A 5'-monophosphate form of bredinin selectively inhibits the activities of mammalian DNA polymerases in vitro.
Bredinin is an immunosuppressive drug which is used clinically in Japan. In this study, we investigated bredinin's molecular mode of action to clarify its immunosuppressive effects. We focused on the DNA polymerases in the somatic DNA synthesis which may be required in the process of lymphocyte differentiation. We found that bredinin-5'-monophosphate (breMP) could be a potent inhibitor of mammalian DNA polymerase alpha(pol.alpha) and (pol.beta) in vitro, although bredinin itself has no such effects. BreMP inhibited the pol. alpha activity at less than 7 micrograms/ml and the pol. activity at 7 micrograms/ml. Neither breMP nor bredinin influenced the activities of a plant DNA polymerase, prokaryotic DNA polymerases such as E. coli DNA polymerase I and Taq DNA polymerase, or DNA-metabolic enzymes such as DNase I, indicating that breMP selectively suppressed the activities of the mammalian DNA polymerases. For pol., beta breMP acted by competing with both the substrate and template-primer. For pol. alpha, it acted by competing only with the substrate, and non-competitively with the template-primer. The ribose of bredinin is quickly and quantitatively converted to its ribose-5'-phosphate form in vivo as soon as it is incorporated into cells. The action mode of bredinin and its use as an immunosuppressive drug are discussed based on these results.
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Document Type: Research Article
Affiliations: Department of Applied Biological Science, Science University of Tokyo, Noda, Chiba 278, Japan.
Publication date: January 1, 1998
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- The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.
The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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