HK2
Hexokinase 2 also known as HK2 is an enzyme which in humans is encoded by the HK2 gene on chromosome 2.[5][6] Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the outer membrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells. [provided by RefSeq, Apr 2009][6]
Structure
HK2 is one of four highly homologous hexokinase isoforms in mammalian cells.[7][8][9][10][11]
Gene
The HK2 gene spans approximately 50 kb and consists of 18 exons. There is also an HK2 pseudogene integrated into a long interspersed nuclear repetitive DNA element located on the X chromosome. Though its DNA sequence is similar to the cDNA product of the actual HK2 mRNA transcript, it lacks an open reading frame for gene expression.[10]
Protein
This gene encodes a 100-kDa, 917-residue enzyme with highly similar N- and C-terminal domains that each form half of the protein.[10][12] This high similarity, along with the existence of a 50-kDa hexokinase (HK4), suggests that the 100-kDa hexokinases originated from a 50-kDa precursor via gene duplication and tandem ligation.[10][11] Both N- and C-terminal domains possess catalytic ability and can be inhibited by G6P, though the C-terminal domain demonstrates lower affinity for ATP and is only inhibited at higher concentrations of G6P.[10] Despite there being two binding sites for glucose, it is proposed that glucose binding at one site induces a conformational change which prevents a second glucose from binding the other site.[13] Meanwhile, the first 12 amino acids of the highly hydrophobic N-terminal serve to bind the enzyme to the mitochondria, while the first 18 amino acids contribute to the enzyme’s stability.[9][11]
Function
As an isoform of hexokinase and a member of the sugar kinase family, HK2 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P.[11] Physiological levels of G6P can regulate this process by inhibiting HK2 as negative feedback, though inorganic phosphate (Pi) can relieve G6P inhibition.[8][10][11] Pi can also directly regulate HK2, and the double regulation may better suit its anabolic functions.[8] By phosphorylating glucose, HK2 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism.[10][12] Moreover, its localization and attachment to the OMM promotes the coupling of glycolysis to mitochondrial oxidative phosphorylation, which greatly enhances ATP production to meet the cell’s energy demands.[14][15] Specifically, HK2 binds VDAC to trigger opening of the channel and release mitochondrial ATP to further fuel the glycolytic process.[8][15]
Another critical function for OMM-bound HK2 is mediation of cell survival.[8][9] Activation of Akt kinase maintains HK2-VDAC coupling, which subsequently prevents cytochrome c release and apoptosis, though the exact mechanism remains to be confirmed.[8] One model proposes that HK2 competes with the pro-apoptotic proteins BAX to bind VDAC, and in the absence of HK2, BAX induces cytochrome c release.[8][15] In fact, there is evidence that HK2 restricts BAX and BAK oligomerization and binding to the OMM. In a similar mechanism, the pro-apoptotic creatine kinase binds and opens VDAC in the absence of HK2.[8] An alternative model proposes the opposite, that HK2 regulates binding of the anti-apoptotic protein Bcl-Xl to VDAC.[15]
In particular, HK2 is ubiquitously expressed in tissues, though it is majorly found in muscle and adipose tissue.[8][10][15] In cardiac and skeletal muscle, HK2 can be found bound to both the mitochondrial and sarcoplasmic membrane.[16] HK2 gene expression is regulated by a phosphatidylinositol 3-kinaselp70 S6 protein kinase-dependent pathway and can be induced by factors such as insulin, hypoxia, cold temperatures, and exercise.[10][17] Its inducible expression indicates its adaptive role in metabolic responses to changes in the cellular environment.[17]
Clinical significance
Cancer
HK2 is highly expressed in several cancers, including breast cancer and colon cancer.[9][15][18] Its role in coupling ATP from oxidative phosphorylation to the rate-limiting step of glycolysis may help drive the tumor cells’ growth.[15] Notably, inhibition of HK2 has demonstrably improved the effectiveness of anticancer drugs.,[18] Thus, HK2 stands as a promising therapeutic target, though considering its ubiquitous expression and crucial role in energy metabolism, a reduction rather than complete inhibition of its activity should be pursued.[15][18]
Non-insulin-dependent diabetes mellitus
A study on non-insulin-dependent diabetes mellitus (NIDDM) revealed low basal G6P levels in NIDDM patients that failed to increase with the addition of insulin. One possible cause is decreased phosphorylation of glucose due to a defect in HK2, which was confirmed in further experiments. However, the study could not establish any links between NIDDM and mutations in the HK2 gene, indicating that the defect may lie in HK2 regulation.[10]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
See also
References
- GRCh38: Ensembl release 89: ENSG00000159399 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000000628 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Lehto M, Xiang K, Stoffel M, Espinosa R, Groop LC, Le Beau MM, Bell GI (Dec 1993). "Human hexokinase II: localization of the polymorphic gene to chromosome 2". Diabetologia. 36 (12): 1299–302. doi:10.1007/BF00400809. PMID 8307259.
- "Entrez Gene: HK2 hexokinase 2".
