Sandbox GGC2

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1QHA HUMAN HEXOKINASE TYPE I1QHA HUMAN HEXOKINASE TYPE I


Function

falls under the protein category of a kinase and is located within the cytosol and along the mitochondrial outer membrane [1][2]. A kinase is a protein that is responsible for the modification of a molecule through the covalent addition of the phosphate group. The source of the phosphate group is . Human Hexokinase 1 catalyzes the phosphorylation of hexose sugars, primarily to form Glucose-6-Phosphate. This is typically observed during the initial step of glycolysis and is performed in order to attach a charge to the glucose, preventing it from diffusing out of the cell through the cell membrane. Typically, a cofactor also participates in a chelation complex with ATP [3].

Human Hexokinase 1 is seen to have a function in both innate immunity and inflammation in which the protein acts as a pattern recognition receptor for N-acetyl-D-glucosamine, a hexose present in the peptidoglycan layer of bacterial cell walls. Upon binding to N-acetyl-D-glucosamine, Human Hexokinase 1 dissociates from the mitochondria, which results in the activation of NLRP3 inflammasome [4]. Human Hexokinase 1 is also seen to play a role in tumor suppression. It does so by form a complex with voltage-dependent anion channel-1 (VDAC1) when acted phosphorylated by activating transcription factor 2 (ATF2). The HK1-VDAC1 complex functions to increase the permeability of the mitochondria outer membrane. This causes a release of mitochondrial enzymes which trigger apoptosis [5].

Disease

There are multiple diseases associated with Human Hexokinase 1. It is possible for illness to arise from a deficiency in the protein. A deficiency is a rare autosomal recessive disease in which the and residues in the 529 and the 680 positions are mutated and translated as a Serine. This disease results in nonspherocytic hemolytic anemia [6].

Also, diseases of Human Hexokinase can also result in diseases that affect the nervous system. A nervous system disease associated with the protein is neuropathy, hereditary motor and sensory, Russe type (HMSNR), also known as Charcot-Marie-Tooth disease. Laboratory studies suggest that this disease is caused by a mutation in a 26 kb range in upstream exons in the Human Hexokinase 1 gene. HMSNR is also autosomal recessive and is usually apparent in the first 10 years of life, characterized by muscular atrophy and impairment in the distal lower limbs. This weakness and atrophy results in those affected by the disease experiencing difficulty walking. HMSNR can later develop into weakness in the distal upper limbs and the proximal lower limbs. It is suspected that this disease is a result of demyelination of the neuronal axon which in turn has negative effects on neuron action potential velocity [7].

Another nervous system disease is a neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA). This disease is found to primarily impact the brain, eyes, and heart. NEDVIBA is characterized by speech delay, intellectual disability, structural brain abnormalities, and visual impairments. The disease is caused by mutations in the 414 position (G → E), the 418 position (K → E), the 445 position (S → L), and in the 457 position (T → M) [8].

Retinitis pigmentosa is also a disease caused by mutation of the residue in the 847 positions to a Lysine in Human Hexokinase 1. This disease is an autosomal dominant disease. Retinitis pigmentosa is a form of retinal dystrophy and is characterized by retinal pigment deposits. There is also a loss of both the rod and cone photoreceptors in the eye. Patients typically experience visual difficulty in poorly lit environments and loss of the mid-peripheral visual field. As the condition progresses, patients continue to experience deterioration of the visual field [9][10].

Structural highlights

The Human Hexokinase 1 protein is a homodimer formed from an and . There are only a few post-translational modifications that the Human Hexokinase 1 protein undergoes, those being acetylation at the Methionine residue in the 1 position and phosphorylation of the Serine residue in the 337 position, a modification that is also seen in the Rattus norvegicus (Rat) variation of the gene [11][12]. This serine phosphorylation results in the presence of a phosphoserine.

There are several relevant regions of importance in the Human Hexokinase 1 protein. The N-terminal spanning from residue 1-10, are responsible for the binding interaction between the Human Hexokinase 1 protein and the mitochondria[13]. Further, there are multiple Glucose-6-Phosphate binding domains. These binding domains are seen at residues , 413-415, 532-536, and 861-863. There are also multiple glucose binding sites present at residues , 208-209, and 291-294 [14][15][16][17].

