* 601125

HEXOKINASE 2; HK2


HGNC Approved Gene Symbol: HK2

Cytogenetic location: 2p12     Genomic coordinates (GRCh38): 2:74,832,654-74,893,353 (from NCBI)


TEXT

▼ Description

Hexokinase (EC 2.7.1.1) catalyzes the first step in glucose metabolism, using ATP for the phosphorylation of glucose to glucose-6-phosphate. Four different types of hexokinase, designated HK1 (142600), HK2, HK3 (142570), and HK4 (138079), encoded by different genes, are present in mammalian tissues.

▼ Cloning and Expression

Printz et al. (1993) isolated rat HK2 cDNAs from a library prepared from rat adipose tissue mRNA.

Lehto et al. (1993) described the isolation of genomic clones for human hexokinase-2. These clones were isolated by screening a human placenta genomic library with a rat hexokinase-2 cDNA clone.

Deeb et al. (1993) isolated human HK2 cDNA clones from a skeletal muscle cDNA library. HK2 encodes a deduced 917-amino acid protein that shares 94% sequence identity with rat HK2 but only 72% sequence identity with human HK1.

Heikkinen et al. (2000) found that mouse Hk2 cDNA is approximately 5.5 kb long and encodes a deduced 917-amino acid protein. The transcription initiation and polyadenylation sites of mouse Hk2 mRNA are similar to those of rat and human HK2. By Northern blot analysis, Heikkinen et al. (2000) found that HK2 is primarily expressed in insulin-sensitive tissues such as skeletal and cardiac muscle and adipose tissue. Minor expression was detected in lung, spleen, ovary, and testis.


▼ Gene Structure

Heikkinen et al. (2000) found that the Hk2 gene in the mouse contains 18 exons that span approximately 50 kb of DNA. The nucleotide sequence of the proximal promoter shows a number of conserved putative transcription factor-binding motifs.


▼ Mapping

By fluorescence in situ hybridization, Lehto et al. (1993) mapped the HK2 gene to chromosome 2p13.1. They also screened human HK2 genomic clones for dinucleotide repeats. Primers were selected to amplify an approximately 224-bp CA-repeat-rich region. This repeat region was highly polymorphic; the level of heterozygosity was 0.63 in Caucasians and 0.51 in Chinese subjects. Lehto et al. (1993) carried out linkage studies between this HK2 polymorphism and 9 markers on chromosome 2. No recombinants were observed between HK2 and TGFA (190170) and D2S45; the most likely map order with respect to several chromosomal markers was determined.


▼ Gene Function

Printz et al. (1993) found that HK2 mRNA was decreased in adipose tissue from diabetic rats, but was restored by insulin treatment to levels found in nondiabetic control rats. Insulin also induced HK2 mRNA in 2 adipose cell lines and 2 skeletal muscle cell lines. In one of the skeletal muscle cells, this increase was accounted for by a corresponding increase of HK2 gene transcription.

Deeb et al. (1993) suggested that genetic variation in hexokinase-2 may underlie insulin resistance in peripheral tissues and cause noninsulin-dependent diabetes mellitus (NIDDM; 125853).

The HK2 gene is highly expressed in rapidly growing tumors to facilitate high rates of glucose catabolism. Mathupala et al. (1995) cloned and characterized the promoter of the rat HK2 gene from a highly glycolytic hepatoma cell line (AS-30D). Mathupala et al. (1997) showed that the HK2 promoter contains functionally active response elements for p53 (191170). Using coexpression assays, they showed that overexpression of a mutant p53 gene found in the tumor cell line significantly and reproducibly activated the HK2 promoter and increased HK2 gene expression. Mathupala et al. (1997) stated that theirs was the first report of a possible link between loss of cell cycle control in rapidly growing cells and their high glycolytic rate.


