Hexokinase 3

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Hexokinase 3
other names
  • Hexokinase 3 (White Cell)
  • Hexokinase Type III
  • Hexokinase-3
  • HK III
  • HKIII
  • HXK3

Existing structural data : 3HM8

Properties of human protein
Mass / length primary structure 923 amino acids, 99025 Da
Identifier
Gene name HK3
External IDs
Enzyme classification
EC, category 2.7.1.1
Orthologue
human House mouse
Entrez 3101 212032
Ensemble ENSG00000160883 ENSMUSG00000025877
UniProt P52790 Q3TRM8
Refseq (mRNA) NM_002115 NM_001033245
Refseq (protein) NP_002106 NP_001028417
Gene locus Chr 5: 176.88 - 176.9 Mb Chr 13: 55.01 - 55.02 Mb
PubMed search 3101 212032

Hexokinase 3 (also known as HK3 ) is an enzyme belonging to the hexokinase group that is encoded by the HK3 gene on chromosome 5 in humans. Hexokinases phosphorylate glucose to form glucose-6-phosphate (G6P) and form the first step in most glucose metabolic pathways. The HK3 gene codes for hexokinase 3. Similar to hexokinases 1 and 2 , hexokinase 3 is inhibited as an allosteric enzyme by its product glucose-6-phosphate.

structure

HK3 is one of four highly homologous hexokinase isoforms in mammalian cells. This protein has a molecular weight of about 100 kDa and consists of two very similar 50 kDa domains at its N - and C -terminal ends. 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 .

As with HK1, only the C -terminal domain has 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. In addition, the catalytic activity depends on the interaction between the two terminal domains. In contrast to HK1 and HK2, HK3 lacks a mitochondrial binding sequence at the N terminus.

function

As a cytoplasmic isoform of hexokinase and a member of the sugar kinase family, HK3 catalyzes the rate-determining and first obligatory step in glucose metabolism, namely the ATP- dependent phosphorylation of glucose to G6P. Physiological G6P levels can regulate this process by inhibiting HK3 as negative feedback, although inorganic phosphate can ameliorate G6P inhibition. Inorganic phosphate can also directly regulate HK3 and the dual regulation may be better suited to its anabolic functions. By phosphorylating glucose, HK3 effectively prevents glucose from leaving the cell and thus binds glucose to the energy metabolism. Compared to HK1 and HK2, HK3 has a higher affinity for glucose and also binds the substrate at a physiological level, although this binding can be weakened by intracellular ATP. It is unique that HK3 can be inhibited by glucose in high concentrations. HK3 is also less sensitive to G6P inhibition.

Despite its lack of mitochondrial association, HK3 also protects the cell from apoptosis . An overexpression of HK3 has increased ATP levels, reduced production of reactive oxygen species (ROS), an attenuated decrease in the mitochondrial membrane potential and improved mitochondrial biogenesis performed. Overall, HK3 can promote cell survival by controlling ROS levels and increasing energy production. All that is currently known is that hypoxia induces HK3 expression via an HIF -dependent pathway. The inducible expression of HK3 shows its adaptive role in metabolic processes to changes in the cellular environment.

In particular, HK3 is ubiquitously expressed in tissues, albeit at a relatively low frequency. Higher frequencies of HC3 were reported in the lung, kidney and liver tissue. In cells, HK3 localizes in the cytoplasm and possibly binds to the nuclear envelope . HK3 is the predominant hexokinase in myeloid cells, especially granulocytes .

Clinical significance

HK3 is overexpressed in malignant follicular thyroid nodules . In conjunction with cyclin A and galectin-3 , HK3 could be used as a diagnostic biomarker for screening for malignancy in patients. HD3 has been found to be suppressed in patients with acute myeloid leukemia (AML) and promyelocytic leukemia (M3).

It is known that the transcription factor PU.1 directly activates the transcription of the anti-apoptotic BCL2A1 gene or inhibits the transcription of the p53 tumor suppressor to promote cell survival and that it also directly activates HK3 transcription during differentiation of neutrophils to support short-term cell survival of mature neutrophils. Regulators that suppress HK3 expression in AML include PML , RARA, and CEBPA . With regard to acute lymphoblastic leukemia (ALL), a functional enrichment analysis revealed that HK3 is a key gene and suggests that HK3 shares anti-apoptotic function with HK1 and HK2.

Individual evidence

  1. ↑ H. Furuta, S. Nishi, MM Le Beau, AA Fernald, H. Yano, GI Bell: 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. In: Genomics. Volume 36, Number 1, August 1996, pp. 206-209, doi : 10.1006 / geno.1996.0448 , PMID 8812439 .
  2. ^ A. Colosimo, G. Calabrese, M. Gennarelli, AM Ruzzo, F. Sangiuolo, M. Magnani, G. Palka, G. Novelli, B. Dallapiccola: Assignment of the hexokinase type 3 gene (HK3) to human chromosome band 5q35.3 by somatic cell hybrids and in situ hybridization. In: Cytogenetics and cell genetics. Volume 74, Number 3, 1996, pp. 187-188, doi : 10.1159 / 000134409 , PMID 8941369 .
  3. ↑ HK3 hexokinase 3 (human)
  4. ↑ 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).
  5. ↑ a b c d e f g h i j 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 .
  6. ↑ a b c d e f g h i j k l 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).
  7. ↑ a b c d W. Lowes, M. Walker, KG Alberti, L. Agius: Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis. In: Biochimica et Biophysica Acta . Volume 1379, Number 1, January 1998, pp. 134-142, doi : 10.1016 / s0304-4165 (97) 00092-5 , PMID 9468341 .
  8. ^ 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 .
  9. ^ RL 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).
  10. ↑ 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).
  11. ↑ a b c H. Y. Gao, XG Luo, X. Chen, JH Wang: Identification of key genes affecting disease free survival time of pediatric acute lymphoblastic leukemia based on bioinformatic analysis. In: Blood cells, molecules & diseases. Volume 54, number 1, January 2015, pp. 38-43, doi : 10.1016 / j.bcmd.2014.08.002 , PMID 25172542 .
  12. ^ A b E. A. Federzoni, M. Humbert, BE Torbett, G. Behre, MF Fey, MP Tschan: CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation. In: Scientific Reports . Volume 4, March 2014, p. 4261, doi : 10.1038 / srep04261 , PMID 24584857 , PMC 3939455 (free full text).
  13. ^ L. Hooft, AA van der Veldt, OS Hoekstra, M. Boers, CF Molthoff, PJ van Diest: Hexokinase III, cyclin A and galectin-3 are overexpressed in malignant follicular thyroid nodules. In: Clinical endocrinology. Volume 68, Number 2, February 2008, pp. 252-257, doi : 10.1111 / j.1365-2265.2007.03031.x , PMID 17868400 .
  14. ↑ a b E. A. Federzoni, PJ Valk, BE Torbett, T. Haferlach, B. Lowenberg, MF Fey, MP Tschan: PU.1 is linking the glycolytic enzyme HC3 in neutrophil differentiation and survival of APL cells. In: Blood. Volume 119, number 21, May 2012, pp. 4963-4970, doi : 10.1182 / blood-2011-09-378117 , PMID 22498738 , PMC 3367898 (free full text).