HUMAN HEXOKINASE TYPE I COMPLEXED WITH ATP ANALOGUE AMP-PNP

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ReferencesReferences

  1. ↑ Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K, Wheeler ML, Cho HC, Popescu NI, Coggeshall KM, Arditi M, Underhill DM. Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan. Cell. 2016 Jul 28;166(3):624-636. doi: 10.1016/j.cell.2016.05.076. Epub 2016 Jun , 30. PMID:27374331 doi:http://dx.doi.org/10.1016/j.cell.2016.05.076
  2. ↑ Magnani M, Serafini G, Bianchi M, Casabianca A, Stocchi V. Human hexokinase type I microheterogeneity is due to different amino-terminal sequences. J Biol Chem. 1991 Jan 5;266(1):502-5. PMID:1985912
  3. ↑ Garfinkel L, Garfinkel D. Magnesium regulation of the glycolytic pathway and the enzymes involved. Magnesium. 1985;4(2-3):60-72. PMID:2931560
  4. ↑ Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K, Wheeler ML, Cho HC, Popescu NI, Coggeshall KM, Arditi M, Underhill DM. Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan. Cell. 2016 Jul 28;166(3):624-636. doi: 10.1016/j.cell.2016.05.076. Epub 2016 Jun , 30. PMID:27374331 doi:http://dx.doi.org/10.1016/j.cell.2016.05.076
  5. ↑ Lau E, Kluger H, Varsano T, Lee K, Scheffler I, Rimm DL, Ideker T, Ronai ZA. PKCepsilon promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Cell. 2012 Feb 3;148(3):543-55. doi: 10.1016/j.cell.2012.01.016. PMID:22304920 doi:http://dx.doi.org/10.1016/j.cell.2012.01.016
  6. ↑ Bianchi M, Magnani M. Hexokinase mutations that produce nonspherocytic hemolytic anemia. Blood Cells Mol Dis. 1995;21(1):2-8. doi: 10.1006/bcmd.1995.0002. PMID:7655856 doi:http://dx.doi.org/10.1006/bcmd.1995.0002
  7. ↑ Hantke J, Chandler D, King R, Wanders RJ, Angelicheva D, Tournev I, McNamara E, Kwa M, Guergueltcheva V, Kaneva R, Baas F, Kalaydjieva L. A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR). Eur J Hum Genet. 2009 Dec;17(12):1606-14. doi: 10.1038/ejhg.2009.99. Epub 2009, Jun 17. PMID:19536174 doi:http://dx.doi.org/10.1038/ejhg.2009.99
  8. ↑ Okur V, Cho MT, van Wijk R, van Oirschot B, Picker J, Coury SA, Grange D, Manwaring L, Krantz I, Muraresku CC, Hulick PJ, May H, Pierce E, Place E, Bujakowska K, Telegrafi A, Douglas G, Monaghan KG, Begtrup A, Wilson A, Retterer K, Anyane-Yeboa K, Chung WK. De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment. Eur J Hum Genet. 2019 Jul;27(7):1081-1089. doi: 10.1038/s41431-019-0366-9. Epub, 2019 Feb 18. PMID:30778173 doi:http://dx.doi.org/10.1038/s41431-019-0366-9
  9. ↑ 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. A dominant mutation in hexokinase 1 (HK1) causes retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2014 Sep 4;55(11):7147-58. doi: 10.1167/iovs.14-15419. PMID:25190649 doi:http://dx.doi.org/10.1167/iovs.14-15419
  10. ↑ 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. A missense mutation in HK1 leads to autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2014 Oct 14;55(11):7159-64. doi:, 10.1167/iovs.14-15520. PMID:25316723 doi:http://dx.doi.org/10.1167/iovs.14-15520
  11. ↑ Gauci S, Helbig AO, Slijper M, Krijgsveld J, Heck AJ, Mohammed S. Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal Chem. 2009 Jun 1;81(11):4493-501. PMID:19413330 doi:http://dx.doi.org/10.1021/ac9004309
  12. ↑ Lundby A, Secher A, Lage K, Nordsborg NB, Dmytriyev A, Lundby C, Olsen JV. Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun. 2012 Jun 6;3:876. doi: 10.1038/ncomms1871. PMID:22673903 doi:http://dx.doi.org/10.1038/ncomms1871
  13. ↑ Magnani M, Serafini G, Bianchi M, Casabianca A, Stocchi V. Human hexokinase type I microheterogeneity is due to different amino-terminal sequences. J Biol Chem. 1991 Jan 5;266(1):502-5. PMID:1985912
  14. ↑ Aleshin AE, Zeng C, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB. 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. 1998 Jan 15;6(1):39-50. PMID:9493266
  15. ↑ Aleshin AE, Zeng C, Bartunik HD, Fromm HJ, Honzatko RB. Regulation of hexokinase I: crystal structure of recombinant human brain hexokinase complexed with glucose and phosphate. J Mol Biol. 1998 Sep 18;282(2):345-57. PMID:9735292 doi:10.1006/jmbi.1998.2017
  16. ↑ Rosano C, Sabini E, Rizzi M, Deriu D, Murshudov G, Bianchi M, Serafini G, Magnani M, Bolognesi M. Binding of non-catalytic ATP to human hexokinase I highlights the structural components for enzyme-membrane association control. Structure. 1999 Nov 15;7(11):1427-37. PMID:10574795
  17. ↑ Aleshin AE, Kirby C, Liu X, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB. Crystal structures of mutant monomeric hexokinase I reveal multiple ADP binding sites and conformational changes relevant to allosteric regulation. J Mol Biol. 2000 Mar 3;296(4):1001-15. PMID:10686099 doi:10.1006/jmbi.1999.3494

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