Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function
Tóm tắt
The first step in metabolism of glucose (Glc) is usually phosphorylation,catalyzed by hexokinase. However, the Glc-6-P produced can then enter one or more of several alternative pathways. Selective expression of isozymic forms of hexokinase, differing in catalytic and regulatory properties as well as subcellular localization, is likely to be an important factor in determining the pattern of Glc metabolism in mammalian tissues/cells. Despite their overall structural similarity, the Type I, Type II and Type III isozymes differ in important respects. All three isozymes are inhibited by the product,Glc-6-P, but with the Type I isozyme, this inhibition is antagonized by PI, whereas with the Type II and Type III isozymes, Piactually causes additional inhibition. Reciprocal changes in intracellular levels of Glc-6-P and Pi are closely associated with cellular energy status, and it is proposed that the response of the Type I isozyme to these effectors adapts it for catabolic function, introducing Glc into glycolytic metabolism for energy production. In contrast, the Type II, and probably the Type III, isozymes are suggested to serve primarily anabolic functions, e.g. to provide Glc-6-P for glycogen synthesis or metabolism via the pentose phosphate pathway for lipid synthesis. Type I hexokinase binds to mitochondria through interaction with porin, the protein that forms channels through which metabolites traverse the outer mitochondrial membrane. Several experimental approaches have led to the conclusion that the Type I isozyme, bound to actively phosphorylating mitochondria, selectively uses intramitochondrial ATP as substrate. Such interactions are thought to facilitate coordination of the introduction of Glc into glycolysis, via the hexokinase reaction, with the terminal oxidative stages of Glc metabolism occurring in the mitochondria, thus ensuring an overall rate of Glc metabolism commensurate with cellular energy demands and avoiding excessive production of lactate. The Type II isozyme also binds to mitochondria. Whether such coupling occurs with mitochondrially bound Type II hexokinase in normal tissues, and how it might be related to the proposed anabolic role of this isozyme, remain to be determined. The Type III isozyme lacks the hydrophobic N-terminal sequence known to be critical for binding of the Type I and Type II isozymes to mitochondria. Immunolocalization studies have indicated that, in many cell types, the Type III has a perinuclear localization, the possible metabolic consequences of which remain unclear.
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Ardehali, H., Yano, Y., Printz, R. L., Koch, S., Whitesell, R. R., May, J. M. and Granner, D. K. (1996). Functional organization of mammalian hexokinase II. Retention of catalytic and regulatory functions in both the NH2 and COOH-terminal halves. J. Biol. Chem.271,1849-1852.
Arora, A. K. and Peterson, P. L. (1988). Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP+. J. Biol. Chem.263,17422-17428.
Baijal, M. and Wilson, J. E. (1992). Functional consequences of mutation of highly conserved serine residues, found at equivalent positions in the N- and C-terminal domains of mammalian hexokinases. Arch. Biochem. Biophys. 298,271-278.
BeltrandelRio, H. and Wilson, J. E. (1991). Hexokinase of rat brain mitochondria: relative importance of adenylate kinase and oxidative phosphorylation as sources of substrate ATP, and interaction with intramitochondrial compartments of ATP and ADP. Arch. Biochem. Biophys.286,183-194.
BeltrandelRio, H. and Wilson, J. E. (1992a). Coordinated regulation of cerebral glycolysis and oxidative metabolism,mediated by mitochondrially bound hexokinase dependent on intramitochondrially generated ATP. Arch. Biochem. Biophys.296,667-677.
BeltrandelRio, H. and Wilson, J. E. (1992b). Interaction of mitochondrially bound rat brain hexokinase with intramitochondrial compartments of ATP generated by oxidative phosphorylation and creatine kinase. Arch. Biochem. Biophys.299,116-124.
Bork, P., Sander, C. and Valencia, A. (1993). Convergent evolution of similar enzymatic function on different protein folds:the hexokinase, ribokinase, and galactokinase families of sugar kinases. Prot. Sci.2,31-40.
Cárdenas, M. L., Cornish-Bowden, A. and Ureta, T.(1998). Evolution and regulatory role of the hexokinases. Biochim. Biophys. Acta1401,242-264.
Clarke, D. D. and Sokoloff, L. (1998). Circulation and energy metabolism in the brain. In Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th edition (ed. G. J. Siegel, B. W. Agranoff, R. W. Albers, S. K. Fisher and M. D. Uhler), pp. 637-669. Philadelphia: Lippincott,Williams & Wilkins.
Crane, R. K. and Sols, A. (1953). The association of hexokinase with particulate fractions of brain and other tissue homogenates. J. Biol. Chem.203,273-292.
De Cerqueira Cesar, M. and Wilson, J. E.(1995). Application of a double isotope labeling method to a study of the interaction of mitochondrially bound rat brain hexokinase with intramitochondrial compartments of ATP generated by oxidative phosphorylation. Arch. Biochem. Biophys.324, 9-14.
