Alutenusin, a specific neutral sphingomyelinase inhibitor, produced by Penicillium sp. FO-7436.

Sphingomyelin is an abundant constituent of the plasma membranes of mammaliancells1\ Recently the catabolic intermediates of sphingomyelin e.g., ceramides2), sphingosine3), sphingosin l-phosphate4), have been recognized to function as a potential second messenger. Amongthem, ceramide is the primary catabolic intermediate of sphingomyelin, and is released by either acid sphingomyelinase (aSMase) or neutral sphingomyelinase (nSMase). Activation of the sphingomyelin pathway by aSMase or nSMase in several normal and myeloid cell lines has been described to increase the production of ceramides, which subsequently trigger signaling pathways leading to either cell proliferation and differentiation or to apoptosis5'6). Two kinds of microbial nSMase inhibitors, F-10463a (scyphostatin)7) and F-1 1334A18), were discovered as potential pharmaceutical agents by Sankyo group. In the course of our screening program for SMase inhibitors of microbial origin, we have isolated a known compound, alutenusin (Fig. 1)9), as a specific nSMase inhibitor from the culture broth of Penicillium sp. FO-7436. In this paper, we describe the fermentation, isolation, and SMase inhibitory activity of alutenusin. A slant culture of the strain FO-7436 was used to inoculate a 500-ml Erlenmeyer flask containing 100ml