Hexokinase 3 also known as HK3 is an enzyme which in humans is encoded by the HK2gene on chromosome 5.[1][2]Hexokinasesphosphorylateglucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes hexokinase 3. Similar to hexokinases 1 and 2, this allosteric enzyme is inhibited by its product glucose-6-phosphate. [provided by RefSeq, Apr 2009][3]
HK3 is one of four highly homologous hexokinase isoforms in mammalian cells.[4][5][6][7] This protein has a molecular weight of 100 kDa and is composed of two highly similar 50-kDa domains at its N- and C-terminals.[5][6][7][8][9] This high similarity, along with the[clarification needed] and 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.[6][9] Like with HK1, only the C-terminal domain possesses catalytic ability, whereas the N-terminal domain is predicted to contain glucose and G6P binding sites, as well as a 32-residue region essential for proper protein folding.[5][6] Moreover, the catalytic activity depends on the interaction between the two terminal domains.[6] Unlike HK1 and HK2, HK3 lacks a mitochondrial binding sequence at its N-terminal.[6][10][11]
Function
As a cytoplasmic isoform of hexokinase and a member of the sugar kinase family, HK3 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P.[6][7][12] Physiological levels of G6P can regulate this process by inhibiting HK3 as negative feedback, though inorganic phosphate can relieve G6P inhibition.[5][9] Inorganic phosphate can also directly regulate HK3, and the double regulation may better suit its anabolic functions.[5] By phosphorylating glucose, HK3 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism.[5][6][8][9] Compared to HK1 and HK2, HK3 possesses a higher affinity for glucose and will bind the substrate even at physiological levels, though this binding may be attenuated by intracellular ATP.[5] Uniquely, HK3 can be inhibited by glucose at high concentrations.[10][13] HK3 is also less sensitive to G6P inhibition.[5][10]
Despite its lack of mitochondrial association, HK3 also functions to protect the cell against apoptosis.[6][12] Overexpression of HK3 has resulted in increased ATP levels, decreased reactive oxygen species (ROS) production, attenuated reduction in the mitochondrial membrane potential, and enhanced mitochondrial biogenesis. Overall, HK3 may promote cell survival by controlling ROS levels and boosting energy production. Currently, only hypoxia is known to induce HK3 expression through a HIF-dependent pathway. The inducible expression of HK3 indicates its adaptive role in metabolic responses to changes in the cellular environment.[6]
HK3 is found to be overexpressed in malignantfollicularthyroid nodules. In conjunction with cyclin A and galectin-3, HK3 could be used as diagnostic biomarker to screen for malignancy in patients.[12][15] Meanwhile, HK3 was found to be repressed in acute myeloid leukemia (AML) blast cells and acute promyelocytic leukemia (APL) patients. The transcription factorPU.1 is known to directly activate transcription of the antiapoptotic BCL2A1 gene or inhibit transcription of the p53 tumor suppressor to promote cell survival, and is proposed to also directly activate HK3 transcription during neutrophil differentiation to support short-term cell survival of mature neutrophils.[11] Regulators repressing HK3 expression in AML include PML-RARA and CEBPA.[11][14] Regarding acute lymphoblastic leukemia (ALL), functional enrichment analysis revealed HK3 as a key gene and suggests that HK3 shares antiapoptotic function with HK1 and HK2.[12]
↑Furuta H, Nishi S, Le Beau MM, Fernald AA, Yano H, Bell GI (August 1996). "Sequence of human hexokinase III cDNA and assignment of the human hexokinase III gene (HK3) to chromosome band 5q35.2 by fluorescence in situ hybridization". Genomics. 36 (1): 206–9. doi:10.1006/geno.1996.0448. PMID8812439.
↑Colosimo A, Calabrese G, Gennarelli M, Ruzzo AM, Sangiuolo F, Magnani M, Palka G, Novelli G, Dallapiccola B (1996). "Assignment of the hexokinase type 3 gene (HK3) to human chromosome band 5q35.3 by somatic cell hybrids and in situ hybridization". Cytogenetics and Cell Genetics. 74 (3): 187–8. doi:10.1159/000134409. PMID8941369.
↑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. PMID12432216.
↑ 5.05.15.25.35.45.55.65.75.85.9Okatsu K, Iemura S, Koyano F, Go E, Kimura M, Natsume T, Tanaka K, Matsuda N (November 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. PMID23068103.
↑ 7.07.17.2Reid 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. PMID4058069.
↑ 8.08.1Aleshin 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. PMID9493266.
