Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function

Abstract

SUMMARY 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.

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

“…HXK1 is normally localized to the outer membrane of mitochondria through specific binding to voltage dependent anion channel (VDAC), where it couples cytosolic glycolysis to mitochondrial ATP production and interacts with the Na+/K+ ATPase (23, 57). This confers HXK1 direct access to ATP generated by mitochondria and facilitates increased activity/high glycolytic rates when needed.…”

“…Abnormalities in bioenergetic function are likely to have implications for neuronal and circuit activity. Glucose is converted to glucose-6-phosphate (G6P) via HXK in the first step of glycolysis, where it may be further converted to other bioenergetic intermediates by highly regulated enzymes, such as phosphofructokinase, ultimately yielding pyruvate and ATP (23). Pyruvate may be converted to lactate by lactate dehydrogenase (LDH) and shuttled via monocarboxylate transporters (MCTs) into neurons, providing energy for receptor trafficking, spine formation and other neurotransmission events (24, 25).…”

Evolution of glucose utilization: Glucokinase and glucokinase regulator protein

“…Enzymes, called hexokinases, phosphorylate glucose, and other six-carbon sugars. In mammals, and other vertebrates, four hexokinase isozymes have been identified (Ureta, 1982;Wilson, 1995Wilson, , 1997Wilson, , 2003Wilson, , 2004Cárdenas et al, 1998). The different isozymes of hexokinase were initially distinguished by letters (i.e., hexokinase (HK) A, B, C, and D) based on their elution time from DEAE cellulose columns (González et al, 1964), but subsequently given numbers (i.e., hexokinase I, II, III, and IV) based on their migration in electrophoretic gels (Katzen et al, 1965).…”

“…Hexokinase IV (or D) is most often called glucokinase (GCK), although it is not specific for glucose (Cárdenas et al, 1998;Wilson, 2004). Genes encoding these hexokinases use Arabic numbers; e.g., HK1 encodes hexokinase I. Mammalian hexokinases have been extensively characterized, with possibly their most striking difference being their molecular weights (Ureta, 1982;Wilson, 1995Wilson, , 1997Wilson, , 2003Wilson, , 2004Cárdenas et al, 1998). Hexokinases I, II, and III have a molecular weight of approximately 100kD, while glucokinase has a molecular mass of about 50kD.…”

“…Hexokinases I, II, and III have a molecular weight of approximately 100kD, while glucokinase has a molecular mass of about 50kD. Hexokinases having a molecular weight of 50kD, but not 100kD, have also been found, and characterized, in many other eukaryotes species, including nonvertebrate animals, plants, and yeast (Ureta, 1982;Wilson, 1995Wilson, , 1997Wilson, , 2003Wilson, , 2004Cárdenas et al, 1998). In some of these non-mammalian species multiple isozymes have been characterized (Wilson, 1995(Wilson, , 2004Cárdenas et al, 1998).…”