig. 1). In most cells, the major source of pyruvate is the last step of glycolysis, where pyruvate kinase converts phosphoenolpyruvate to pyruvate. Other significant sources include Fig. 2 Pyruvate and citric acid cycle carbon flux. Pyruvate is the master carbon fuel input supporting overall citric acid cycle carbon flux. Pyruvate transits the inner mitochondrial membrane (IMM) through the mitochondrial pyruvate carrier (MPC) to reach the mitochondrial matrix. In the matrix, pyruvate carbon enters the citric acid cycle as citrate or oxaloacetate, depending on the need to replenish oxaloacetate. Numerous metabolic pathways intersect the citric acid cycle. The modulation of mitochondrial pyruvate flux balances for anaplerotic carbon entrance and cataplerotic carbon exit to ensure continued cycle flux. Disruption of mitochondrial pyruvate flux may subsequently disrupt carbon flux through any of the pathways intersecting the citric acid cycle Table 1 Overview of enzymes involved in proximal pyruvate metabolism Pyruvate dehydrogenase (PDH) Lactate dehydrogenase (LDH) Alanine aminotransferase (ALT) Pyruvate +NAD CO2 + Acetyl-CoA + NADH Pyruvate + ATP + CO2 Oxaloacetate + ADP Pyruvate + glutamate Alanine + -ketoglutarate PyruvateIMS pyruvateMatrix Metabolic deficiency symptoms Myoglobinuria, elevate pyruvate levels, low endurance/exercise intolerance Highly variable, depends upon classification (Types A, B, or C) May include lactic acidosis, developmental delay, and elevated proline and alanine levels Hemolytic anemia, hyperbilirubinemia Neurodegeneration, lactic acidosis, hyper- v ery rare (2 cases) [1, 68] pyruvicemia, psychomotor retardation Lactic acidosis, elevated pyruvate and alanine levels, exercise intolerance, hypotonia v ery rare (2 cases) [113, 114] This table summarizes the reactions catalyzed by the enzymes involved in proximal pyruvate metabolism as well as the symptoms and incidences, where known, of the metabolic deficiencies characterized by their misregulation, mutation, or loss in human patients lactate via lactate dehydrogenase (LDH) and alanine via alanine aminotransferase (ALT). Pyruvate kinase (PK) catalyzes the dephosphorylation of phosphoenolpyruvate into pyruvate during the final, irreversible step of glycolysis. The breakdown of glucose via glycolysis yields two molecules of pyruvate and two net molecules of ATP. Thus, glycolysis is an important source of energy for most cells in the body. It is especially important in red blood cells which lack mitochondria and in skeletal muscle during intense periods of work, when ATP production by oxidative phosphorylation is insufficient to power muscle contraction. PK plays a prominent role here because it catalyzes one of the two energy-generating reactions in gly (...truncated)