CTP: phosphocholine cytidylyltransferase

The most convincing example that inhibition of PC synthesis can induce apoptosis comes from a cell line with a temperature-sensitive defect in one of the enzymes in the CDP-choline pathway (Cui et al, 1996). The MT58 cell line is a Chinese hamster ovary (CHO) derived cell line with a mutation in CTP phosphocholine cytidylyltransferase (CT), which renders the... 

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.

Wieder, T., PerUtz, C., Wieprecht, M., Huang, R.T., Geilenm C.C. and Orfanosm, CR., 1995, Two new sphingomyelin analogs inhibit phosphatidylcholine biosynthesis by decreasing membrane-bound CTP phosphocholine cytidylyltransferase levels in HaCaT cells. Biochem. J. 311 873-879... 

CTP-phosphocholine cytidylyltransferase (CT) is found in two forms, an active form bound to cellular membranes and an inactive form when in a soluble form. The active form of CT is favored by low concentrations of phosphatidylcholine, high concentrations of diacylglycerol and fatty acids and the unphosphorylated state of the enzyme. 

Lyso-PtdCho is not simply a lipid metabolite producing neurotrophic and neurotoxic effects. It participates in many signal transduction processes. Lyso-PtdCho activates protein kinases such as protein kinase C, protein kinase A, and c-jun terminal kinase. Lyso-PtdCho stimulates phospholipase D and inhibits CTP-phosphocholine cytidylyltransferase (Gomez-Munoz et al., 1999 Boggs et al., 1995). Lyso-PtdCho acts as an agonist for certain G-protein coupled receptors and can be converted to another bioactive lipid, lyso-phosphatidic acid. 

Boggs K. P., Rock C. O., and Jackowski S. (1995). Lysophosphatidylcholine and l-O-octadecyl-2-O- methyl-rac-glycero-3-phosphocholine inhibit the CDP-choline pathway of phosphatidylcholine synthesis at the CTP phosphocholine cytidylyltransferase step. J. Biol. Chem. 270 7757-7764. 

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

CTP phosphocholine cytidylyltransferase (3) glycerol kinase (4) acyl-CoA glycerol-3-phosphate acyltransferase (5) acyl-CoA acyl glycerol-3-phosphate acyltransferase (6) phosphatidic acid phosphatase (7) CDP-choline diacylglycerol phosphocholine transferase. 

Vivekananda, J., Smith, D., and King, R.J. (2001). Sphingomyelin metabolites inhibit sphingomyelin S3mthase and CTP phosphocholine cytidylyltransferase. Am J Physiol Lung Cell Mol Physiol 281, L98-107. 

Adibhatla, R. M., Hatcher, J. F., Larsen, E. C., Chen, X., Sun, D. and Tsao, F. CDP-choline significantly restores the phosphatidylcholine levels by differentially affecting phospholipase A2 and CTP-phosphocholine cytidylyltransferase after stroke. J Biol Chem 281 (2006b)6718-6725. 

Bodennec J., Pelled D., Riebeling C., Trajkovic S., Futerman A.H., Phosphatidylcholine synthesis is elevated in neuronal models of Gaucher disease due to direct activation of CTP phosphocholine cytidylyltransferase by glucosylceramide, Faseb J 16 (2002) 1814-1816. 

Fig. 1. Phospholipid biosynthetic pathways in animal cells. The abbreviations are DHAP, dihydroxyacetone phosphate G-3-P, glycerol-3-phosphate PA, phosphatidic acid DG, diacylglycerol CDP-DG, cytidine diphosphodiacylglycerol PI, phosphatidylinositol PG, phosphatidylglycerol PG-P, phosphatidylglycerol phosphate DPG, diphosphatidylglycerol PP, phosphatidic acid phosphatase PE, phosphatidylethanolamine PC phosphatidylcholine PEMT, phosphatidylethanolamine A-methyltransferase CT, CTP phosphocholine cytidylyltransferase PS, phosphatidylserine CK/EK, choline/ethanolamine kinase CPT, CDP-choline 1,...

Fig. 3. Regulation of PC biosynthesis via the CDP-choline pathway by modulation of the binding of CTP phosphocholine cytidylyltransferase (CT) to membranes. Three different modes of regulation of CT activity are indicated. The abbreviations are CK, choline kinase CPT, CDP-choline 1,2-diacylglycerol cholinephos-photransferase PEMT, phosphatidylethanolamine Af-methyltransferase PC, phosphatidylcholine PE, phos-phatidylethanolamine DG, diacylglycerol.

Fig. 6. Translocation of CTP phosphocholine cytidylyltransferase (CT) from an inactive soluble form (CTsol) to a membrane-associated activated form (CTm). The reversible interaction of CT with membranes involves the amphipathic helical region lying on the surface of the membrane so that the hydrophilic region interacts with the negatively charged lipid head groups and the hydrophobic side intercalates into the membrane core. N, amino terminal domain C, carboxyl terminal domain M, membrane-binding domain. Figure kindly supplied by Prof. R. Cornell, Simon Fraser University. (See color plate section, plate no. 7.)...

Pelech, S.L., Pritchard, P.H., Brindley, D.N.,Vance, D.E. 1983. Fatty acids promote translocation of CTP Phosphocholine cytidylyltransferase to the endoplasmic reticulum and stimulate rat hepatic phosphatidylcholine synthesis. J. Biol. Chem. 2 6782-6788. 

Adibhatla RM, Hatcher JF, Dempsey RJ (2004) Cytidine-5 -diphosphocholine affects CTP-phosphocholine cytidylyltransferase and lyso-phosphatidylcholine after transient brain ischemia. J Neurosci Res 76 390-396... 

SEQUENCE ANALYSIS OF CTP PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE cDNA FROM ARABIDOPSIS THALIANA... 

Fig. 1. Nucleotide and amino acid sequences of A. thaliana CTP phosphocholine cytidylyltransferase cDNA.

Kalmar, G.B., Kay, R.J., LaChance, A., Aebersold, R., and Cornell, R.B. (1990) Cloning and expression of rat liver CTP phosphocholine cytidylyltransferase an amphipathic protein that controls phosphatidylcholine synthesis, Proc. Natl Acad. Scl USA. 87, 6029-6033. 

BRASSICA NAPUS CTP PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE MOLECULAR CLONING AND SUBCELLULAR LOCALIZATION IN YEAST, AND ENZYME CHARACTERIZATION... 

Sequence Analysis of CTP Phosphocholine Cytidylyltransferase cDNA from Arabidopsis thaliana. 

Brassica napus CTP Phosphocholine Cytidylyltransferase Molecular Cloning and Subcellular Localization in Yeast, and Enzyme Characterization. 

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