▼ Molecular Genetics

Laakso et al. (1995), Vidal-Puig et al. (1995), and Echwald et al. (1995) investigated HK2 as a promising candidate gene for noninsulin-dependent diabetes mellitus (125853). Laakso et al. (1995) studied 40 Finnish patients with typical NIDDM and subsequently an additional 72 patients with NIDDM. Among the 112 patients, ala314-to-val was found in 1 patient, arg353-to-cys in 3 patients, and arg775-to-gln in 3 patients. They also screened 97 subjects with completely normal glucose tolerance and a negative family history of diabetes for these mutations. The ala314-to-val and the arg353-to-cys substitutions were not found in control subjects, but the arg775-to-gln substitution was found in 2 control subjects. None of these mutations was located close to the glucose- and ATP-binding sites of HK2. Laakso et al. (1995) concluded that mutations of the HK2 gene are not a major etiologic factor for NIDDM in the Finnish population. In the U.K., Vidal-Puig et al. (1995) did a similar study with similar conclusions.

In a study of Danish Caucasians, Echwald et al. (1995) found several amino acid substitutions in HK2. However, these, including a frequent gln142-to-his mutation, did not seem to be associated with an increased susceptibility to NIDDM or major abnormalities in whole-body glucose effectiveness or insulin sensitivity. The frequency of the gln142-to-his chain substitution was 18.9% among controls and 17.0% among NIDDM patients.

Ardehali et al. (1996) reported identification of a TA repeat polymorphism in intron 12 of the HK2 gene. The authors used the polymorphism in linkage studies designed to investigate the mapping of NIDDM in Pima Indians and to refine the map position of HK2 on chromosome 2. Twenty different alleles were detected. Linkage studies indicated the least recombination between HK2 and marker D2S286 (lod = 15.8 at theta = 0.02). There was no evidence of linkage of this HK2 polymorphism and NIDDM in Pima Indians.


▼ REFERENCES

  1. Ardehali, H., Tiller, G. E., Printz, R. L., Mochizuki, H., Prochazka, M., Granner, D. K. A novel (TA)n polymorphism in the hexokinase II gene: application to noninsulin-dependent diabetes mellitus in the Pima Indians. Hum. Genet. 97: 482-485, 1996. [PubMed: 8834247, related citations]

  2. Deeb, S., Malkki, M., Laasko, M. Human hexokinase II: sequence and homology to other hexokinases. Biochem. Biophys. Res. Commun. 197: 68-74, 1993. [PubMed: 8250948, related citations] [Full Text]

  3. Echwald, S. M., Bjorbaek, C., Hansen, T., Clausen, J. O., Vestergaard, H., Zierarth, J. R., Printz, R. L., Granner, D. K., Pedersen, O. Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. Diabetes 44: 347-353, 1995. [PubMed: 7883123, related citations] [Full Text]

  4. Heikkinen, S., Suppola, S., Malkki, M., Deeb, S. S., Janne, J., Laakso, M. Mouse hexokinase II gene: structure, cDNA, promoter analysis, and expression pattern. Mammalian Genome 11: 91-96, 2000. [PubMed: 10656921, related citations]

  5. Katzen, H. M. The multiple forms of mammalian hexokinase and their significance to insulin action. Adv. Enzyme Regul. 5: 335-356, 1967. [PubMed: 5603267, related citations]

  6. Katzen, H. M., Schimke, R. T. Multiple forms of hexokinase in the rat: tissue distribution, age dependency, and properties. Proc. Nat. Acad. Sci. 54: 1218-1225, 1965. [PubMed: 5219826, related citations]

  7. Laakso, M., Malkki, M., Deeb, S. S. Amino acid substitutions in hexokinase II among patients with NIDDM. Diabetes 44: 330-334, 1995. [PubMed: 7883120, related citations] [Full Text]

  8. Lehto, M., Xiang, K., Stoffel, M., Espinosa, R., III, Groop, L. C., Le Beau, M. M., Bell, G. I. Human hexokinase II: localization of the polymorphic gene to chromosome 2. Diabetologia 36: 1299-1302, 1993. [PubMed: 8307259, related citations]

  9. Mathupala, S. P., Heese, C., Pedersen, P. L. Glucose catabolism in cancer cells: the type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J. Biol. Chem. 272: 22776-22780, 1997. [PubMed: 9278438, related citations] [Full Text]

