Hexokinase 2

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Hexokinase 2
Hexokinase 2
according to PDB  2NZT
other names
  • Muscle form hexokinase
  • Hexokinase Type II
  • Hexokinase-2
  • HK II
  • HKII
  • HXK2

Existing structural data : 5HFU , 5HG1 , 5HEX

Properties of human protein
Mass / length primary structure 917 amino acids, 102380 Da
Identifier
Gene name HK2
External IDs
Enzyme classification
EC, category 2.7.1.1
Orthologue
human House mouse
Entrez 3099 15277
Ensemble ENSG00000159399 ENSMUSG00000000628
UniProt P52789 O08528
Refseq (mRNA) NM_000189 NM_013820
Refseq (protein) NP_000180 NP_038848
Gene locus Chr 2: 74.83 - 74.89 Mb Chr 6: 82.73 - 82.77 Mb
PubMed search 3099 15277

Hexokinase 2 (also known as HK2 ) is an enzyme from the hexokinase group that is encoded by the HK2 gene on chromosome 2 in humans. Hexokinases phosphorylate glucose to form glucose-6-phosphate (G6P) and is the first step in most glucose metabolic pathways. The HK2 gene codes for hexokinase 2, the predominant form in skeletal muscle . It is on the outer membrane of the mitochondria (engl. Outer mitochondrial membrane , OMM) localized. The expression of this gene respond to insulin, and studies in rats suggest that it is involved in the increased glycolysis rate, which can be observed in rapidly growing cancer cells.

structure

HK2 is one of four highly homologous hexokinase isoforms in mammalian cells.

gene

The HK2 gene spans approximately 50 kb and consists of 18 exons . There is also a HC2 - pseudogene that in a long-scattered repetitive DNA core element on the X chromosome is integrated. Although its DNA sequence is similar to the cDNA product of the actual HK2 mRNA transcript, it lacks an open reading frame for gene expression.

protein

The HC2 gene encoding an enzyme of about 100 kDa molecular weight , 917 amino acid residues and very similar N - and C -terminal domains, each of which forms one half of the protein. The high similarity with a 50 kDa hexokinase ( GCK ) and its existence suggest that the 100 kDa hexokinases are derived from a 50 kDa precursor via gene duplication and tandem ligation . Both N - and C -terminal domains have catalytic capabilities and can be inhibited by G6P, although the C -terminal domain has a lower affinity for ATP has and is inhibited only at higher concentrations of G6P.

Although there are two binding sites for glucose, it is suggested that glucose binding at one site induces a conformational change that prevents a second glucose from binding at the other site. The first 12 amino acids of the strongly hydrophobic N terminus are used to bind the enzyme to the mitochondria, while the first 18 amino acids contribute to the stability of the enzyme.

function

As an isoform of the hexokinase and member of the sugar kinase family, HK2 catalyzes the rate-determining and first mandatory step of glucose metabolism, namely the ATP-dependent phosphorylation of glucose to G6P. Physiological levels of G6P can regulate this process by inhibiting HC2 as negative feedback, although inorganic phosphate (P i ) can ameliorate G6P inhibition. Inorganic phosphate can also regulate HC2 directly. This dual regulation may be better suited to its anabolic functions.

By phosphorylating glucose, HK2 effectively prevents glucose from leaving the cell and thus binds glucose to the energy metabolism. In addition, its location and attachment to the outer mitochondrial membrane promotes the coupling of glycolysis to mitochondrial oxidative phosphorylation , which significantly increases ATP production to meet the cell's energy needs. In particular, HK2 binds to VDAC to trigger the opening of the channel and release mitochondrial ATP to further advance the glycolytic process.

Another crucial function for OMM-bound HK2 is the mediation of cell survival. Activation of the Akt kinase maintains HK2-VDAC coupling, which subsequently prevents the release of cytochrome c and apoptosis . However, the exact mechanism has yet to be confirmed. One model suggests that HK2 competes with the pro-apoptotic proteins Bax to bind VDAC, and in the absence of HK2, Bax induces the release of cytochrome c . Indeed, there is evidence that HK2 limits the oligomerization of Bax and BAK and binding to the OMM. In a similar mechanism, the pro-apoptotic creatine kinase VDAC binds and opens in the absence of HK2. An alternative model suggests the opposite: HK2 regulates the binding of the anti-apoptotic protein Bcl-xL to VDAC.

In particular, HK2 is ubiquitously expressed in tissues, although it is mainly found in muscle and adipose tissue. In the heart and skeletal muscles, HK2 is bound to both the mitochondrial and the sarcoplasmic membrane . The HC2 gene expression is a PI3K / RPS6KB1 regulated -dependent pathway and can by factors such as insulin , hypoxia induced, low temperatures and physical activity. Its inducible expression suggests its adaptive role in metabolic processes for changes in the cellular environment.

Clinical significance

cancer

HK2 is highly expressed in several cancers, including breast cancer and colon cancer . Its role in coupling ATP from oxidative phosphorylation to the rate-limiting step of glycolysis could help fuel tumor cell growth. In particular, inhibiting HD2 has been shown to improve the effectiveness of cancer drugs. Therefore, HK2 has promising therapeutic applications, although in view of its ubiquitous expression and its critical role in energy metabolism, a decrease in its activity should be pursued, rather than a complete inhibition.

