Chemistry of enzyme inhibitors of microbial origin.

Abstract

Study of antibiotics has furnished interesting materials to chemistry of natural products. I initiated the screening study of enzyme inhibitors produced by microorganisms and isolated leupeptin and antipain inhibiting trypsin and papain, chymostatin inhibiting chymotrypsin, pepstatin inhibiting pepsin, panosialin inhibiting sialidases, oudenone inhibiting tyrosine hydroxylase, dopastin inhibiting dopamine 3-hydroxylase, aquayamycin and chrothiomycin inhibiting tyrosine hydroxylase and dopamine J3-hydroxylase. Structures and syntheses of most of these compounds have been studied. I also found dopamine 3-hydroxylase-inhibiting activity of fusaric acid and oosponol, and xanthineoxidase inhibiting activity of 5-formyluracil which were produced by microorganisms. Chemical study of enzyme inhibitors has given useful information on the structure/activity relation. The effect of pepstatin on stomach ulcer, and the hypotensive effect of oudenone and fusaric acid have been observed clinically. Enzyme inhibitors produced by microorganisms are the most valuable new area extended from antibiotics and will furnish new materials interesting in chemistry. biosynthesis, pharmacology, and utility. Research on antibiotics has contributed to the chemistry of natural products, furnishing materials of interesting structures, chemical syntheses, biosyntheses and of interesting bioactivity. However, because the field has been so extensively studied, the probability of discovering new antibiotics, especially new and useful agents, is now significantly reduced. In these circumstances, it is felt that the most valuable contribution would be to extend these studies to a new and potentially more fruitful area. In 1965, in the hope of exploiting a new area, I initiated the screening of enzyme inhibitors in culture filtrates of microorganisms, with the collaboration of Doctors Takeuchi, Aoyagi, Kondo, Maeda, Hamada, Takita and others in my laboratories, Doctor Nagatsu, Department of Biochemistry, Dental School of Aichi Gakuin University, Nagoya, and Doctor Ohno, Basic Research Laboratories, Toray Industries. At present, the structures of small molecular compounds can be determined rapidly, and their syntheses accomplished in a short period of time. This recent progress in the chemistry of natural products through the use of physical methods is a driving force in the study of enzyme inhibitors in microbial culture filtrates. The structures elucidated stimulate the study of 129