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Pyrimidine Nucleoside Monophosphate Kinase from Human Leukemic Blast Cells¹

Clinical Pharmacology Branch, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20014

Pyrimidine nucleoside monophosphate kinase (EC 2.7.4.14) catalyzes the phosphorylation of various pyrimidine nucleoside monophosphates to their corresponding diphosphates. In addition to its role in the synthesis of nucleic acid precursors, this enzyme is essential for the conversion of the antileukemic agent 1-ß-D-arabinofuranosylcytosine to its active metabolite 1-ß-D-arabinofuranosyl 5'-triphosphate. Pyrimidine nucleoside monophosphate kinase has been purified 520-fold from human leukemic blast cells. Substrate specificity and kinetics for various pyrimidine nucleoside monophosphates and analogs have been investigated and compared with previous studies of this kinase isolated from other sources. A single enzyme appears responsible for the phosphorylation of cytidine 5'-monophosphate, deoxycytidine 5'-monophosphate, uridine 5'-monophosphate, and deoxyuridine 5'-monophosphate as well as the pharmacological substrates 1-ß-D-arabinofuranosylcytosine 5'-monophosphate, 5-fluorouridine 5'-monophosphate, 5-fluorodeoxyuridine 5'-monophosphate, and 1-ß-D-arabinofuranosyluracil 5'-monophosphate. Enzyme levels of pyrimidine nucleoside monophosphate kinase have been determined in leukocyte blast cells isolated from normal human donors (1.16 units/mg protein) and from patients with acute lymphocytic leukemia (1.96 units/mg protein), acute myelogenous leukemia (1.99 units/mg protein), and chronic myelogenous leukemia (1.88 units/mg protein). These levels are 100-fold higher than those of deoxycytidine kinase, the enzyme responsible for the initial phosphorylation of 1-ß-D-arabinofuranosylcytosine. However, the affinity of deoxycytidine kinase for 1-ß-D-arabinofuranosylcytosine (K_m, 2.56 x 10^–5 M) is greater than that of the monophosphate kinase for 1-ß-D-arabinofuranosylcytosine 5'-monophosphate (K_m, 6.8 x 10^–4 M).

¹ Presented in part at the Annual Meeting of the American Association For Cancer Research, May 8, 1976 (14).

² To whom requests for reprints should be addressed, at Building 10, Room 6N119; NIH, Bethesda, Md. 20014.

Received 6/ 7/77. Accepted 11/16/77.

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