Choline kinase

Crilly, K.S., Tomono, M. and Kiss, Z. (1998) The choline kinase inhibitor hemicholinium-3 can inhibit mitogen-induced DNA synthesis independent of its effect on phosphocholine formation. Archives of Biochemistry and Biophysics 352, 137-143. 

Houston, KM. and Harnett, W. (1999b) Mechanisms underlying the transfer of phosphorylcholine to filarial nematode glycoproteins - a possible role for choline kinase. Parasitology 118, 311-318. 

Ratnam, S. and Kent, C. (1995) Early increase in choline kinase-activity upon induction of the H-Ras oncogene in mouse fibroblast cell-lines. Archives of Biochemistry and Biophysics 323, 313—322. 

The majority of PC is synthesized in mammalian cells by the CDP-choline or Kennedy pathway in the endoplasmic reticulum (Eigiue 1). In this pathway, choline taken up from the external medium or released in the cytosol by breakdown of choline containing compoimds, is first converted to phosphocholine by the enzyme choline kinase (CK) (Ishidate, 1997). There are two isoforms of CK cloned which both can convert also ethanolamine to phosphoethanolamine, albeit with a lesser affinity (Aoyama et al 2000). Alternatively phosphocholine can be generated by enzymes that preferentially phosphorylate ethanolamine and are therefore designated ethanolamine kinases (EK). As yet also two different EKs are known (EKI 1 and 2 Lykidis etal., 2001). 

Figure 1. Pathways for the synthesis of phosphatidylcholine, phosphatidylethanolamine and sphingomyelin. Abbreviations CK, choline kinase CPT, cholinephosphotransferase CT, CTP phosphooholine cytidylyltransferase DAG, diacylglycerol PC, phosphatidylcholine PE, phosphatidylethanolamine PEMT, phosphatidylethanolamine-N-methyltransferase SM, sphingomyelin SMase, sphingomyelinase SMsyn, sphingomyelin synthase.

Figure 3. Inhibition of phosphatidylcholine biosynthesis by apoptosis-inducing compounds. The target enzyme for the inhibition of PC biosynthesis is shown for several compounds that have further in common that they all induce apoptosis. Abbreviations are as follows CK, choline kinase CPT, cholinephosphotransferase CT, CTP phosphocholine cytidylyltransferase PC, phosphatidylcholine.

CARNOSINE SYNTHETASE CHAPERONES CHOLINE KINASE CHOLOYL-CoA SYNTHETASE COBALAMIN ADENOSYLTRANSFERASE 4-COUMAROYL-CoA SYNTHETASE CREATINE KINASE CTP SYNTHETASE CYTIDYLATE KINASE 2-DEHYDRO-3-DEOXYGLUCONOKINASE DEHYDROGLUCONOKINASE DEOXYADENOSINE KINASE DEOXYADENYLATE KINASE DEOXYCYTIDINE KINASE (DEOXYjNUCLEOSIDE MONOPHOSPHATE KINASE DEOXYTHYMIDINE KINASE DEPHOSPHO-CoA KINASE DETHIOBIOTIN SYNTHASE DIACYLGLYCEROL KINASE DIHYDROFOLATE SYNTHETASE DNA GYRASES DNA REVERSE GYRASE ETHANOLAMINE KINASE EXONUCLEASE V... 

ETHANOLAMINE AMMONIA-LYASE ETHANOLAMINE KINASE CHOLINE KINASE... 

N. M. S. Al-Saffar, H. Troy, A. Ramirez de Molina, L. E. Jackson, B. Madhu, J. R. Griffiths, M. O. Leach, P. Workman, J. C. Lacal, 1. R. Judson and Y.-L. Chung, Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models. Cancer Res., 2006,66,427-434. 

Finally, an antimony analogue of choline, HOCH2CH2NMe3X, has been synthesized (Scheme 5). The compound acted as a substrate for choline kinase.181... 