  10. Mathupala, S. P., Rempel, A., Pedersen, P. L. Glucose catabolism in cancer cells: isolation, sequence, and activity of the promoter for type II hexokinase. J. Biol. Chem. 270: 16918-16925, 1995. [PubMed: 7622509, related citations] [Full Text]

  11. Printz, R. L., Koch, S., Potter, L. R., O'Doherty, R. M., Tiesinga, J. J., Moritz, S., Granner, D. K. Hexokinase II mRNA and gene structure, regulation by insulin, and evolution. J. Biol. Chem. 268: 5209-5219, 1993. Note: Erratum: J. Biol. Chem. 268: 9936 only, 1993. [PubMed: 8444897, related citations] [Full Text]

  12. Vidal-Puig, A., Printz, R. L., Stratton, I. M., Granner, D. K., Moller, D. E. Analysis of the hexokinase II gene in subjects with insulin resistance and NIDDM and detection of a gln142-to-his substitution. Diabetes 44: 340-346, 1995. [PubMed: 7883122, related citations] [Full Text]


Contributors:
Victor A. McKusick - updated : 5/18/2000
Victor A. McKusick - updated : 3/19/1998
Mark H. Paalman - updated : 9/12/1997
Moyra Smith - updated : 4/7/1996
Creation Date:
Moyra Smith : 3/13/1996
Edit History:
carol : 09/16/2016
terry : 11/13/2012
carol : 7/12/2010
carol : 7/8/2010
carol : 5/25/2000
terry : 5/18/2000
dkim : 7/2/1998
terry : 3/19/1998
mark : 9/15/1997
terry : 9/12/1997
terry : 7/28/1997
mark : 9/12/1996
mark : 4/7/1996
mark : 3/13/1996
terry : 3/13/1996
mark : 3/13/1996

* 601125

HEXOKINASE 2; HK2


HGNC Approved Gene Symbol: HK2

Cytogenetic location: 2p12     Genomic coordinates (GRCh38): 2:74,832,654-74,893,353 (from NCBI)


TEXT

Description

Hexokinase (EC 2.7.1.1) catalyzes the first step in glucose metabolism, using ATP for the phosphorylation of glucose to glucose-6-phosphate. Four different types of hexokinase, designated HK1 (142600), HK2, HK3 (142570), and HK4 (138079), encoded by different genes, are present in mammalian tissues.

Cloning and Expression

Printz et al. (1993) isolated rat HK2 cDNAs from a library prepared from rat adipose tissue mRNA.

Lehto et al. (1993) described the isolation of genomic clones for human hexokinase-2. These clones were isolated by screening a human placenta genomic library with a rat hexokinase-2 cDNA clone.

Deeb et al. (1993) isolated human HK2 cDNA clones from a skeletal muscle cDNA library. HK2 encodes a deduced 917-amino acid protein that shares 94% sequence identity with rat HK2 but only 72% sequence identity with human HK1.

Heikkinen et al. (2000) found that mouse Hk2 cDNA is approximately 5.5 kb long and encodes a deduced 917-amino acid protein. The transcription initiation and polyadenylation sites of mouse Hk2 mRNA are similar to those of rat and human HK2. By Northern blot analysis, Heikkinen et al. (2000) found that HK2 is primarily expressed in insulin-sensitive tissues such as skeletal and cardiac muscle and adipose tissue. Minor expression was detected in lung, spleen, ovary, and testis.


Gene Structure

Heikkinen et al. (2000) found that the Hk2 gene in the mouse contains 18 exons that span approximately 50 kb of DNA. The nucleotide sequence of the proximal promoter shows a number of conserved putative transcription factor-binding motifs.


Mapping

By fluorescence in situ hybridization, Lehto et al. (1993) mapped the HK2 gene to chromosome 2p13.1. They also screened human HK2 genomic clones for dinucleotide repeats. Primers were selected to amplify an approximately 224-bp CA-repeat-rich region. This repeat region was highly polymorphic; the level of heterozygosity was 0.63 in Caucasians and 0.51 in Chinese subjects. Lehto et al. (1993) carried out linkage studies between this HK2 polymorphism and 9 markers on chromosome 2. No recombinants were observed between HK2 and TGFA (190170) and D2S45; the most likely map order with respect to several chromosomal markers was determined.


