The Human Gene for the Type III Isozyme of Hexokinase: Structure, Basal Promoter, and Evolution

Sebastian, Siby; Edassery, Seby L.; Wilson, John E.

doi:10.1006/abbi.2001.2584

Cited by 13 publications

(9 citation statements)

References 43 publications

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“…Analysis of the HKI promoter, as well as the ubiquitous tissue expression of this isoform, indicate that HKI is constitutively expressed, while HKII expression is tissue specific and regulated by stimuli such as insulin and hypoxia [7], [30], [31], [32], [39], [40]. HKIII is primarily expressed in the lung, kidney, and liver [7], [9], [41], and an Oct-1 binding site is necessary for basal HKIII expression [9], but little else is known about the regulation of HKIII activity. Sequence analysis of the HKIII promoter identified several putative regulatory elements that may respond to cAMP, AMPK, or HIF signal transduction.…”

Section: Discussionmentioning

confidence: 99%

“…HKI is ubiquitously expressed, while HKII is primarily expressed in insulin sensitive tissue such as skeletal and cardiac muscle. HKIII expression is relatively low in most tissue, with the highest levels reported in lung, kidney, and liver [7], [8], [9]. HKIV has a low affinity for glucose, is not inhibited by G6P, and is expressed mainly in pancreatic B cells and the liver, where it is believed to function as a ‘glucose sensor’ [8].…”

Section: Introductionmentioning

confidence: 99%

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Regulation and Cytoprotective Role of Hexokinase III

Wyatt

Rabeh

et al. 2010

PLoS ONE

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BackgroundHexokinases (HKs) catalyze the first step in glucose metabolism. Of the three mammalian 100-kDa HK isoforms, HKI and II can bind to mitochondria and protect against cell death. HKIII does not bind mitochondria, and little is known about its regulation or cytoprotective effects. We studied the regulation of HKIII at the transcriptional and protein levels and investigated its role in cellular protection.Methodology/Principal FindingsWe show that like HKII, HKIII expression is regulated by hypoxia, but other factors that regulate HKII expression have no effect on HKIII levels. This transcriptional regulation is partially dependent on hypoxia-inducible factor (HIF) signaling. We also demonstrate regulation at the protein level, as mutations in putative N-terminal substrate binding residues altered C-terminal catalytic activity, suggesting that HKIII activity is governed, in part, by interactions between these two domains. Overexpression of HKIII reduced oxidant-induced cell death, increased ATP levels, decreased the production of reactive oxygen species (ROS), and preserved mitochondrial membrane potential. HKIII overexpression was also associated with higher levels of transcription factors that regulate mitochondrial biogenesis, and greater total mitochondrial DNA content. Attempts to target HKIII to the mitochondria by replacing its N-terminal 32-amino-acid sequence with the mitochondrial-targeting sequence of HKII led to protein aggregation, suggesting that this region is necessary to maintain proper protein folding and solubility.Conclusions/SignificanceThese results suggest that HKIII is regulated by hypoxia and there are functional interactions between its two halves. Furthermore, HKIII exerts protective effects against oxidative stress, perhaps by increasing ATP levels, reducing oxidant-induced ROS production, preserving mitochondrial membrane potential, and increasing mitochondrial biogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation and Cytoprotective Role of Hexokinase III

Wyatt

Rabeh

et al. 2010

PLoS ONE

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“…HK2 is uncommonly expressed in normal tissues, with the exception of insulin sensitive tissues like skeletal and cardiac muscle, renal mesangial cells, and adipose tissue [22][23][24]. HK3 is mainly expressed in liver, lung and kidney [25] while HK4 is a specific enzyme for pancreatic B cells and the liver, because of its low affinity for glucose [23].…”

Section: Hexokinase (Hk)mentioning

confidence: 98%

Enzymes of the central carbon metabolism: Are they linkers between transcription, DNA replication, and carcinogenesis?

et al. 2015

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“…Promoter regions governing the transcription of the Type I (White et al, 1996;Liu and Wilson, 1997), Type II (Mathupala et al, 1995;Osawa et al, 1996;Heikkinen et al, 2000) and Type III (Sebastian et al, 1999(Sebastian et al, , 2001) isozymes have been isolated and characterized to some extent. It is clear that these are distinct in character, and responsive to quite different transcription factors.…”

Section: Isozymes Of Mammalian Hexokinasementioning

confidence: 99%

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

Wilson

2003

Journal of Experimental Biology

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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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The Human Gene for the Type III Isozyme of Hexokinase: Structure, Basal Promoter, and Evolution

Cited by 13 publications

References 43 publications

Regulation and Cytoprotective Role of Hexokinase III

Regulation and Cytoprotective Role of Hexokinase III

Enzymes of the central carbon metabolism: Are they linkers between transcription, DNA replication, and carcinogenesis?

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

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