- Murakami K, Kanno H, Tancabelic J, Fujii H (2002). "Gene expression and biological significance of hexokinase in erythroid cells". Acta Haematologica. 108 (4): 204–9. doi:10.1159/000065656. PMID 12432216. S2CID 23521290.
- Okatsu K, Iemura S, Koyano F, Go E, Kimura M, Natsume T, Tanaka K, Matsuda N (Nov 2012). "Mitochondrial hexokinase HKI is a novel substrate of the Parkin ubiquitin ligase". Biochemical and Biophysical Research Communications. 428 (1): 197–202. doi:10.1016/j.bbrc.2012.10.041. PMID 23068103.
- Schindler A, Foley E (Dec 2013). "Hexokinase 1 blocks apoptotic signals at the mitochondria". Cellular Signalling. 25 (12): 2685–92. doi:10.1016/j.cellsig.2013.08.035. PMID 24018046.
- Printz RL, Osawa H, Ardehali H, Koch S, Granner DK (Feb 1997). "Hexokinase II gene: structure, regulation and promoter organization". Biochemical Society Transactions. 25 (1): 107–12. doi:10.1042/bst0250107. PMID 9056853.
- Ahn KJ, Kim J, Yun M, Park JH, Lee JD (Jun 2009). "Enzymatic properties of the N- and C-terminal halves of human hexokinase II". BMB Reports. 42 (6): 350–5. doi:10.5483/bmbrep.2009.42.6.350. PMID 19558793.
- Aleshin AE, Zeng C, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB (Jan 1998). "The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate". Structure. 6 (1): 39–50. doi:10.1016/s0969-2126(98)00006-9. PMID 9493266.
- Cárdenas, ML; Cornish-Bowden, A; Ureta, T (5 March 1998). "Evolution and regulatory role of the hexokinases". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1401 (3): 242–64. doi:10.1016/s0167-4889(97)00150-x. PMID 9540816.
- Shan D, Mount D, Moore S, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE (Apr 2014). "Abnormal partitioning of hexokinase 1 suggests disruption of a glutamate transport protein complex in schizophrenia". Schizophrenia Research. 154 (1–3): 1–13. doi:10.1016/j.schres.2014.01.028. PMC 4151500. PMID 24560881.
- Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ, Davis S, Stark AM, Merino MJ, Kurek R, Mehdorn HM, Davis G, Steinberg SM, Meltzer PS, Aldape K, Steeg PS (Sep 2009). "Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis". Molecular Cancer Research. 7 (9): 1438–45. doi:10.1158/1541-7786.MCR-09-0234. PMC 2746883. PMID 19723875.
- Reid, S; Masters, C (1985). "On the developmental properties and tissue interactions of hexokinase". Mechanisms of Ageing and Development. 31 (2): 197–212. doi:10.1016/s0047-6374(85)80030-0. PMID 4058069. S2CID 40877603.
- Wyatt, E; Wu, R; Rabeh, W; Park, HW; Ghanefar, M; Ardehali, H (3 November 2010). "Regulation and cytoprotective role of hexokinase III". PLOS ONE. 5 (11): e13823. doi:10.1371/journal.pone.0013823. PMC 2972215. PMID 21072205.
- Peng Q, Zhou J, Zhou Q, Pan F, Zhong D, Liang H (2009). "Silencing hexokinase II gene sensitizes human colon cancer cells to 5-fluorouracil". Hepato-Gastroenterology. 56 (90): 355–60. PMID 19579598.
Further reading
- Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
- Mamede M, Higashi T, Kitaichi M, Ishizu K, Ishimori T, Nakamoto Y, Yanagihara K, Li M, Tanaka F, Wada H, Manabe T, Saga T (Apr 2005). "[18F]FDG uptake and PCNA, Glut-1, and Hexokinase-II expressions in cancers and inflammatory lesions of the lung". Neoplasia. 7 (4): 369–79. doi:10.1593/neo.04577. PMC 1501150. PMID 15967114.
- Machida K, Ohta Y, Osada H (May 2006). "Suppression of apoptosis by cyclophilin D via stabilization of hexokinase II mitochondrial binding in cancer cells". The Journal of Biological Chemistry. 281 (20): 14314–20. doi:10.1074/jbc.M513297200. PMID 16551620.
- Ahn KJ, Kim J, Yun M, Park JH, Lee JD (Jun 2009). "Enzymatic properties of the N- and C-terminal halves of human hexokinase II". BMB Reports. 42 (6): 350–5. doi:10.5483/BMBRep.2009.42.6.350. PMID 19558793.
- Printz RL, Osawa H, Ardehali H, Koch S, Granner DK (Feb 1997). "Hexokinase II gene: structure, regulation and promoter organization". Biochemical Society Transactions. 25 (1): 107–12. doi:10.1042/bst0250107. PMID 9056853.
- Peng Q, Zhou J, Zhou Q, Pan F, Zhong D, Liang H (2009). "Silencing hexokinase II gene sensitizes human colon cancer cells to 5-fluorouracil". Hepato-Gastroenterology. 56 (90): 355–60. PMID 19579598.
