HK1

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Hexokinase 1
Protein HK1 PDB 1bg3.png
PDB rendering based on 1bg3.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HK1 ; HK1-ta; HK1-tb; HK1-tc; HKD; HKI; HMSNR; HXK1
External IDs OMIM142600 MGI96103 HomoloGene100530 ChEMBL: 2688 GeneCards: HK1 Gene
EC number 2.7.1.1
RNA expression pattern
PBB GE HK1 200697 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3098 15275
Ensembl ENSG00000156515 ENSMUSG00000037012
UniProt P19367 P17710
RefSeq (mRNA) NM_000188 NM_001146100
RefSeq (protein) NP_000179 NP_001139572
Location (UCSC) Chr 10:
69.27 – 69.4 Mb
Chr 10:
62.27 – 62.38 Mb
PubMed search [1] [2]

Hexokinase-1 (HK1) is an enzyme that in humans is encoded by the HK1 gene on chromosome 10. Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in five transcript variants which encode different isoforms, some of which are tissue-specific. Each isoform has a distinct N-terminus; the remainder of the protein is identical among all the isoforms. A sixth transcript variant has been described, but due to the presence of several stop codons, it is not thought to encode a protein. [provided by RefSeq, Apr 2009][1]

Structure[edit]

HK1 is one of four highly homologous hexokinase isoforms in mammalian cells.[2][3]

Gene[edit]

The HK1 gene spans approximately 131 kb and consists of 25 exons. Alternative splicing of its 5’ exons produces 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 of the testis-specific exons, is the erythroid-specific exon (exon R); and exon 7, located approximately 2.85 kb downstream of exon R, is the first 5’ exon for the ubiquitously expressed HK1 isoform. Moreover, exon 7 encodes the porin-binding domain (PBD) conserved in mammalian HK1 genes. Meanwhile, the remaining 17 exons are shared among all HK1 isoforms.

In addition to exon R, a stretch of the proximal promoter that contains a GATA element, an SP1 site, CCAAT, and an Ets-binding motif is necessary for expression of HK-R in erythroid cells.[2]

Protein[edit]

This gene encodes a 100 kDa homodimer with a regulatory N-terminal domain (1-475), catalytic C-terminal domain (residues 476-917), and an alpha-helix connecting its two subunits.[2][4][5][6] Both terminal domains are composed of a large subdomain and a small subdomain. The flexible region of the C-terminal large subdomain (residues 766–810) can adopt various positions and is proposed to interact with the base[disambiguation needed] of ATP. Moreover, glucose and G6P bind in close proximity at the N- and C-terminal domains and stabilize a common conformational state of the C-terminal domain.[4][5] According to one model, G6P acts as an allosteric inhibitor which binds the N-terminal domain to stabilize its closed conformation, which then stabilizes a conformation of the C-terminal flexible subdomain that blocks ATP. A second model posits that G6P acts as an active inhibitor that stabilizes the closed conformation and competes with ATP for the C-terminal binding site.[4] Results from several studies suggest that the C-terminal is capable of both catalytic and regulatory action.[7] Meanwhile, the hydrophobic N-terminal lacks enzymatic activity by itself but contains the G6P regulatory site and the PBD, which is responsible for the protein’s stability and binding to the outer mitochondrial membrane (OMM).[2][8][6][9]

Function[edit]

As As one of two mitochondrial isoforms of hexokinase and a member of the sugar kinase family, HK1 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P.[4][3][6][10] Physiological levels of G6P can regulate this process by inhibiting HK1 as negative feedback, though inorganic phosphate (Pi) can relieve G6P inhibition.[4][8][6] However, unlike HK2 and HK3, HK1 itself is not directly regulated by Pi, which better suits its ubiquitous catabolic role.[3] By phosphorylating glucose, HK1 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism.[4][9][8][6] Moreover, its localization and attachment to the OMM promotes the coupling of glycolysis to mitochondrial oxidative phosphorylation, which greatly enhances ATP production by direct recycling of mitochondrial ATP/ADP to meet the cell’s energy demands.[10][6][11] Specifically, OMM-bound HK1 binds VDAC1 to trigger opening of the mitochondrial permeability transition pore and release mitochondrial ATP to further fuel the glycolytic process.[6][3]