Gene Function

Printz et al. (1993) found that HK2 mRNA was decreased in adipose tissue from diabetic rats, but was restored by insulin treatment to levels found in nondiabetic control rats. Insulin also induced HK2 mRNA in 2 adipose cell lines and 2 skeletal muscle cell lines. In one of the skeletal muscle cells, this increase was accounted for by a corresponding increase of HK2 gene transcription.

Deeb et al. (1993) suggested that genetic variation in hexokinase-2 may underlie insulin resistance in peripheral tissues and cause noninsulin-dependent diabetes mellitus (NIDDM; 125853).

The HK2 gene is highly expressed in rapidly growing tumors to facilitate high rates of glucose catabolism. Mathupala et al. (1995) cloned and characterized the promoter of the rat HK2 gene from a highly glycolytic hepatoma cell line (AS-30D). Mathupala et al. (1997) showed that the HK2 promoter contains functionally active response elements for p53 (191170). Using coexpression assays, they showed that overexpression of a mutant p53 gene found in the tumor cell line significantly and reproducibly activated the HK2 promoter and increased HK2 gene expression. Mathupala et al. (1997) stated that theirs was the first report of a possible link between loss of cell cycle control in rapidly growing cells and their high glycolytic rate.


Molecular Genetics

Laakso et al. (1995), Vidal-Puig et al. (1995), and Echwald et al. (1995) investigated HK2 as a promising candidate gene for noninsulin-dependent diabetes mellitus (125853). Laakso et al. (1995) studied 40 Finnish patients with typical NIDDM and subsequently an additional 72 patients with NIDDM. Among the 112 patients, ala314-to-val was found in 1 patient, arg353-to-cys in 3 patients, and arg775-to-gln in 3 patients. They also screened 97 subjects with completely normal glucose tolerance and a negative family history of diabetes for these mutations. The ala314-to-val and the arg353-to-cys substitutions were not found in control subjects, but the arg775-to-gln substitution was found in 2 control subjects. None of these mutations was located close to the glucose- and ATP-binding sites of HK2. Laakso et al. (1995) concluded that mutations of the HK2 gene are not a major etiologic factor for NIDDM in the Finnish population. In the U.K., Vidal-Puig et al. (1995) did a similar study with similar conclusions.

In a study of Danish Caucasians, Echwald et al. (1995) found several amino acid substitutions in HK2. However, these, including a frequent gln142-to-his mutation, did not seem to be associated with an increased susceptibility to NIDDM or major abnormalities in whole-body glucose effectiveness or insulin sensitivity. The frequency of the gln142-to-his chain substitution was 18.9% among controls and 17.0% among NIDDM patients.

Ardehali et al. (1996) reported identification of a TA repeat polymorphism in intron 12 of the HK2 gene. The authors used the polymorphism in linkage studies designed to investigate the mapping of NIDDM in Pima Indians and to refine the map position of HK2 on chromosome 2. Twenty different alleles were detected. Linkage studies indicated the least recombination between HK2 and marker D2S286 (lod = 15.8 at theta = 0.02). There was no evidence of linkage of this HK2 polymorphism and NIDDM in Pima Indians.


See Also:

<a href="#Katzen1967" class="entry-reference" title="Katzen, H. M. The multiple forms of mammalian hexokinase and their significance to insulin action. Adv. Enzyme Regul. 5: 335-356, 1967.">Katzen (1967)</a>; <a href="#Katzen1965" class="entry-reference" title="Katzen, H. M., Schimke, R. T. Multiple forms of hexokinase in the rat: tissue distribution, age dependency, and properties. Proc. Nat. Acad. Sci. 54: 1218-1225, 1965.">Katzen and Schimke (1965)</a>