↑ 9.09.19.29.39.4Printz RL, Osawa H, Ardehali H, Koch S, Granner DK (February 1997). "Hexokinase II gene: structure, regulation and promoter organization". Biochemical Society Transactions. 25 (1): 107–12. doi:10.1042/bst0250107. PMID9056853.
↑ 10.010.110.210.310.4Lowes W, Walker M, Alberti KG, Agius L (Jan 1998). "Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis". Biochimica et Biophysica Acta. 1379 (1): 134–42. doi:10.1016/s0304-4165(97)00092-5. PMID9468341.
↑ 12.012.112.212.3Gao HY, Luo XG, Chen X, Wang JH (Jan 2015). "Identification of key genes affecting disease free survival time of pediatric acute lymphoblastic leukemia based on bioinformatic analysis". Blood Cells, Molecules & Diseases. 54 (1): 38–43. doi:10.1016/j.bcmd.2014.08.002. PMID25172542.
↑ 13.013.1Cárdenas ML, Cornish-Bowden A, Ureta T (March 1998). "Evolution and regulatory role of the hexokinases". Biochimica et Biophysica Acta. 1401 (3): 242–64. doi:10.1016/s0167-4889(97)00150-x. PMID9540816.
↑Hooft L, van der Veldt AA, Hoekstra OS, Boers M, Molthoff CF, van Diest PJ (February 2008). "Hexokinase III, cyclin A and galectin-3 are overexpressed in malignant follicular thyroid nodules". Clinical Endocrinology. 68 (2): 252–7. doi:10.1111/j.1365-2265.2007.03031.x. PMID17868400.
Further reading
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. PMID4058069.
Rijksen G, Staal GE, Beks PJ, Streefkerk M, Akkerman JW (December 1982). "Compartmentation of hexokinase in human blood cells. Characterization of soluble and particulate enzymes". Biochimica et Biophysica Acta. 719 (3): 431–7. doi:10.1016/0304-4165(82)90230-6. PMID7150652.
Adkins JN, Varnum SM, Auberry KJ, Moore RJ, Angell NH, Smith RD, Springer DL, Pounds JG (December 2002). "Toward a human blood serum proteome: analysis by multidimensional separation coupled with mass spectrometry". Molecular & Cellular Proteomics. 1 (12): 947–55. doi:10.1074/mcp.M200066-MCP200. PMID12543931.
Palma F, Agostini D, Mason P, Dachà M, Piccoli G, Biagiarelli B, Fiorani M, Stocchi V (February 1996). "Purification and characterization of the carboxyl-domain of human hexokinase type III expressed as fusion protein". Molecular and Cellular Biochemistry. 155 (1): 23–9. doi:10.1007/BF00714329. PMID8717435.
Povey S, Corney G, Harris H (May 1975). "Genetically determined polymorphism of a form of hexokinase, HK III, found in human leucocytes". Annals of Human Genetics. 38 (4): 407–15. doi:10.1111/j.1469-1809.1975.tb00630.x. PMID1190733.
Anderson NL, Anderson NG (November 2002). "The human plasma proteome: history, character, and diagnostic prospects". Molecular & Cellular Proteomics. 1 (11): 845–67. doi:10.1074/mcp.R200007-MCP200. PMID12488461.
Fonteyne P, Casneuf V, Pauwels P, Van Damme N, Peeters M, Dierckx R, Van de Wiele C (August 2009). "Expression of hexokinases and glucose transporters in treated and untreated oesophageal adenocarcinoma". Histology and Histopathology. 24 (8): 971–7. PMID19554504.
Sui D, Wilson JE (October 2000). "Interaction of insulin-like growth factor binding protein-4, Miz-1, leptin, lipocalin-type prostaglandin D synthase, and granulin precursor with the N-terminal half of type III hexokinase". Archives of Biochemistry and Biophysics. 382 (2): 262–74. doi:10.1006/abbi.2000.2019. PMID11068878.
Lowes W, Walker M, Alberti KG, Agius L (Jan 1998). "Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis". Biochimica et Biophysica Acta. 1379 (1): 134–42. doi:10.1016/s0304-4165(97)00092-5. PMID9468341.
Furuta H, Nishi S, Le Beau MM, Fernald AA, Yano H, Bell GI (August 1996). "Sequence of human hexokinase III cDNA and assignment of the human hexokinase III gene (HK3) to chromosome band 5q35.2 by fluorescence in situ hybridization". Genomics. 36 (1): 206–9. doi:10.1006/geno.1996.0448. PMID8812439.