Another critical function for OMM-bound HK1 is cell survival and protection against oxidative damage.[10][3] Activation of Akt kinase is mediated by HK1-VDAC1 coupling as part of the growth factor-mediated phosphatidyl inositol 3-kinase (PI3)/Akt cell survival intracellular signaling pathway, thus preventing cytochrome c release and subsequent apoptosis.[10][2][6][3] In fact, there is evidence that VDAC binding by the anti-apoptotic HK1 and by the pro-apoptotic creatine kinase are mutually exclusive, indicating that the absence of HK1 allows creatine kinase to bind and open VDAC.[3] Furthermore, HK1 has demonstrated anti-apoptotic activity by antagonizing Bcl-2 proteins located at the OMM, which then inhibits TNF-induced apoptosis.[2][9]

In the prefrontal cortex, HK1 putatively forms a protein complex with EAAT2, Na+/K+ ATPase, and aconitase, which functions to remove glutamate from the perisynaptic space and maintain low basal levels in the synaptic cleft.[11]

In particular, HK1 is the most ubiquitously expressed isoform out of the four hexokinases, and constitutively expressed expressed in most tissues, though it is majorly found in brain, kidney, and red blood cells (RBCs).[2][4][9][3][11][6][12] Its high abundance in the retina, specifically the photoreceptor inner segment, outer plexiform layer, inner nuclear layer, inner plexiform layer, and ganglion cell layer, attests to its crucial metabolic purpose.[13] It is also expressed in cells derived from hematopoietic stem cells, such as RBCs, leukocytes, and platelets, as well as from erythroid-progenitor cells.[2] Of note, HK1 is the sole hexokinase isoform found in the cells and tissues which rely most heavily on glucose metabolism for their function, including brain, erythrocytes, platelets, leukocytes, and fibroblasts.[14] In rats, it is also the predominant hexokinase in fetal tissues, likely due to their constitutive glucose utilization.[8][12]

Clinical significance[edit]

Mutations in this gene are associated with type 4H of Charcot–Marie–Tooth disease, also known as Russe-type hereditary motor and sensory neuropathy (HMSNR).[15] Due to the crucial role of HK1 in glycolysis, hexokinase deficiency has been identified as a cause of erythroenzymopathies associated with hereditary nonspherocytic hemolytic anemia (HNSHA). Likewise, HK1 deficiency has resulted in cerebral white matter injury, malformations, and psychomotor retardation, as well as latent diabetes mellitus and panmyelopathy.[2] Meanwhile, HK1 is highly expressed in cancers, and its anti-apoptotic effects have been observed in highly glycolytic hepatoma cells.[9][2]

Neurodegenerative disorders[edit]

HK1 may be causally linked to mood and psychotic disorders, including unipolar depression (UPD), bipolar disorder (BPD), and schizophrenia via both its roles in energy metabolism and cell survival. For instance, the accumulation of lactate in the brains of BPD and SCHZ patients potentially results from the decoupling of HK1 from the OMM, and by extension, glycolysis from mitochondrial oxidative, phosphorylation. In the case of SCHZ, decreasing HK1 attachment to the OMM in the parietal cortex resulted in decreased glutamate reuptake capacity and, thus, glutamate spillover from the synapses. The released glutamate activates extrasynaptic glutamate receptors, leading to altered structure and function of glutamate circuits, synaptic plasticity, frontal cortical dysfunction, and ultimately, the cognitive deficits characteristic of SCHZ.[11] Similarly, Hk1 mitochondrial detachment has been associated with hypothyroidism, which involves abnormal brain development and increased risk for depression, while its attachment leads to neural growth.[10] In Parkinson’s disease, HK1 detachment from VDAC via Parkin-mediated ubiquitylation and degradation disrupts the MPTP on depolarized mitochondria, consequently blocking mitochondrial localization of Parkin and halting glycolysis.[3] Further research is required to determine the relative HK1 detachment needed in various cell types for different psychiatric disorders. This research can also contribute to developing therapies to target causes of the detachment, from gene mutations to interference by factors such as beta-amyloid peptide and insulin.[10]

Retinitis pigmentosa[edit]

