Hexokinase 1

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Hexokinase 1
Hexokinase 1
according to PDB  3O08
other names
  • Brain form hexokinase
  • HMSNR
  • HK 1

Existing structural data : 1CZA , 1DGK , 1HKB , 1HKC , 1QHA , 4F9O

Properties of human protein
Mass / length primary structure 917 amino acids, 102486 Da
Identifier
External IDs
Enzyme classification
EC, category 2.7.1.1
Orthologue
human House mouse
Entrez 3098 15275
Ensemble ENSG00000156515 ENSMUSG00000037012
UniProt P19367 P17710
Refseq (mRNA) NM_000188 NM_001146100
Refseq (protein) NP_000179 NP_001139572
Gene locus Chr 10: 69.27 - 69.4 Mb Chr 10: 62.27 - 62.38 Mb
PubMed search 3098 15275

Hexokinase 1 ( HK1 ) is an enzyme that is encoded in humans by the HK1 gene on chromosome 10 and belongs to the group of hexokinases . Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), marking the first step in most glucose metabolic pathways. The gene codes for a ubiquitous form of hexokinase that is located on the outer membrane of the mitochondria.

Mutations in this gene have been linked to hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in five transcript variants that encode different isoforms , some of which are tissue specific. Each isoform has a different N terminus ; the rest of the protein is identical for all isoforms. A sixth variant of the transcript has been described, but due to the presence of multiple stop codons , it is not believed to encode a protein.

structure

Hexokinase 1 is one of four highly homologous hexokinase isoforms in mammalian cells.

gene

The HK1 gene is approximately 131  kb and consists of 25 exons . Alternative splicing of its 5 ′ exons generates different transcripts in different cell types: exons 1-5 and exon 8 (exons T1-6) are testis -specific exons; Exon 6, located approximately 15 kb "downstream" (eng. Downstream ) of the testis-specific exons is, the erythroid -specific exon (exon R); and exon 7, located approximately 2.85 kb downstream from exon R, is the first 5 'exon for the ubiquitously expressed HK1 isoform. In addition, exon 7 encodes the porin binding domain (PBD) conserved in HK1 genes in mammals . The remaining 17 exons share all HK1 isoforms.

In addition to exon R, a portion of the proximal promoter containing a GATA element, an SP1 site, a CCAAT nucleotide sequence, and an Ets binding motif is required for the expression of Hexokinase R (HK-R) in erythrocytes.

protein

The HK1 gene codes for a 100 kDa homodimer with a regulatory N -terminal domain (residues 1-475), a catalytic C -terminal domain (residues 476-917) and an α-helix connecting the two subunits. Both end domains consist of a large sub-domain and a small sub-domain. The flexible region of the C -terminal large subdomain (residues 766-810) can occupy various positions and is said to interact with the ATP base adenine .

Moreover bind glucose and glucose-6-phosphate in close proximity to the N - and C -terminal domains and stabilize a common conformational state of the C -terminal domain. According to one model, glucose-6-phosphate acts as an allosteric inhibitor that binds the N -terminal domain to stabilize its closed conformation, which then stabilizes a conformation of the flexible C -terminal subdomain that blocks ATP. A second model states that glucose-6-phosphate acts as an active inhibitor that stabilizes the closed conformation and competes with ATP for the C -terminal binding site. The results of several studies suggest that the C terminus can have both catalytic and regulatory effects. Meanwhile, the hydrophobic N terminus lacks enzymatic activity, but contains the G6P regulatory site and the PBD, which is responsible for the stability of the protein and the binding to the mitochondrial outer membrane (OMM).

function

As one of two mitochondrial isoforms of hexokinase and as a member of the sugar kinase family (kinases that phosphorylate the hydroxyl groups of sugar molecules), hexokinase 1 catalyzes the rate-determining and first mandatory step of glucose metabolism, which involves the ATP-dependent glucose- glucose- 6-phosphate. Physiological concentrations of glucose-6-phosphate can regulate this process by inhibiting HK1 as negative feedback, although inorganic phosphate (P i ) can ameliorate G6P inhibition. Unlike HK2 and HK3 , HK1 is not directly regulated by P i , which better fits its ubiquitous catabolic role. By phosphorylating glucose, HK1 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 through direct recycling of mitochondrial ATP / ADP to meet the cell's energy needs. In particular, OMM-bound HK1 binds to VDAC1 to trigger the opening of the mitochondrial permeability transition pore (mPTP) and release mitochondrial ATP to further fuel the glycolytic process.

