Reduction of cinerulose in aclacinomycin-A by soluble and microsomal cinerulose reductases.
The in vitro metabolism of the antitumor anthracycline antibiotic, aclacinomycin-A, was studied using rat liver homogenate. In the presence of NADH or NADPH, aclacinomycin-A was converted to aclacinomycin-A analogs, MA144 M1 and MA144 N1, which were stereospecifically reduced at the keto group of the C-4''' position of L-cinerulose in aclacinomycin-A. Subcellular fractionation indicated that the production of MA144 M1, which was reduced to L-amicetose, was catalyzed by NADPH-dependent soluble cinerulose reductase I, and the production of MA144 N1, which was reduced to L-rhodinose, was catalyzed by NADPH-dependent soluble cinerulose reductase II and NADH-dependent microsomal cinerulose reductase. The properties of these three enzymes were studied. Soluble cinerulose reductase I which produces MA144 M1 showed a optimum pH at 6.3, Km values of 3.3 x 10(-4) M for aclacinomycin-A and 3.2 x 10(-5) M for NADPH. Soluble cinerulose reductase II which produces MA144 N1 showed a pH optimum at 6.3 and Km values of 2.0 x 10(-3) M for aclacinomycin-A and 4.0 x 10(-5) M for NADPH. All thesse reductases were sensitive to sulfhydryl reagents and were inhibited by vitamin K3. Microsomal cinerulose reductase showed sensitivity to diconmarol and ferrous ion. The main nondegradative pathways of aclacinomycin-A were discussed from these results.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000201:enzymology; D009243:NAD / Q000494:pharmacology; D009249:NADP / Q000494:pharmacology; D009279:Naphthacenes / Q000378:metabolism*; D051381:Rats; D013401:Sugar Alcohol Dehydrogenases / Q000378:metabolism*; D014312:Trisaccharides
D000903:Antibiotics, Antineoplastic; D009279:Naphthacenes; D014312:Trisaccharides; D009243:NAD; D009249:NADP; D013401:Sugar Alcohol Dehydrogenases; C019900:cinerulose reductase