Although the role of lipid composition in membrane function is not entirely understood, changes in composition can produce dramatic effects. Researchers have isolated fruit flies with mutations in the gene that encodes ethanolamine kinase (analogous to choline kinase Fig. 21-28). Lack of this enzyme eliminates one pathway for phosphatidylethanolamine synthesis, thereby reducing the amount of this lipid in cellular membranes. Flies with this mutation—those with the genotype easily shocked—exhibit transient paralysis following electrical stimulation or mechanical shock that would not affect wild-type flies. 

Mellor, R.B., Christense, T.M.I.E. Werner, D. (1986). Choline kinase II is present only in nodules that synthesize stable peribacteroid membranes. Proceedings of the National Academy of Sciences (USA) 83, 659-63. 

Sher, R. B., Aoyama, C., Huebsch, K. A., Ji, S., Kerner, J., Yang, Y., et al. (2006) A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis. J Biol Chem 281, 4938-4948. 

Choubey V, Maity P, Guha M et al (2007) Inhibition of Plasmodium falciparum choline kinase by hexadecyltrimethylammonium bromide a possible antimalarial mechanism. Antimicrob Agents Chemother 51(2) 696-706... 

Wernimont AK, Pizarro JC, Artz JD et al. Crystal structure of choline kinase from Plasmodium Falciparum, PF14 0020. 

Phosphatidylcholine is synthesized via the Kennedy pathway (Kennedy and Weiss, 1956) in three consecutive steps catalyzed by the enzymes choline kinase, phosphocholine cytidyltransferase, and phosphocholine transferase. Phospha-tidylethanolamine is synthesized via the corresponding pathway for ethanolamine or by decarboxylation of phosphatidylserine (Borkenhagen et al., 1961) or by base exchange (Bjerve, 1973). In immobilized breast cancer cells, flux in these pathways... 

The enzymatic radioassay method for the analysis of acetylcholine and choline in brain tissue has been reported by Reid et al. [210]. The method describes the determination of nanogram amounts of acetylcholine and choline in as little as 10 mg of brain tissue, involves isolation of acetylcholine by high-voltage paper electrophoresis, alkaline hydrolysis of acetylcholine to choline, and conversion of this into [32P]-phosphoryl choline in the presence of choline kinase and [y32P] ATP. The labeled derivative is isolated by column chromatography on Bio-Rad AG1-X8 resin, using Tris buffer solution as the eluent. Cerenkov radiation from 32P is counted (at 33% efficiency) in a liquid scintillation spectrometer. The amount of phosphorylcholine is proportional to the amount of choline over the range of 0.08-8.25 nmol. 

Synthesis of phosphatidylcholine and phosphatidylethanolamine begins with activation of choline (or ethanolamine) with ATP via choline kinase to yield phosphocholine (phosphoethanolamine) + ADP the activated base is transferred via CTP and phosphocholine cytidyl transferase to form CDP-choline (CDP-ethanolamine) and PPi. The base is then transferred to the sn-3 of diacylglycerol via phosphocholine diacylglycerol transferase to yield phosphatidylcholine (phosphatidylethanolamine) + CMP. The cytidyl transferase is believed to be the rate-limiting or regulatory step in the pathway. Phospha-tidylserine is formed by a direct transfer and substitution of serine for ethanolamine in phosphatidylethanolamine. Phosphatidyl serine can be dec-arboxylated to form phosphatidylethanolamine. 

Phosphatidylcholine is preferentially synthesized in lactating mammary tissue (Kinsella, 1973), possibly regulated by the differential activities of choline kinase and ethanolamine kinase. Choline kinase has a lower Km and a higher Vmax with its substrate than does ethanolamine kinase. Also, choline kinase is inhibited slightly by ethanolamine, whereas choline is a potent competitive inhibitor of ethanolamine kinase. Thus, the intracellular concentration of choline probably regulates the synthesis of these two phos-phoglycerides (Infante and Kinsella, 1976). 

---