Inhibition of Ribonucleic Acid Polymerase by 5-Hydroxyuridine 5'-Triphosphate
S. Roy-Burman 1, P. Roy-Burman 1, and Donald W. Visser 1
From the
1 From the Department of Biochemistry, University of Southern California School of Medicine, Los Angeles, California 90033
5-Hydroxyuridine triphosphate was synthesized and its effectiveness as substrate for deoxyribonucleic acid-dependent ribonucleic acid polymerase was determined. The analogue was incorporated into RNA to a very low extent as compared to naturally occurring nucleoside triphosphates, and it replaced uridine triphosphate to a much greater extent than any of the other nucleoside triphosphates. The ability of the analogue to replace UTP in RNA synthesis was greatest at pH 7 and decreased markedly with increasing pH values. This behavior was related to the low pKa of 5-hydroxyuridine as compared to uridine.
5-Hydroxy-UTP strongly inhibited synthesis of RNA and acted as a competitive inhibitor of UTP in the polymerase reaction. This inhibitory effect was lowest at pH 7.0 and increased with increasing pH values to a maximum at pH 9.0. Thus, in contrast to the data on analogue incorporation, the inhibitory effect of the analogue is predominant when the pyrimidine exists in ionized form.
The nucleoside analogue exerted its strong inhibitory effect only when it existed as the triphosphate. 5-Hydroxy-UDP and 5-hydroxy-UMP inhibited incorporation of UMP into RNA only slightly as compared to 5-hydroxy-UTP.
Submitted on August 11, 1965
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