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Crystal structures of human choline kinase isoforms in complex with hemicholinium-3: single amino acid near the active site influences inhibitor sensitivity.

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Hong BS, Allali-Hassani A, Tempel W, Finerty PJ, Mackenzie F, Dimov S, Vedadi M, Park HW
OpenAccess logo J Biol Chem 285 16330-40 (2010)
Related entries: 3g15, 3lq3

Cited: 35 times
EuropePMC logo PMID: 20299452

Abstract

Human choline kinase (ChoK) catalyzes the first reaction in phosphatidylcholine biosynthesis and exists as ChoKalpha (alpha1 and alpha2) and ChoKbeta isoforms. Recent studies suggest that ChoK is implicated in tumorigenesis and emerging as an attractive target for anticancer chemotherapy. To extend our understanding of the molecular mechanism of ChoK inhibition, we have determined the high resolution x-ray structures of the ChoKalpha1 and ChoKbeta isoforms in complex with hemicholinium-3 (HC-3), a known inhibitor of ChoK. In both structures, HC-3 bound at the conserved hydrophobic groove on the C-terminal lobe. One of the HC-3 oxazinium rings complexed with ChoKalpha1 occupied the choline-binding pocket, providing a structural explanation for its inhibitory action. Interestingly, the HC-3 molecule co-crystallized with ChoKbeta was phosphorylated in the choline binding site. This phosphorylation, albeit occurring at a very slow rate, was confirmed experimentally by mass spectroscopy and radioactive assays. Detailed kinetic studies revealed that HC-3 is a much more potent inhibitor for ChoKalpha isoforms (alpha1 and alpha2) compared with ChoKbeta. Mutational studies based on the structures of both inhibitor-bound ChoK complexes demonstrated that Leu-401 of ChoKalpha2 (equivalent to Leu-419 of ChoKalpha1), or the corresponding residue Phe-352 of ChoKbeta, which is one of the hydrophobic residues neighboring the active site, influences the plasticity of the HC-3-binding groove, thereby playing a key role in HC-3 sensitivity and phosphorylation.

Articles - 3feg mentioned but not cited (4)

  1. Crystal structures of human choline kinase isoforms in complex with hemicholinium-3: single amino acid near the active site influences inhibitor sensitivity. Hong BS, Allali-Hassani A, Tempel W, Finerty PJ, Mackenzie F, Dimov S, Vedadi M, Park HW. J Biol Chem 285 16330-16340 (2010)
  2. Hepatitis E virus genotypes and subgenotypes causing acute hepatitis, Bulgaria, 2013-2015. Bruni R, Villano U, Equestre M, Chionne P, Madonna E, Trandeva-Bankova D, Peleva-Pishmisheva M, Tenev T, Cella E, Ciccozzi M, Pisani G, Golkocheva-Markova E, Ciccaglione AR. PLoS One 13 e0198045 (2018)
  3. Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors. Schiaffino-Ortega S, Mariotto E, Luque-Navarro PM, Kimatrai-Salvador M, Rios-Marco P, Hurtado-Guerrero R, Marco C, Carrasco-Jimenez MP, Viola G, López-Cara LC. Pharmaceutics 13 1360 (2021)
  4. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Reviews citing this publication (7)

  1. p53 and metabolism: from mechanism to therapeutics. Simabuco FM, Morale MG, Pavan ICB, Morelli AP, Silva FR, Tamura RE. Oncotarget 9 23780-23823 (2018)
  2. Involvement of human choline kinase alpha and beta in carcinogenesis: a different role in lipid metabolism and biological functions. Gallego-Ortega D, Gómez del Pulgar T, Valdés-Mora F, Cebrián A, Lacal JC. Adv Enzyme Regul 51 183-194 (2011)
  3. Choline kinase alpha-Putting the ChoK-hold on tumor metabolism. Arlauckas SP, Popov AV, Delikatny EJ. Prog Lipid Res 63 28-40 (2016)
  4. Approved and Experimental Small-Molecule Oncology Kinase Inhibitor Drugs: A Mid-2016 Overview. Fischer PM. Med Res Rev 37 314-367 (2017)
  5. Molecular structure and differential function of choline kinases CHKα and CHKβ in musculoskeletal system and cancer. Chen X, Qiu H, Wang C, Yuan Y, Tickner J, Xu J, Zou J. Cytokine Growth Factor Rev 33 65-72 (2017)
  6. Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases. Lacal JC, Zimmerman T, Campos JM. Pharmaceutics 13 788 (2021)
  7. ChoK-ing the Pathogenic Bacteria: Potential of Human Choline Kinase Inhibitors as Antimicrobial Agents. Khalifa M, Few LL, See Too WC. Biomed Res Int 2020 1823485 (2020)

