Hexokinase III is one of four homologous hexokinase isoforms in mammalian cells.[8][9][10][11] This protein has a molecular mass of 100 kDa and is composed of two highly similar 50-kDa domains at itsN- andC-terminals.[9][10][11][12][13] This high similarity, along with the[clarification needed] and the existence of a 50-kDa hexokinase (Glucokinase, or hexokinase IV), suggests that the 100-kDa hexokinases originated from a 50-kDa precursor viagene duplication and tandem ligation.[13][14][10] As withhexokinase I, only theC-terminal domain possesses catalytic ability, whereas theN-terminal domain is predicted to containglucose andglucose 6-phosphate binding sites, as well as a 32-residue region essential for properprotein folding.[9][10] Moreover, the catalytic activity depends on the interaction between the two terminal domains.[10] Unlikehexokinase I andhexokinase II, hexokinase III lacks amitochondrial binding sequence at its N-terminal.[10][15][16]
As a cytoplasmic isoform of hexokinase and a member of the sugar kinase family, hexokinase IIIcatalyzes therate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to glucose 6-phosphate.[10][11][17] Physiological levels of glucose 6-phosphate can regulate this process by inhibiting hexokinase III asnegative feedback, thoughinorganic phosphate can relieve glucose 6-phosphate inhibition.[9][13] Inorganic phosphate can also directly regulate hexokinase III, and the double regulation may better suit itsanabolic functions.[9] By phosphorylating glucose, hexokinase III effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism.[9][10][12][13] Compared to hexokinase I and hexokinase II, hexokinase III possesses a higher affinity for glucose and will bind thesubstrate even at physiological levels, though this binding may beattenuated by intracellular ATP.[9] Uniquely, hexokinase III can be inhibited by glucose at high concentrations.[15][14] hexokinase III is also less sensitive to glucose 6-phosphate inhibition.[9][15]
Despite its lack of mitochondrial association, hexokinase III also functions to protect the cell againstapoptosis.[10][17] Overexpression of hexokinase III has resulted in increased ATP levels, decreasedreactive oxygen species (ROS) production, attenuatedreduction in the mitochondrialmembrane potential, and enhanced mitochondrialbiogenesis. Overall, hexokinase III may promote cell survival by controlling ROS levels and boosting energy production. Currently, onlyhypoxia is known to induce hexokinase III expression through aHIF-dependent pathway. The inducible expression of hexokinase III indicates its adaptive role in metabolic responses to changes in the cellular environment.[10]
Hexokinase III is found to be overexpressed inmalignantfollicularthyroid nodules. In conjunction withcyclin A andgalectin-3, hexokinase III could be used as diagnostic biomarker to screen for malignancy in patients.[17][19] Meanwhile, hexokinase III was found to be repressed inacute myeloid leukemia (AML)blast cells andacute promyelocytic leukemia (APL) patients. Thetranscription factorPU.1 is known to directly activate transcription of the antiapoptoticBCL2A1 gene or inhibit transcription of thep53 tumor suppressor to promote cell survival, and is proposed to also directly activateHk3 transcription during neutrophil differentiation to support short-term cell survival of matureneutrophils.[16] Regulators repressing hexokinase III expression in AML includePML-RARA andCEBPA.[16][18] Regardingacute lymphoblastic leukemia (ALL), functional enrichment analysis revealedHk3 as a key gene and suggests that hexokinase III shares antiapoptotic function with HK1 and HK2.[17]
^"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.
^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 (hexokinase III) 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 Hk3 gene (hexokinase III) 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.S2CID23521290.
^abcdefghijOkatsu 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.
^abcdePrintz 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.S2CID1851264.
^abcCárdenas ML, Cornish-Bowden A, Ureta T (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.PMID9540816.
^abcdeLowes 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 (BBA) - General Subjects.1379 (1):134–42.doi:10.1016/s0304-4165(97)00092-5.PMID9468341.
^abcdGao 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.
^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.S2CID25298962.
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 (BBA) - General Subjects.719 (3):431–7.doi:10.1016/0304-4165(82)90230-6.hdl:1874/15535.PMID7150652.S2CID24438788.
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.S2CID6748596.
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 (BBA) - General Subjects.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 (hexokinase III) to chromosome band 5q35.2 by fluorescence in situ hybridization".Genomics.36 (1):206–9.doi:10.1006/geno.1996.0448.PMID8812439.
