The Role of Isozymes in Metabolism: A Model of Metabolic Pathways as the Basis for the Biological Role of Isozymes

Ureta, Tito

doi:10.1016/b978-0-12-152813-3.50011-2

Cited by 54 publications

(16 citation statements)

References 258 publications

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“…hormonal effects or chronic changes in physiological activity (Hofmann and Pette, 1994); (3) differences in subcellular location of the isozymes may result in compartmentation of Glc metabolism, with 'channeling' of Glc-6-P to particular metabolic pathways (Ureta, 1978;Ovádi and Srere, 2000).…”

Section: Isozymes Of Mammalian Hexokinasementioning

confidence: 99%

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

Wilson

2003

Journal of Experimental Biology

944

905

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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.

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Section: Isozymes Of Mammalian Hexokinasementioning

confidence: 99%

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

Wilson

2003

Journal of Experimental Biology

944

905

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“…Most of the glycolytic enzymes exist as multiple forms of activity (isozymes), for example, and attention has been drawn to the fact that the possibility may allow a tailoring of individual sequences to suit the requirements of different areas of carbohydrate metabolism. Ureta (21) postulates that there may be as many as ten different combinations of the glycolytic isozymes forming pathways associated with distinct aspects of carbohydrate metabolism.…”

Section: Assemblies Of Glycolytic Enzymes and The Cytomatrixmentioning

confidence: 99%

Interactions between glycolytic enzymes and components of the cytomatrix.

Masters¹

1984

The Journal of Cell Biology

166

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Evidence is provided that enzymes absorb to cellular structures in a wide range of tissues . In particular, the interactions between glycolytic enzymes and the microfilaments of the cytoplasm are described . The relevance of these interactions to the compartmentation of carbohydrate metabolism is discussed . Examples are given of the variations in degree of binding during alteration of tissue metabolism and, for individual glycolytic enzymes, during fetal development and differentiation . Overall, these data support the concept that metabolic activities in the cytoplasm have an organized structure . just as the structural elements of the cytosolic compartment have evolved with the capacity to assemble and disassemble in response to the changing requirements of the organism, so the metabolic elements appear to have evolved a parallel system that provides for the appropriate positioning of an energyproducing sequence in relation to the specific, dynamic requirements of the cytoskeleton .In other papers in this supplement there are many fascinating examples of the structural role of the cytomatrix and of the phenomena of directed motion in relation to this complex spatial organization. Cell shape, motility, cytoplasmic streaming, organelle distribution, cell division, and differentiation have all been viewed from this perspective, and the data leave little doubt as to the extraordinarily broad involvement of the cytomatrical structure (16) . At a functional level, the intricate choreography of structural reorganization during these cellular processes clearly requires an appropriate energy source, one with several special features. In this paper I describe the characteristics of the interactions between the glycolytic enzymes and the components of the cytomatrix, characteristics that may be of particular relevance in this context . Enzyme Binding and CompartmentationRecent studies (11, 12, 18) on intermediary metabolism have focused on the importance of compartmentation in the regulation of cellular processes and, to quote a recent treatise on this topic . ... . . it has become overtly clear that, in biology, order in metabolism is generated by the introduction of inhomogeneity, i.e., by compartmentation" (18).To most cell biologists, the most familiar examples of the metabolic advantages of the segregation of enzymes and metabolites are associated with compartmentation of cells and subcellular organelles, where a particular metabolic organization is surrounded and separated from other metabolic compartments by a physical permeability barrier, such as a 2225 membrane. Although this type of spatial compartmentation is undoubtedly the most intensively studied at this time, it is important to stress that effective metabolic compartmentation may also be achieved within a single membrane-enclosed space by means of the binding of key enzymes and metabolites. Thus, in the case of the cytoplasmic matrix, compartmentation by binding of soluble enzymes to the matrical structures may confer advantages over and above t...

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“…Both the residual hexokinase D and the high-affinity hexokinases would thus contribute to the low glucose phosphorylation observed by Bontemps et al (1978) in hepatocytes isolated from diabetic adult rats. If each isoenzyme had a specific role in a particular metabolic pathway, as postulated by Ureta (1978) Spence (1983).…”

Section: Discussionmentioning

confidence: 99%

Stability of hexokinases A, B and C and N-acetylglucosamine kinase in liver cells isolated from rats submitted to diabetes and several dietary conditions

1985

Biochemical Journal

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The Role of Isozymes in Metabolism: A Model of Metabolic Pathways as the Basis for the Biological Role of Isozymes

Cited by 54 publications

References 258 publications

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

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

Interactions between glycolytic enzymes and components of the cytomatrix.

Stability of hexokinases A, B and C and N-acetylglucosamine kinase in liver cells isolated from rats submitted to diabetes and several dietary conditions

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