Articles citing this publication (24)

  1. Combined 5-FU and ChoKα inhibitors as a new alternative therapy of colorectal cancer: evidence in human tumor-derived cell lines and mouse xenografts. de la Cueva A, Ramírez de Molina A, Alvarez-Ayerza N, Ramos MA, Cebrián A, Del Pulgar TG, Lacal JC. PLoS One 8 e64961 (2013)
  2. Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death. Serrán-Aguilera L, Denton H, Rubio-Ruiz B, López-Gutiérrez B, Entrena A, Izquierdo L, Smith TK, Conejo-García A, Hurtado-Guerrero R. Sci Rep 6 33189 (2016)
  3. The mechanism of allosteric coupling in choline kinase α1 revealed by the action of a rationally designed inhibitor. Sahún-Roncero M, Rubio-Ruiz B, Saladino G, Conejo-García A, Espinosa A, Velázquez-Campoy A, Gervasio FL, Entrena A, Hurtado-Guerrero R. Angew Chem Int Ed Engl 52 4582-4586 (2013)
  4. Phosphatidylcholine metabolism and choline kinase in human osteoblasts. Li Z, Wu G, van der Veen JN, Hermansson M, Vance DE. Biochim Biophys Acta 1841 859-867 (2014)
  5. Antiplasmodial activity and mechanism of action of RSM-932A, a promising synergistic inhibitor of Plasmodium falciparum choline kinase. Zimmerman T, Moneriz C, Diez A, Bautista JM, Gómez Del Pulgar T, Cebrián A, Lacal JC. Antimicrob Agents Chemother 57 5878-5888 (2013)
  6. New non-symmetrical choline kinase inhibitors. Schiaffino-Ortega S, López-Cara LC, Ríos-Marco P, Carrasco-Jimenez MP, Gallo MA, Espinosa A, Marco C, Entrena A. Bioorg Med Chem 21 7146-7154 (2013)
  7. Novel 4-amino bis-pyridinium and bis-quinolinium derivatives as choline kinase inhibitors with antiproliferative activity against the human breast cancer SKBR-3 cell line. Gómez-Pérez V, McSorley T, See Too WC, Konrad M, Campos JM. ChemMedChem 7 663-669 (2012)
  8. Choline Kinase, A Novel Drug Target for the Inhibition of Streptococcus pneumoniae. Zimmerman T, Ibrahim S. Antibiotics (Basel) 6 E20 (2017)
  9. Determination of potential scaffolds for human choline kinase α1 by chemical deconvolution studies. Sahún-Roncero M, Rubio-Ruíz B, Conejo-García A, Velázquez-Campoy A, Entrena A, Hurtado-Guerrero R. Chembiochem 14 1291-1295 (2013)
  10. A new family of choline kinase inhibitors with antiproliferative and antitumor activity derived from natural products. Estévez-Braun A, Ravelo AG, Pérez-Sacau E, Lacal JC. Clin Transl Oncol 17 74-84 (2015)
  11. New more polar symmetrical bipyridinic compounds: new strategy for the inhibition of choline kinase α1. Castro-Navas FF, Schiaffino-Ortega S, Carrasco-Jimenez MP, Ríos-Marco P, Marco C, Espinosa A, Gallo MA, Mariotto E, Basso G, Viola G, Entrena-Guadix A, López-Cara LC. Future Med Chem 7 417-436 (2015)
  12. Structural and enzymatic characterization of the choline kinase LicA from Streptococcus pneumoniae. Wang L, Jiang YL, Zhang JR, Zhou CZ, Chen Y. PLoS One 10 e0120467 (2015)