REFERENCES

  1. Ardehali, H., Tiller, G. E., Printz, R. L., Mochizuki, H., Prochazka, M., Granner, D. K. A novel (TA)n polymorphism in the hexokinase II gene: application to noninsulin-dependent diabetes mellitus in the Pima Indians. Hum. Genet. 97: 482-485, 1996. [PubMed: 8834247]

  2. Deeb, S., Malkki, M., Laasko, M. Human hexokinase II: sequence and homology to other hexokinases. Biochem. Biophys. Res. Commun. 197: 68-74, 1993. [PubMed: 8250948] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(83)72442-3]

  3. Echwald, S. M., Bjorbaek, C., Hansen, T., Clausen, J. O., Vestergaard, H., Zierarth, J. R., Printz, R. L., Granner, D. K., Pedersen, O. Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. Diabetes 44: 347-353, 1995. [PubMed: 7883123] [Full Text: http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=7883123]

  4. Heikkinen, S., Suppola, S., Malkki, M., Deeb, S. S., Janne, J., Laakso, M. Mouse hexokinase II gene: structure, cDNA, promoter analysis, and expression pattern. Mammalian Genome 11: 91-96, 2000. [PubMed: 10656921]

  5. Katzen, H. M. The multiple forms of mammalian hexokinase and their significance to insulin action. Adv. Enzyme Regul. 5: 335-356, 1967. [PubMed: 5603267]

  6. Katzen, H. M., Schimke, R. T. Multiple forms of hexokinase in the rat: tissue distribution, age dependency, and properties. Proc. Nat. Acad. Sci. 54: 1218-1225, 1965. [PubMed: 5219826]

  7. Laakso, M., Malkki, M., Deeb, S. S. Amino acid substitutions in hexokinase II among patients with NIDDM. Diabetes 44: 330-334, 1995. [PubMed: 7883120] [Full Text: http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=7883120]

  8. Lehto, M., Xiang, K., Stoffel, M., Espinosa, R., III, Groop, L. C., Le Beau, M. M., Bell, G. I. Human hexokinase II: localization of the polymorphic gene to chromosome 2. Diabetologia 36: 1299-1302, 1993. [PubMed: 8307259]

  9. Mathupala, S. P., Heese, C., Pedersen, P. L. Glucose catabolism in cancer cells: the type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J. Biol. Chem. 272: 22776-22780, 1997. [PubMed: 9278438] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9278438]

  10. Mathupala, S. P., Rempel, A., Pedersen, P. L. Glucose catabolism in cancer cells: isolation, sequence, and activity of the promoter for type II hexokinase. J. Biol. Chem. 270: 16918-16925, 1995. [PubMed: 7622509] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=7622509]

  11. Printz, R. L., Koch, S., Potter, L. R., O'Doherty, R. M., Tiesinga, J. J., Moritz, S., Granner, D. K. Hexokinase II mRNA and gene structure, regulation by insulin, and evolution. J. Biol. Chem. 268: 5209-5219, 1993. Note: Erratum: J. Biol. Chem. 268: 9936 only, 1993. [PubMed: 8444897] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8444897]

  12. Vidal-Puig, A., Printz, R. L., Stratton, I. M., Granner, D. K., Moller, D. E. Analysis of the hexokinase II gene in subjects with insulin resistance and NIDDM and detection of a gln142-to-his substitution. Diabetes 44: 340-346, 1995. [PubMed: 7883122] [Full Text: http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=7883122]


Contributors:
Victor A. McKusick - updated : 5/18/2000
Victor A. McKusick - updated : 3/19/1998
Mark H. Paalman - updated : 9/12/1997
Moyra Smith - updated : 4/7/1996
Creation Date:
Moyra Smith : 3/13/1996
Edit History:
carol : 09/16/2016
terry : 11/13/2012
carol : 7/12/2010
carol : 7/8/2010
carol : 5/25/2000
terry : 5/18/2000
dkim : 7/2/1998
terry : 3/19/1998
mark : 9/15/1997
terry : 9/12/1997
terry : 7/28/1997
mark : 9/12/1996
mark : 4/7/1996
mark : 3/13/1996
terry : 3/13/1996
mark : 3/13/1996