De Cerqueira Cesar, M. and Wilson, J. E.(1998). Further studies on the coupling of mitochondrially bound hexokinase to intramitochondrially compartmented ATP, generated by oxidative phosphorylation. Arch. Biochem. Biophys.350,109-117.
De Cerqueira Cesar, M. and Wilson, J. E.(2002). Functional characteristics of hexokinase bound to the Type A and Type B sites of bovine brain mitochondria. Arch. Biochem. Biophys.397,106-112.
Dorbani, L., Jancsik, V., Lindén, M., Leterrier, J. F.,Nelson, B. D. and Rendon, A. (1987). Subfractionation of the outer membrane of rat brain mitochondria: evidence for the existence of a domain containing the porinhexokinase complex. Arch. Biochem. Biophys.252,188-196.
Felgner, P. L., Messer, J. L. and Wilson, J. E.(1979). Purification of a hexokinase-binding protein from the outer mitochondrial membrane. J. Biol. Chem.254,4946-4949.
Fiek, C., Benz, R., Roos, N. and Brdiczka, D.(1982). Evidence for identity between the hexokinase-binding protein and the mitochondrial porin in the outer membrane of rat liver mitochondria. Biochim. Biophys. Acta688,429-440.
Gelb, B. D., Adams, V., Jones, S. N., Griffin, L. D., MacGregor,G. R. and McCabe, E. R. B. (1992). Targeting of hexokinase 1 to liver and hepatoma mitochondria. Proc. Natl. Acad. Sci. USA89,202-206.
González, C., Ureta, T., Sanchez, R. and Niemeyer, H.(1964). Multiple molecular forms of ATP:hexose 6-phosphotransferase from rat liver. Biochem. Biophys. Res. Commun.16,347-352.
Hashimoto, M. and Wilson, J. E. (2000). Membrane potential-dependent conformational changes in mitochondrially bound hexokinase of brain. Arch. Biochem. Biophys.384,163-173.
Heikkinen, S., Supploa, S., Malkki, M. and Deeb, S.(2000). Mouse hexokinase II gene: structure, cDNA, promoter analysis, and expression pattern. Mamm. Genome11, 91-96.
Hofmann, S. and Pette, D. (1994). Low-frequency stimulation of rat fast-twitch muscle enhances the expression of hexokinase II and both the translocation and expression of glucose transporter 4 (GLUT-4). Eur. J. Biochem.219,307-315.
Johnson, M. K. (1960). The intracellular distribution of glycolytic and other enzymes in rat brain homogenates and mitochondrial preparations. Biochem. J.77,610-618.
Kaselonis, G. L., McCabe, E. R. B. and Gray, S. M.(1999). Expression of hexokinase 1 and hexokinase 2 in mammary tissue of nonlactating and lactating rats: Evaluation by RT-PCR. Mol. Gen. Metab.68,371-374.
Katzen, H. M. and Schimke, R. T. (1965). Multiple forms of hexokinase in the rat: Tissue distribution, age dependency,and properties. Proc. Natl. Acad. Sci. USA54,1218-1225.
Kottke, M., Adam, V., Riesinger, I., Bremm, G., Bosch, W.,Brdiczka, D., Sandri, G. and Panfili, E. (1988). Mitochondrial boundary membrane contact sites in brain: points of hexokinase and creatine kinase location, and control of Ca2+ transport. Biochim. Biophys. Acta935,87-102.
Kropp, E. S. and Wilson, J. E. (1970). Hexokinase binding sites on mitochondrial membranes. Biochem. Biophys. Res. Commun.38,74-79.
Laterveer, F., Nicolay, K., BeltrandelRio, H. and Wilson, J. E. (1993). Brain hexokinase and intramitochondrial compartments of ATP: fact and artifact. Arch. Biochem. Biophys.306,285-286.
Lindén, M., Gellerfors, P. and Nelson, B. D.(1982). Pore protein and the hexokinase-binding protein from the outer membrane of rat liver mitochondria are identical. FEBS Lett.141,189-192.
Liu, W. and Wilson, J. E. (1997). Two Sp sites are important cis elements regulating the upstream promoter region of the gene for rat Type I hexokinase. Arch. Biochem. Biophys.346,142-150.
Lowry, O. H., Passonneau, J. V., Hasselberger, F. X. and Schulz,D. W. (1964). Effect of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J. Biol. Chem.239,18-30.
Marie, C. and Bralet, J. (1991). Blood glucose level and morphological brain damage following cerebral ischemia. Cerebrovasc. Brain Metab. Rev.3,29-38.
Mathupala, S. P., Rempel, A. and Pedersen, P. L.(1995). Glucose catabolism in cancer cells. Isolation, sequence,and activity of the promoter for Type II hexokinase. J. Biol. Chem.270,16918-16925.