  13. Kinetic and mechanistic characterisation of Choline Kinase-α. Hudson CS, Knegtel RM, Brown K, Charlton PA, Pollard JR. Biochim Biophys Acta 1834 1107-1116 (2013)
  14. Phosphorylation of Human Choline Kinase Beta by Protein Kinase A: Its Impact on Activity and Inhibition. Chang CC, Few LL, Konrad M, See Too WC. PLoS One 11 e0154702 (2016)
  15. Choline Kinase Emerges as a Promising Drug Target in Gram-Positive Bacteria. Zimmerman T, Lacal JC, Ibrahim SA. Front Microbiol 6 2146 (2019)
  16. KDM2B regulates choline kinase expression and neuronal differentiation of neuroblastoma cells. Domizi P, Malizia F, Chazarreta-Cifre L, Diacovich L, Banchio C. PLoS One 14 e0210207 (2019)
  17. A New Classification Method of Metastatic Cancers Using a 1H-NMR-Based Approach: A Study Case of Melanoma, Breast, and Prostate Cancer Cell Lines. Schepkens C, Dallons M, Dehairs J, Talebi A, Jeandriens J, Drossart LM, Auquier G, Tagliatti V, Swinnen JV, Colet JM. Metabolites 9 E281 (2019)
  18. Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase. Kall SL, Whitlatch K, Smithgall TE, Lavie A. Sci Rep 9 17121 (2019)
  19. Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase α1. Serrán-Aguilera L, Nuti R, López-Cara LC, Mezo MÁ, Macchiarulo A, Entrena A, Hurtado-Guerrero R. Mol Inform 34 458-466 (2015)
  20. Upregulation of Nicotinic Acetylcholine Receptor alph4+beta2 through a Ligand-Independent PI3Kbeta Mechanism That Is Enhanced by TNFalpha and the Jak2/p38Mapk Pathways. Rogers SW, Gahring LC. PLoS One 10 e0143319 (2015)
  21. Novel Non-Congeneric Derivatives of the Choline Kinase Alpha Inhibitor ICL-CCIC-0019. Wang N, Brickute D, Braga M, Barnes C, Lu H, Allott L, Aboagye EO. Pharmaceutics 13 1078 (2021)
  22. Anticancer Activity of the Choline Kinase Inhibitor PL48 Is Due to Selective Disruption of Choline Metabolism and Transport Systems in Cancer Cell Lines. García-Molina P, Sola-Leyva A, Luque-Navarro PM, Laso A, Ríos-Marco P, Ríos A, Lanari D, Torretta A, Parisini E, López-Cara LC, Marco C, Carrasco-Jiménez MP. Pharmaceutics 14 426 (2022)
  23. Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly. Klöckner C, Fernández-Murray JP, Tavasoli M, Sticht H, Stoltenburg-Didinger G, Scholle LM, Bakhtiari S, Kruer MC, Darvish H, Firouzabadi SG, Pagnozzi A, Shukla A, Girisha KM, Narayanan DL, Kaur P, Maroofian R, Zaki MS, Noureldeen MM, Merkenschlager A, Gburek-Augustat J, Cali E, Banu S, Nahar K, Efthymiou S, Houlden H, Jamra RA, Williams J, McMaster CR, Platzer K. Brain 145 1916-1923 (2022)
  24. Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors. Luque-Navarro PM, Mariotto E, Ballarotto M, Rubbini G, Aguilar-Troyano FJ, Fasiolo A, Torretta A, Parisini E, Macchiarulo A, Laso A, Marco C, Viola G, Carrasco-Jimenez MP, López-Cara LC. Pharmaceutics 14 715 (2022)


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