Differential Inhibitory Effects of 5-Substituted 1-β-D-Xylofuranosyluracil 5′-Triphosphates and Related Nucleotides on DNA-Dependent RNA Polymerases I and II from the Cherry Salmon (Oncorhynchus masou)

• Published in: Journal of biochemistry (Tokyo) Vol. 98; no. 2; pp. 417 - 425
• Main Authors: NAKAYAMA, Chikao, SANEYOSHI, Mineo
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 1985
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Brackish; enzymes; Enzymes and enzyme inhibitors; Freshwater; Fundamental and applied biological sciences. Psychology; inhibitors; Kinetics; Marine; Oncorhynchus masou; RNA; RNA polymerase; RNA Polymerase I - antagonists & inhibitors; RNA Polymerase II - antagonists & inhibitors; Salmon; Structure-Activity Relationship; Transferases; Uracil Nucleotides; Uridine Triphosphate - analogs & derivatives; Uridine Triphosphate - chemical synthesis; Uridine Triphosphate - pharmacology; UTP; Vertebrata; Synthetic product; RNA polymerase 1; Enzyme; RNA synthesis; Transferase; Animal; Pisces; RNA polymerase 2; Nucleotide; Inhibition; Catalyst activity
• ISSN: 0021-924X; 1756-2651
• DOI: 10.1093/oxfordjournals.jbchem.a135296

Various 5-substituted 1-β-D-xylofuranosyluracil 5′-triphosphates (hydrogen, methylethyl-, n-propyl, n-butyl, fluoro-, chloro-, bromo-, and iodo derivatives) and some of the 3′-deoxyribofuranosyl nucleotides (3′-deoxy UTP and 3′-deoxy TTP) were synthesized chemically and their inhibitory effects on DNA-dependent RNA polymerases I and II of the cherry salmon (Oncorhynchus masou) were studied systematically. These 3′-modified UTP analogues could not be utilized as substrates in place of UTP, but they did inhibit the incorporation of UMP into RNA in vitro. In contrast, 2′-modified UTP analogues, such as 2′-dTTP and Ara TTP, were neither substrates nor inhibitors. Kinetic analysis showed that the inhibition by these compounds was essentially competitive with substrate UTP. The Kl values of RNA polymerase I for the analogues were smaller (2–6 μM) than the Km value for UTP (8 μM), but those for xylo-EtUTP, xylo-PrUTP, and xylo-BuUTP were larger (about 20 μM) than the Km for UTP. In contrast to these alkyl groups with steric and election-donating effects, halogen groups have electron-withdrawing effects on the uracil nucleus. Therefore, it was concluded that the inhibitory activity of these analogues on RNA polymerase I was not affected by the inductive effects of substituent groups at the 5-position of uracil nucleus but by their steric effects. On the other hand, all of the Kl values of RNA polymerase II for UTP analogues