Another important function of OMM-bound HK1 is cell survival and protection against oxidative damage . The activation of protein kinase B by HC1-VDAC1 coupling as part of the intracellular signaling pathway between the growth factor mediated phosphoinositide 3-kinase (PI3) and the intracellular cell survival of protein kinase B enables, whereby the release of cytochrome c and the subsequent apoptosis prevents become. Indeed, there is evidence that VDAC binding by anti-apoptotic HK1 and pro-apoptotic creatine kinase are mutually exclusive, suggesting that the absence of HK1 enables VDAC to bind and open by creatine kinase. In addition, HK1 shows anti-apoptotic activity in that it antagonizes Bcl-2 proteins located at the OMM , which then inhibit TNF- induced apoptosis.

In the prefrontal cortex , HK1 presumably forms a protein complex with EAAT2 , Na + / K + -ATPase, and aconitase , which serves to remove glutamate from the perisynaptic space and maintain low basal levels in the synaptic cleft .

In particular, HK1 is the most commonly expressed isoform among the four hexokinases and is constitutively expressed in most tissues, although it is primarily found in the brain, kidneys and red blood cells. The high frequency of HK1 in the retina, particularly in the inner segment of the photoreceptor, in the outer plexiform layer , in the inner granular layer , in the inner plexiform layer, and in the ganglion cell layer confirms the crucial metabolic purpose. It is also expressed in cells derived from hematopoietic stem cells such as erythrocytes, leukocytes, and platelets, as well as erythroid progenitor cells. Notably, HK1 is the only hexokinase isoform in cells and tissues whose function is most dependent on glucose metabolism, including the brain, erythrocytes, platelets, leukocytes, and fibroblasts. In rats, it is also the predominant hexokinase in fetal tissues, probably due to its constitutive glucose utilization.

Clinical significance

Mutations in this gene are associated with type 4G of Charcot-Marie-Tooth disease, also known as Russe-type hereditary motor and sensory neuropathy (HMSNR). Due to the critical role of HC1 in glycolysis, hexokinase deficiency has been identified as the cause of erythroenzymopathies associated with hereditary non-spherocytic hemolytic anemia (HNSHA). HK1 deficiency has also led to white matter damage , malformations, psychomotor retardation, and latent diabetes mellitus and panmyelopathy . HK1 is highly expressed in cancers and its anti-apoptotic effects have been observed in highly glycolytic hepatoma cells .

Neurodegenerative Diseases

HD1 can be causally linked to mood and psychotic disorders , including unipolar depression (UPD), bipolar disorder (BPD), and schizophrenia , both through its role in energy metabolism and through cell survival. For example, the accumulation of lactate in the brains of BPD and schizophrenia patients may result from the uncoupling of HC1 from the OMM and subsequently from glycolysis through mitochondrial oxidative phosphorylation. In the case of schizophrenia, reduced HK1 binding to the OMM in the parietal cortex led to a reduced glutamate reuptake capacity and thus to a glutamate overflow from the synapses. The released glutamate activates extrasynaptic glutamate receptors , which leads to an altered structure and function of the glutamate neurocirculation, synaptic plasticity , frontal brain syndrome and ultimately to the cognitive deficits characteristic of schizophrenia.

Similarly, HD1 detachment in mitochondria has been linked to hypothyroidism , which causes abnormal brain development and an increased risk of depression, while its attachment to mitochondria leads to neuronal growth. In Parkinson's disease , HK1 detachment from VDAC by Parkin- mediated ubiquitination and degradation disrupts the mPTP on depolarized mitochondria, thereby blocking the mitochondrial localization of Parkin and stopping glycolysis. Further research is needed to determine the relative HC1 shedding required for different mental disorders in different cell types. Research can also help develop therapies that target the causes of HC1 detachment from OMM, from gene mutations to disorders caused by factors such as amyloid beta peptide and insulin .

Retinopathia pigmentosa

A heterozygous missense mutation in the HK1 gene (a change at position 847 from glutamate to lysine) has been implicated in retinopathia pigmentosa . Because this substitution mutation is located far from known functional sites and does not affect the glycolytic activity of the enzyme, it is likely that the mutation is acting through a different biological mechanism that is unique to the retina.