- Shulga N, Wilson-Smith R, Pastorino JG (Oct 2009). "Hexokinase II detachment from the mitochondria potentiates cisplatin induced cytotoxicity through a caspase-2 dependent mechanism". Cell Cycle. 8 (20): 3355–64. doi:10.4161/cc.8.20.9853. PMC 2829766. PMID 19770592.
- He HC, Bi XC, Zheng ZW, Dai QS, Han ZD, Liang YX, Ye YK, Zeng GH, Zhu G, Zhong WD (2009). "Real-time quantitative RT-PCR assessment of PIM-1 and hK2 mRNA expression in benign prostate hyperplasia and prostate cancer". Medical Oncology. 26 (3): 303–8. doi:10.1007/s12032-008-9120-9. PMID 19003546. S2CID 44560397.
- Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY (May 2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID 16713569. S2CID 13709685.
- Sakai N, Terami H, Suzuki S, Haga M, Nomoto K, Tsuchida N, Morohashi K, Saito N, Asada M, Hashimoto M, Harada D, Asahara H, Ishikawa T, Shimada F, Sakurada K (Sep 2008). "Identification of NR5A1 (SF-1/AD4BP) gene expression modulators by large-scale gain and loss of function studies". The Journal of Endocrinology. 198 (3): 489–97. doi:10.1677/JOE-08-0027. PMID 18579725.
- Foster LJ, Rudich A, Talior I, Patel N, Huang X, Furtado LM, Bilan PJ, Mann M, Klip A (Jan 2006). "Insulin-dependent interactions of proteins with GLUT4 revealed through stable isotope labeling by amino acids in cell culture (SILAC)". Journal of Proteome Research. 5 (1): 64–75. doi:10.1021/pr0502626. PMID 16396496.
- Arzoine L, Zilberberg N, Ben-Romano R, Shoshan-Barmatz V (Feb 2009). "Voltage-dependent anion channel 1-based peptides interact with hexokinase to prevent its anti-apoptotic activity". The Journal of Biological Chemistry. 284 (6): 3946–55. doi:10.1074/jbc.M803614200. PMID 19049977.
- Gimenez-Cassina A, Lim F, Cerrato T, Palomo GM, Diaz-Nido J (Jan 2009). "Mitochondrial hexokinase II promotes neuronal survival and acts downstream of glycogen synthase kinase-3". The Journal of Biological Chemistry. 284 (5): 3001–11. doi:10.1074/jbc.M808698200. PMID 19033437.
- Peng Q, Zhou Q, Zhou J, Zhong D, Pan F, Liang H (Jul 2008). "Stable RNA interference of hexokinase II gene inhibits human colon cancer LoVo cell growth in vitro and in vivo". Cancer Biology & Therapy. 7 (7): 1128–35. doi:10.4161/cbt.7.7.6199. PMID 18535403.
- Rodríguez-Enríquez S, Marín-Hernández A, Gallardo-Pérez JC, Moreno-Sánchez R (Dec 2009). "Kinetics of transport and phosphorylation of glucose in cancer cells". Journal of Cellular Physiology. 221 (3): 552–9. doi:10.1002/jcp.21885. PMID 19681047. S2CID 45600187.
- Kim JW, Gao P, Liu YC, Semenza GL, Dang CV (Nov 2007). "Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1". Molecular and Cellular Biology. 27 (21): 7381–93. doi:10.1128/MCB.00440-07. PMC 2169056. PMID 17785433.
- Fonteyne P, Casneuf V, Pauwels P, Van Damme N, Peeters M, Dierckx R, Van de Wiele C (Aug 2009). "Expression of hexokinases and glucose transporters in treated and untreated oesophageal adenocarcinoma". Histology and Histopathology. 24 (8): 971–7. PMID 19554504.
- Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ, Davis S, Stark AM, Merino MJ, Kurek R, Mehdorn HM, Davis G, Steinberg SM, Meltzer PS, Aldape K, Steeg PS (Sep 2009). "Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis". Molecular Cancer Research. 7 (9): 1438–45. doi:10.1158/1541-7786.MCR-09-0234. PMC 2746883. PMID 19723875.
- Peng QP, Zhou JM, Zhou Q, Pan F, Zhong DP, Liang HJ (2008). "Downregulation of the hexokinase II gene sensitizes human colon cancer cells to 5-fluorouracil". Chemotherapy. 54 (5): 357–63. doi:10.1159/000153655. PMID 18772588. S2CID 32344187.
- Paudyal B, Oriuchi N, Paudyal P, Higuchi T, Nakajima T, Endo K (Feb 2008). "Expression of glucose transporters and hexokinase II in cholangiocellular carcinoma compared using [18F]-2-fluro-2-deoxy-D-glucose positron emission tomography". Cancer Science. 99 (2): 260–6. doi:10.1111/j.1349-7006.2007.00683.x. PMID 18271924. S2CID 25720472.
External links
- Overview of all the structural information available in the PDB for UniProt: P52789 (Hexokinase-2) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.