Non-insulin dependent diabetes mellitus

A study of non-insulin dependent diabetes mellitus (NIDDM) found low basal G6P levels in NIDDM patients that did not increase with the addition of insulin. One possible cause is decreased phosphorylation of glucose due to a defect in HC2, which was confirmed in further experiments. However, the study failed to establish links between NIDDM and mutations in the HK2 gene, suggesting that the defect may be in HK2 regulation.

Individual evidence

  1. ↑ M. Lehto, K. Xiang, M. Stoffel, R. Espinosa, LC Groop, MM Le Beau, GI Bell: Human hexokinase II: localization of the polymorphic gene to chromosome 2. In: Diabetologia. Volume 36, Number 12, December 1993, pp. 1299-1302, doi : 10.1007 / bf00400809 , PMID 8307259 .
  2. ↑ a b HK2 hexokinase 2 (human)
  3. ↑ K. Murakami, H. Kanno, J. Tancabelic, H. Fujii: Gene expression and biological significance of hexokinase in erythroid cells. In: Acta haematologica. Volume 108, Number 4, 2002, pp. 204-209, doi : 10.1159 / 000065656 , PMID 12432216 (review).
  4. ↑ a b c d e f g h i K. Okatsu, S. Iemura, F. Koyano, E. Go, M. Kimura, T. Natsume, K. Tanaka, N. Matsuda: Mitochondrial hexokinase HKI is a novel substrate of the Parkin ubiquitin ligase. In: Biochemical and biophysical research communications. Volume 428, Number 1, November 2012, pp. 197-202, doi : 10.1016 / j.bbrc.2012.10.041 , PMID 23068103 .
  5. ↑ a b c d e f g h i R. L. Printz, H. Osawa, H. Ardehali, S. Koch, DK Granner: Hexokinase II gene: structure, regulation and promoter organization. In: Biochemical Society transactions. Volume 25, Number 1, February 1997, pp. 107-112, doi : 10.1042 / bst0250107 , PMID 9056853 (review).
  6. ↑ a b A. E. Aleshin, C. Zeng, GP Bourenkov, HD Bartunik, HJ Fromm, RB Honzatko: The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate. In: Structure. Volume 6, Number 1, January 1998, pp. 39-50, doi : 10.1016 / s0969-2126 (98) 00006-9 , PMID 9493266 .
  7. ↑ a b c K. J. Ahn, J. Kim, M. Yun, JH Park, JD Lee: Enzymatic properties of the N- and C-terminal halves of human hexokinase II. In: BMB reports. Volume 42, Number 6, June 2009, pp. 350-355, doi : 10.5483 / bmbrep.2009.42.6.350 , PMID 19558793 .
  8. ↑ ML Cárdenas, A. Cornish-Bowden, T. Ureta: Evolution and regulatory role of the hexokinases. In: Biochimica et Biophysica Acta . Volume 1401, Number 3, March 1998, pp. 242-264, doi : 10.1016 / s0167-4889 (97) 00150-x , PMID 9540816 (review).
  9. ↑ a b c A. Schindler, E. Foley: Hexokinase 1 blocks apoptotic signals at the mitochondria. In: Cellular signaling. Volume 25, Number 12, December 2013, pp. 2685-2692, doi : 10.1016 / j.cellsig.2013.08.035 , PMID 24018046 .
  10. ↑ D. Shan, D. Mount, S. Moore, V. Haroutunian, JH Meador-Woodruff, RE McCullumsmith: Abnormal partitioning of hexokinase 1 suggests disruption of a glutamate transport protein complex in schizophrenia. In: Schizophrenia research. Volume 154, number 1–3, April 2014, pp. 1–13, doi : 10.1016 / j.schres.2014.01.028 , PMID 24560881 , PMC 4151500 (free full text).
  11. ↑ a b c d e f g D. Palmieri, D. Fitzgerald, SM Shreeve, E. Hua, JL Bronder, RJ Weil, S. Davis, AM Stark, MJ Merino, R. Kurek, HM Mehdorn, G. Davis, SM Steinberg, PS Meltzer, K. Aldape, PS Steeg: Analyzes of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. In: Molecular cancer research: MCR. Volume 7, Number 9, September 2009, pp. 1438-1445, doi : 10.1158 / 1541-7786.MCR-09-0234 , PMID 19723875 , PMC 2746883 (free full text).
  12. ^ S. Reid, C. Masters: On the developmental properties and tissue interactions of hexokinase. In: Mechanisms of aging and development. Volume 31, Number 2, 1985 Jul-Aug, pp. 197-212, doi : 10.1016 / s0047-6374 (85) 80030-0 , PMID 4058069 .
  13. ^ A b E. Wyatt, R. Wu, W. Rabeh, HW Park, M. Ghanefar, H. Ardehali: Regulation and cytoprotective role of hexokinase III. In: PLOS ONE . Volume 5, number 11, November 2010, p. E13823, doi : 10.1371 / journal.pone.0013823 , PMID 21072205 , PMC 2972215 (free full text).
  14. ^ A b Q. Peng, J. Zhou, Q. Zhou, F. Pan, D. Zhong, H. Liang: Silencing hexokinase II gene sensitizes human colon cancer cells to 5-fluorouracil. In: Hepato-gastroenterology. Volume 56, Number 90, 2009 Mar-Apr, pp. 355-360, PMID 19579598 .