Osawa, H., Robey, R. B., Printz, R. L. and Granner, D. K.(1996). Identification and characterization of basal and cyclic AMP response elements in the promoter of the rat hexokinase II gene. J. Biol. Chem.271,17296-17303.
Ovádi, J. and Srere, P. A. (2000). Macromolecular compartmentation and channeling. Intl. Rev. Cytol.192,255-280.
Polakis, P. G. and Wilson, J. E. (1985). An intact hydrophobic N-terminal sequence is critical for binding of rat brain hexokinase to mitochondria. Arch. Biochem. Biophys.236,328-337.
Postic, C., Shiota, M. and Magnuson, M. A.(2001). Cell-specific roles of glucokinase in glucose metabolism. Recent Prog. Horm. Res.56,195-217.
Preller, A. and Wilson, J. E. (1992). Localization of the Type III isozyme of hexokinase at the nuclear periphery. Arch. Biochem. Biophys.294,482-492.
Radojkovíc, J. and Ureta, T. (1987). Hexokinase isozymes from the Novikoff hepatoma. Purification, kinetic and structural characterization, with emphasis on hexokinase C. Biochem. J.242,895-903.
Rodríguez, A., de la Cera, T., Herrero, P. and Moreno,F. (2001). The hexokinase 2 protein regulates the expression of the GLK1, HXK1 and HXK2 genes of Saccharomyces cerevisiae.Biochem. J.355,625-631.
Rose, I. A. and Warms, J. V. B. (1967). Mitochondrial hexokinase: release, rebinding, and location. J. Biol. Chem.242,1635-1645.
Sebastian, S., White, J. A. and Wilson, J. E.(1999). Characterization of the rat Type III hexokinase gene promoter. A functional octamer 1 motif is critical for basal promoter activity. J. Biol. Chem.274,31700-31706.
Sebastian, S., Horton, J. D. and Wilson, J. E.(2000). Anabolic function of the Type II isozyme of hexokinase in hepatic lipid synthesis. Biochem. Biophys. Res. Commun.270,886-891.
Sebastian, S., Edassery, S. and Wilson, J. E.(2001). The human gen for the Type III isozyme of hexokinase. Structure, basal promoter, and evolution. Arch. Biochem. Biophys.395,113-120.
Shinohara, Y., Yamamoto, K., Kogure, K., Ichihara, J. and Terada, H. (1994). Steady state transcript levels of the type II hexokinase and type 1 glucose transporter in human tumor cells. Cancer Lett.82,27-32.
Sui, D. and Wilson, J. E. (1997). Structural determinants for the intracellular localization of the isozymes of mammalian hexokinase: Intracellular localization of fusion constructs incorporating structural elements from the hexokinase isozymes and the green fluorescent protein. Arch. Biochem. Biophys.345,111-125.
Tielens, A. G. M., van den Heuvel, J. M., van Mazijk, H. J.,Wilson, J. E. and Shoemaker, C. B. (1994). The 50-kDa glucose 6-phosphate-sensitive hexokinase of Schistosoma mansoni. J. Biol. Chem.269,24736-24741.
Tsai, H. J. and Wilson, J. E. (1995). Functional organization of mammalian hexokinases: Characterization of chimeric hexokinases constructed from the N- and C-terminal halves of the rat Type I and Type II isozymes. Arch. Biochem. Biophys.316,206-214.
Tsai, H. J. and Wilson, J. E. (1996). Functional organization of mammalian hexokinases. Both N- and C-terminal halves of the rat Type II isozyme possess catalytic sites. Arch. Biochem. Biophys.329,17-23.
Tsai, H. J. and Wilson, J. E. (1997). Functional organization of mammalian hexokinases. Characterization of the rat Type III isozyme and its chimeric forms, constructed with the N- and C-terminal halves of the Type I and Type II isozymes. Arch. Biochem. Biophys.338,183-192.
Ureta, T. (1978). The role of isozymes in metabolism: A model of metabolic pathways as the basis for the biological role of isozymes. Curr. Top. Cell. Regul.13,233-258.
White, T. K. and Wilson, J. E. (1989). Isolation and characterization of the discrete N- and C-terminal halves of rat brain hexokinase: Retention of full catalytic activity in the isolated C-terminal half. Arch. Biochem. Biophys.274,373-393.
White, J. A., Liu, W. and Wilson, J. E. (1996). Isolation of the promoter for Type I hexokinase from rat. Arch. Biochem. Biophys.335,161-172.
Wilson, J. E. (1985). Regulation of mammalian hexokinase activity. In Regulation of Carbohydrate Metabolism, Vol. I (ed. R. Beitner), pp.45-85. Boca Raton, FL: CRC Press, Inc.
Wilson, J. E. (1997). An introduction to the isoenzymes of mammalian hexokinase types I-III. Biochem. Soc. Trans.25,103-108.