L-pyruvate kinase

Lefrancois-Martinez, A.M., Diaz-Guerra, M.J., Vallet, V., Kahn, A. and Antoine, B. (1994) Glucose-dependent regulation of the L-pyruvate kinase gene in a hepatoma cell line is independent of insulin and cyclic AMP. FASEB. J., 8, 89-96. 

Pyruvate kinase (PK) is one of the three postulated rate-controlling enzymes of glycolysis. The high-energy phosphate of phosphoenolpyruvate is transferred to ADP by this enzyme, which requires for its activity both monovalent and divalent cations. Enolpyruvate formed in this reaction is converted spontaneously to the keto form of pyruvate with the synthesis of one ATP molecule. PK has four isozymes in mammals M, M2, L, and R. The M2 type, which is considered to be the prototype, is the only form detected in early fetal tissues and is expressed in many adult tissues. This form is progressively replaced by the M( type in the skeletal muscle, heart, and brain by the L type in the liver and by the R type in red blood cells during development or differentiation (M26). The M, and M2 isozymes display Michaelis-Menten kinetics with respect to phosphoenolpyruvate. The Mj isozyme is not affected by fructose-1,6-diphosphate (F-1,6-DP) and the M2 is al-losterically activated by this compound. Type L and R exhibit cooperatively in... 

Fig. 4. Schematic representation of expression of the rat pyruvate kinase (PK) gene. Exons specific to each isozyme are indicated by marked boxes. The exons common to Mj- and M2-type PK and common to L- and R-type PK are shown by open boxes. CAAT, CAT box TATA, TATA box AATAAA, polyadenylation signal.

Fig. 9. Mutations in L-type pyruvate kinase gene. [ ] shows the references, ins insertion, del deletion.

B3. Baronciani, L., and Beutler, E., Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. Proc. Natl. Acad. Sci. U.S.A. 90,4324-4327 (1993). 

B7. Baronciani, L., Bianchi, P and Zanella, A., Hematologically important mutations Red cell pyruvate kinase. Blood Cells Mol. Dis. 22,85-89(1996). 

B30. B ianchi, P Terragna, C., Zappa, M., Alfinito, F and Zanella, A., Molecular characterization of L-PK gene in pyruvate kinase (PK) deficient Italian patients. Blood 84 (Suppl. 1), 14a (1994). 

B32. Bianchi, P., Zanella, A., Zappoa, M., Vercellati, C., Terragna, C., Baronciani, L., and Sirchia, G., A new point mutation G/A 1168 (Asp390-Asn) in an Italian patient with erythrocyte pyruvate kinase deficiency. Blood 86 (Suppl. 1), 133a (1995). 

K6. Kanno, H., Fujii, H., and Miwa, S., Structural analysis of human pyruvate kinase L-gene and identification of the promoter activity in erythroid cells. Biochem. Biophys. Res. Commun. 188, 516-523 (1992). 

K9. Kanno, H., Wei, D. C. C., Miwa, S., Chan, L. C., and Fujii, H., Identification of a 5 -splice site mutation and a missense mutation in homozygous pyruvate kinase deficiency cases found in Hong Kong. Blood 82 (Suppl. 1), 97a (1993). 

L8. Lenzner, C Niimberg, P Thiele, B.-J., Reis, A., Brabec, V., Sakalova, A., and Jacobasch, G., Mutations in the pyruvate kinase L gene in patients with hemolytic anemia. Blood 83, 2817-2822(1994). 

N5. Neubauer, B., Lakomek, M., Winkler, H., Parke, M., Hofferbert, S., Schroter, W., Point mutations in the L-type pyruvate kinase gene of two children with hemolytic anemia caused by pyruvate kinase deficiency. Blood 77, 1871-1875 (1991). 

Nil. Noguchi, T., Yamada, K., Inoue, H., Matsuda, T., and Tanaka, T., The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters. J. Biol. Chem. 262,14366-14371 (1987). 

Glutamine synthetase 6.3.1.2 C L-Glutamate NADH ADP Pyruvate Pyruvate kinase Lactate dehydrogenase... 

Feed-forward control is more likely to be focused on a reaction occurring at or near the end of a pathway. Compounds produced early in the pathway act to enhance the activity of the control enzyme and so prevent a back log of accumulated intermediates just before the control point. An example of feed-forward control is the action of glucose-6-phosphate, fructose-1,6-bisphosphate (F-l,6bisP) and phosphoenol pyruvate (PEP), all of which activate the enzyme pyruvate kinase in glycolysis in the liver. 

Staal, G., Koster, J., Kamp, H., Van Milligen-Boersma, L., and Veeger, C., Human erythrocyte pyruvate kinase, its purification and some properties, Biochem. Biophys. Acta, 227, 86-92, 1971. 

Buchbinder, J. L., and Reed, G. H. (1990). Electron paramagnetic resonance studies of the coordination schemes and site selectivities for divalent metal ions in complexes of pyruvate kinase. Biochemistry 29, 1799-1806. 

Exploration of Bulk Tolerance at ATP Sites. Non-covalent type inhibitors have also been used to study bulk tolerance around the ATP binding sites. In this vein Hampton and co-workers have both synthesized and tested as inhibitors a large number of adenine nucleotide analogs (Figure 2f) to probe the bulk tolerance at a number of positions on the parent compound (28-31) These compounds have been used to study systematically the isoenzyme selectivity of adenylate kinases, hexokinases, thymidine kinases and pyruvate kinases with respect to bulk tolerance at many sites on the ATP molecule. Some of the most isoenzyme specific results were obtained with pyruvate kinase isoenzymes K,L and M using ADP derivatives. Here 3 -0Me-ADP was found to inhibit pyruvate kinase preferentially with a ratio of inhibitory potency of 7.6 6.0 1.0 for the K,M and L isoenzymes, respectively. Another compound, 8-NHEt-ADP, was selective for the M isoenzyme, giving a ratio of 7.1 1.2 1.0 for the M, K and L forms, respectively. 

Carrillo, J.J. Ibares, B. Esteban-Gamboa, A. Feliu, J.E. Involvement of both phosphatidylinositol 3-kinase and p44/p42 mitogen-activated protein kinase pathways in the short-term regulation of pyruvate kinase L by insulin. Endocrinology, 142, 1057-1064 (2001)... 

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