Investigations on the retina of mice show interactions between the mouse gene Hk1, the mitochondrial metal chaperone Cox11 and the chaperone protein Ranbp2, which are used to maintain a normal metabolism and normal function in the mouse retina. Therefore, the mutation can disrupt these interactions and lead to the breakdown of the retina. Alternatively, this mutation could influence the anti-apoptotic function of the enzyme, since a disruption of the regulation of the hexokinase-mitochondria association by insulin receptors could trigger apoptosis of photoreceptors and degeneration of the retina. In this case, treatments that preserve the hexokinase-mitochondrial association could serve as a potential therapeutic approach.

Individual evidence

  1. ↑ HK1 hexokinase 1 (human)
  2. ↑ a b c d e f g h i 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).
  3. ↑ a b c d e f g 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 .
  4. ↑ a b c d e f g 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 .
  5. ↑ AE Aleshin, C. Kirby, X. Liu, GP Bourenkov, HD Bartunik, HJ Fromm, RB Honzatko: Crystal structures of mutant monomeric hexokinase I reveal multiple ADP binding sites and conformational changes relevant to allosteric regulation. In: Journal of molecular biology. Volume 296, Number 4, March 2000, pp. 1001-1015, doi : 10.1006 / jmbi.1999.3494 , PMID 10686099 .
  6. ↑ 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).
  7. ↑ a b c 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).
  8. ↑ 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 .
  9. ↑ a b c d e W. T. Regenold, M. Pratt, S. Nekkalapu, PS Shapiro, T. Kristian, G. Fiskum: Mitochondrial detachment of hexokinase 1 in mood and psychotic disorders: implications for brain energy metabolism and neurotrophic signaling. In: Journal of Psychiatric Research. Volume 46, number 1, January 2012, pp. 95-104, doi : 10.1016 / j.jpsychires.2011.09.018 , PMID 22018957 .
  10. ↑ a b c R. B. Robey, N. Hay: Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and act. In: Oncogene . Volume 25, Number 34, August 2006, pp. 4683-4696, doi : 10.1038 / sj.onc.1209595 , PMID 16892082 (review).
  11. ^ A b 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).
  12. ↑ a b c d e F. Wang, Y. Wang, B. Zhang, L. Zhao, V. Lyubasyuk, K. Wang, M. Xu, Y. Li, F. Wu, C. Wen, PS Bernstein, D Lin, S. Zhu, H. Wang, K. Zhang, R. Chen: A missense mutation in HK1 leads to autosomal dominant retinitis pigmentosa. In: Investigative ophthalmology & visual science. Volume 55, number 11, October 2014, pp. 7159-7164, doi : 10.1167 / iovs.14-15520 , PMID 25316723 , PMC 4224578 (free full text).
  13. ↑ AP Gjesing, AA Nielsen, I. Brandslund, C. Christensen, A. Sandbæk, T. Jørgensen, D. Witte, A. Bonnefond, P. Froguel, T. Hansen, O. Pedersen: Studies of a genetic variant in HK1 in relation to quantitative metabolic traits and to the prevalence of type 2 diabetes. In: BMC medical genetics. Volume 12, July 2011, p. 99, doi : 10.1186 / 1471-2350-12-99 , PMID 21781351 , PMC 3161933 (free full text).
  14. ^ 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 .
  15. ↑ CMT4G.  In: Online Mendelian Inheritance in Man . (English)
  16. ↑ a b c LS Sullivan, DC Koboldt, SJ Bowne, S. Lang, SH Blanton, E. Cadena, CE Avery, RA Lewis, K. Webb-Jones, DH Wheaton, DG Birch, R. Coussa, H. Ren, I. Lopez, C. Chakarova, RK Koenekoop, CA Garcia, RS Fulton, RK Wilson, GM Weinstock, SP Daiger: A dominant mutation in hexokinase 1 (HK1) causes retinitis pigmentosa. In: Investigative ophthalmology & visual science. Volume 55, number 11, September 2014, pp. 7147-7158, doi : 10.1167 / iovs.14-15419 , PMID 25190649 , PMC 4224580 (free full text).