Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the following reaction: oxalacetate(OAA) + GTP yields equilibrium PEP + HCO3- + GDP. Large amounts are in liver, kidney, white and brown adipose tissues. Data about its presence and quantity in other tissues are fragmentary. The hepatic cellular distribution of PEPCK varies with species: mitochondrial(M) in birds, cytoplasmic(C) in rodents and both M and C in other species. M and C activities are due to different isozymes. Most studies have used rat tissues to conclude that PEPCK in liver and kidney is essential to gluconeogenesis in all species. C PEPCK supports glycerogenesis in adipose tissue although glycerol formation from its most common source, glucose, does not require PEPCK. M PEPCK supports conversion of lactate carbon to glucose but so does C PEPCK. Thus the only essential role known for PEPCK is for the C isozyme in liver and kidney. No essential role has been defined for the M isozyme in liver or kidney, nor for either isozyme in non-gluconeogenic tissues. The reaction catalyzed by PEPCK is readily reversible and the reverse reaction is enhanced > 20 fold by Mn2+ and Fe2+. Reversal of PEPCK has been shown in hepatic mitochondria and OAA formed from PEP is proposed as an intermediate in lipogenesis. Formation of OAA by reversal of the PEPCK reaction also conserves one equivalent of high-energy phosphate. PEPCK isozymes will be quantitated (using specific monoclonal antibodies to each isozyme) in all major tissues of several diverse laboratory species: rabbit, guinea pig, rat, and chick. The influence of Mn2+ and Fe2+ depletion or repletion on OAA formation from PEP will be studied in isolated rabbit liver mitochondria. Conversion of glucose carbon to fatty acids will be studied in rabbit hepatocytes, white and brown adipocytes in the absence and presence of specific inhibitors of M and C PEPCK and inhibitors of pyruvate transport. The influence of Mn2+ and Fe2+ depletion or repletion on fatty acid formation from glucose by these isolated cells will also be studied. Participation of the reverse reaction catalyzed by PEPCK in lipogenesis would require revising current concepts of this process. Regulation of the reverse reaction by Mn2+ and Fe2+ would underscore the nutritional significance of these trace elements. Quantitation of PEPCK isozymes in other tissues will allow a search for roles for these isozymes in those tissues. Defined roles for PEPCK might help to elucidate the presence or nature of diseases related to carbohydrate or lipid metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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University of North Dakota
Schools of Medicine
Grand Forks
United States
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