A heterozygous missense mutation in the HK1 gene (a change at position 847 from glutamate to lysine) has been linked to retinitis pigmentosa.[16][13] Since this substitution mutation is located far from known functional sites and does not impair the enzyme’s glycolytic activity, it is likely that the mutation acts through another biological mechanism unique to the retina.[16] Notably, studies in mouse retina reveal interactions between Hk1, the mitochondrial metallochaperone Cox11, and the chaperone protein Ranbp2, which serve to maintain normal metabolism and function in the retina. Thus, the mutation may disrupt these interactions and lead to retinal degradation.[13] Alternatively, this mutation may act through the enzyme’s anti-apoptotic function, as disrupting the regulation of the hexokinase-mitochondria association by insulin receptors could trigger photoreceptor apoptosis and retinal degeneration.[16][13] In this case, treatments that preserve the hexokinase–mitochondria association may serve as a potential therapeutic approach.[13]

Interactions[edit]

HK1 is known to interact with:


Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]
Glycolysis and Gluconeogenesis edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534". 

See also[edit]

References[edit]

  1. ^ "Entrez Gene: HK1 hexokinase 1". 
  2. ^ a b c d e f g h i j 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. 
  3. ^ a b c d e f g h i j k 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. 
  4. ^ a b c d e f g 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. 
  5. ^ a b Aleshin AE, Kirby C, Liu X, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB (Mar 2000). "Crystal structures of mutant monomeric hexokinase I reveal multiple ADP binding sites and conformational changes relevant to allosteric regulation". Journal of Molecular Biology 296 (4): 1001–15. doi:10.1006/jmbi.1999.3494. PMID 10686099. 
  6. ^ a b c d e f g h i Robey RB, Hay N (Aug 2006). "Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt". Oncogene 25 (34): 4683–96. doi:10.1038/sj.onc.1209595. PMID 16892082. 
  7. ^ Cárdenas, ML; Cornish-Bowden, A; Ureta, T (5 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. PMID 9540816. 
  8. ^ a b c d 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. 
  9. ^ a b c d e 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. 
  10. ^ a b c d e f Regenold WT, Pratt M, Nekkalapu S, Shapiro PS, Kristian T, Fiskum G (Jan 2012). "Mitochondrial detachment of hexokinase 1 in mood and psychotic disorders: implications for brain energy metabolism and neurotrophic signaling". Journal of Psychiatric Research 46 (1): 95–104. doi:10.1016/j.jpsychires.2011.09.018. PMID 22018957. 
  11. ^ a b c d e f g 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. PMID 24560881. 
  12. ^ a b 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. 
  13. ^ a b c d e Wang F, Wang Y, Zhang B, Zhao L, Lyubasyuk V, Wang K, Xu M, Li Y, Wu F, Wen C, Bernstein PS, Lin D, Zhu S, Wang H, Zhang K, Chen R (Nov 2014). "A missense mutation in HK1 leads to autosomal dominant retinitis pigmentosa". Investigative Ophthalmology & Visual Science 55 (11): 7159–64. doi:10.1167/iovs.14-15520. PMID 25316723. 
  14. ^ Gjesing AP, Nielsen AA, Brandslund I, Christensen C, Sandbæk A, Jørgensen T, Witte D, Bonnefond A, Froguel P, Hansen T, Pedersen O (25 July 2011). "Studies of a genetic variant in HK1 in relation to quantitative metabolic traits and to the prevalence of type 2 diabetes". BMC Medical Genetics 12: 99. doi:10.1186/1471-2350-12-99. PMID 21781351. 
  15. ^ Online 'Mendelian Inheritance in Man' (OMIM) 605285
  16. ^ a b c Sullivan LS, Koboldt DC, Bowne SJ, Lang S, Blanton SH, Cadena E, Avery CE, Lewis RA, Webb-Jones K, Wheaton DH, Birch DG, Coussa R, Ren H, Lopez I, Chakarova C, Koenekoop RK, Garcia CA, Fulton RS, Wilson RK, Weinstock GM, Daiger SP (Nov 2014). "A dominant mutation in hexokinase 1 (HK1) causes retinitis pigmentosa". Investigative Ophthalmology & Visual Science 55 (11): 7147–58. doi:10.1167/iovs.14-15419. PMID 25190649. 

Further reading[edit]