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1-beta-D-arabinofuranosylcytosine-diphosphate-choline is formed by the reversal of cholinephosphotransferase and not via cytidylyltransferase. 1992

G L Kucera, and R L Capizzi
Comprehensive Cancer Center, Wake Forest University, Winston-Salem, North Carolina 27157.

In an effort to identify the pathway leading to the formation of 1-beta-D-arabinofuranosylcytosine-diphosphate (ara-CDP)-choline from 1-beta-D-arabinofuranosylcytosine (ara-C) treatment of cultured cells, as well as of cells obtained from leukemia patients, we probed the enzymatic steps involved in the CDP-choline pathway for phosphatidylcholine biosynthesis. Ara-C-triphosphate was not a substrate for CTP:phosphocholine cytidylyltransferase activity under the conditions employed, whereas CTP and dCTP were utilized to form CDP-choline and dCDP-choline, respectively. When presented together, ara-C-triphosphate and CTP inhibited the enzymatic conversion of CTP to CDP-choline in the presence of phosphocholine, with a Ki of 6 mM. Since CTP:phosphocholine cytidylyltransferase did not appear to be responsible for the increased levels of ara-CDP-choline, we next studied the other enzyme in the pathway for phosphatidylcholine synthesis that could form ara-CDP-choline, CDP-choline:1,2-diacylglycerol cholinephosphotransferase. CDP-choline:1,2-diacylglycerol cholinephosphotransferase activity present in microsomes isolated from L5178Y murine leukemia cells exhibited a reversal of its normal catalytic activity, using CMP and 1-beta-D-arabinofuranosylcytosine-monophosphate (ara-CMP) along with phosphatidylcholine to produce either CDP-choline or ara-CDP-choline, plus diradylglycerol. The Vmax and Km values for CMP were 0.78 +/- 0.04 nmol/min/mg and 340 +/- 20 microM, respectively, whereas the Vmax and Km for ara-CMP were 0.22 +/- 0.06 nmol/min/mg and 1410 +/- 540 microM, respectively. A Ki value of 3 mM was obtained for ara-CMP under the cell-free assay conditions used. These results indicate that ara-CDP-choline most likely arises from a reversal of the CDP-choline:1,2-diacylglycerol cholinephosphotransferase utilizing ara-CMP, rather than from the catalysis of ara-C-triphosphate plus phosphocholine to ara-CDP-choline by CTP:phosphocholine cytidylyltransferase. It is speculated that this mechanism may explain, in part, the rapid cellular lysis observed with high dose ara-C therapy.

UI MeSH Term Description Entries
D007940 Leukemia L5178 An experimental lymphocytic leukemia of mice. Lymphoma L5178,L5178, Leukemia,L5178, Lymphoma
D009713 Nucleotidyltransferases A class of enzymes that transfers nucleotidyl residues. EC 2.7.7. Nucleotidyltransferase
D002798 Diacylglycerol Cholinephosphotransferase An enzyme that catalyzes the synthesis of phosphatidylcholines from CDPcholine and 1,2-diacylglycerols. EC 2.7.8.2. Cholinephosphotransferase,Phosphorylcholine-Glyceride Transferase,1-alkyl-2-Acetylglycerol Cholinephosphotransferase,CDP-Choline 1,2-Diglyceride Choline Phosphotransferase,CDP-Choline Cholinephosphotransferase,CDP-Diacylglycerol Synthase,Diacylglycerol-CDP Choline Phosphotransferase,PAF Phosphocholinetransferase,Phosphocholinetransferase,Phosphorylcholineglyceride Transferase,CDP Choline 1,2 Diglyceride Choline Phosphotransferase,CDP Choline Cholinephosphotransferase,CDP Diacylglycerol Synthase,Choline Phosphotransferase, Diacylglycerol-CDP,Cholinephosphotransferase, 1-alkyl-2-Acetylglycerol,Cholinephosphotransferase, CDP-Choline,Cholinephosphotransferase, Diacylglycerol,Diacylglycerol CDP Choline Phosphotransferase,Phosphocholinetransferase, PAF,Phosphorylcholine Glyceride Transferase,Phosphotransferase, Diacylglycerol-CDP Choline,Synthase, CDP-Diacylglycerol,Transferase, Phosphorylcholine-Glyceride,Transferase, Phosphorylcholineglyceride
D003561 Cytarabine A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472) Ara-C,Arabinofuranosylcytosine,Arabinosylcytosine,Cytosine Arabinoside,Aracytidine,Aracytine,Cytarabine Hydrochloride,Cytonal,Cytosar,Cytosar-U,beta-Ara C,Ara C,Arabinoside, Cytosine,Cytosar U,beta Ara C
D003566 Cytidine Diphosphate Choline Donor of choline in biosynthesis of choline-containing phosphoglycerides. CDP Choline,Citicoline,Cidifos,Citicholine,Cyticholine,Cytidine 5'-Diphosphocholine,5'-Diphosphocholine, Cytidine,Choline, CDP,Choline, Cytidine Diphosphate,Cytidine 5' Diphosphocholine,Diphosphate Choline, Cytidine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001084 Vidarabine Phosphate An adenosine monophosphate analog in which ribose is replaced by an arabinose moiety. It is the monophosphate ester of VIDARABINE with antiviral and possibly antineoplastic properties. Adenine Arabinoside Monophosphate,Ara-AMP,Arabinofuranosyladenine Monophosphate,Vidarabine Monophosphate,9-(5-O-Phosphono-beta-D-arabinofuranosyl)-9H-purin-6-amine,Ara AMP,Monophosphate, Adenine Arabinoside,Monophosphate, Arabinofuranosyladenine,Monophosphate, Vidarabine,Phosphate, Vidarabine
D019916 Choline-Phosphate Cytidylyltransferase An enzyme that catalyzes the transfer of cytidylate (CMP) to choline phosphate to form CDPcholine. It is the rate-limiting enzyme in the choline pathway for the biosynthesis of phosphatidylcholine. Its activity is increased by glucocorticoids. EC 2.7.7.15. CTP Phosphocholine Cytidylyltransferase,CDP-Choline Synthetase,CTP Phosphocholine Cytidylyl-Transferase,CTP Phosphorylcholine Cytidyltransferase,Phosphocholine Cytidyltransferase,Phosphorylcholine Cytidyl Transferase,CDP Choline Synthetase,CTP Phosphocholine Cytidylyl Transferase,Choline Phosphate Cytidylyltransferase,Cytidyl Transferase, Phosphorylcholine,Cytidyltransferase, CTP Phosphorylcholine,Cytidyltransferase, Phosphocholine,Cytidylyl-Transferase, CTP Phosphocholine,Cytidylyltransferase, CTP Phosphocholine,Cytidylyltransferase, Choline-Phosphate,Phosphocholine Cytidylyl-Transferase, CTP,Phosphocholine Cytidylyltransferase, CTP,Phosphorylcholine Cytidyltransferase, CTP,Synthetase, CDP-Choline,Transferase, Phosphorylcholine Cytidyl

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