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

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Wilson, John E.·2003·Journal of Experimental Biology
DOI 10.1242/jeb.00241
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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.

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  • Both hexokinase isoforms are expressed in a variety of cell types; insulin-sensitive cells such as adult muscle cells express primarily HK2, whereas cells that rely heavily on glycolysis such as neurons express predominantly Hk1.

    “Although both hexokinase isoforms are expressed in a variety of cell types, cells that are sensitive to insulin, such as adult muscle cells, express primarily HK2, whereas cells that rely heavily on glycolysis for energy production, such as neurons, express predominantly Hk1 (Mandarino et al., 1995;Wilson, 2003).”

    From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Wilson, 2003

    In the “Isozymes of mammalian hexokinase” section (page not supplied), Wilson describes Type I as ubiquitous and particularly highly expressed in brain, and Type II as found primarily in insulin-sensitive tissues including skeletal muscle. The passage does not establish that HK1 predominates specifically in neurons or that HK2 is the predominant isoform in adult muscle cells; saying where an isoform is found primarily is not the same as saying it predominates there. (LLM, conf=0.84)

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  • HK1 remains associated with mitochondria to promote glycolysis whereas HK2 dynamically translocates between cytosol and mitochondria where it directs the metabolic fate of glucose between anabolic and catabolic metabolism.

    “Additionally, it has been proposed that HK1 remains associated with mitochondria to promote glycolysis whereas HK2 dynamically translocates between cytosol and mitochondria where it directs the metabolic fate of glucose between anabolic (glycogen synthesis and pentose phosphate shunt) and catabolic (glycolysis) metabolism (Wilson, 2003;John et al., 2011).”

    From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Wilson, 2003

    The ‘Isozymes of mammalian hexokinase’ section proposes a glycolytic, energy-generating role for Type I and an anabolic role for Type II, including glycogen synthesis and the pentose phosphate pathway. The ‘Type II isozyme’ section reports both mitochondrial and non-mitochondrial Type II hexokinase, but does not establish dynamic translocation or say that movement between those locations directs glucose’s metabolic fate. The copy supports mitochondrial binding of Type I, not the stronger assertion that it remains associated. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 6

  1. 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.
  2. G. J. Siegel, B. W. Agranoff, R. W. Albers, S. K. Fisher and M. D. Uhler), pp. 637-669. Philadelphia: Lippincott, Williams & Wilkins.
  3. 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. USA 89, 202-206.
  4. 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. USA 54, 1218-1225.
  5. 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.
  6. Wilson, J. E. (1997). An introduction to the isoenzymes of mammalian hexokinase types I-III. Biochem. Soc. Trans. 25, 103-108.

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Authors
Wilson, J. E.
Affiliations
Michigan State University (US)
Corresponding author
Wilson, John E.
Venue
Journal of Experimental Biology
Publisher
The Company of Biologists
Published
2003-06-15
Volume
206
Issue
12
Pages
2049-2057
ISSN
  • 0022-0949 (ISSN-L)
  • 1477-9145
DOI
10.1242/jeb.00241
OpenAlex
W2146885685
Cited by
1,085
References
0
Citations by year
2026: 49 · 2025: 52 · 2024: 70 · 2023: 68 · 2022: 73 · 2021: 59 · 2020: 77 · 2019: 56 · 2018: 63 · 2017: 58 · 2016: 49 · 2015: 37 · 2014: 59 · 2013: 49 · 2012: 40
FWCI
1.59
Type
journal article
Language
en
Open access
Locations
  • Journal of Experimental Biology (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
National Institute of Neurological Disorders and Stroke (NS 09910, R01NS009910)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
hexokinase isozymes, glucose phosphorylation, glucose-6-phosphate, phosphoenolpyruvate inhibition, product inhibition, subcellular localization, mitochondrial binding, porin, glycolysis, pentose phosphate pathway, glycogen synthesis, cellular energy status, lactate
MeSH terms
Animals, Energy Metabolism, Hexokinase, Isoenzymes, Kinetics, Mammals, Glucose-6-Phosphate

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