Can. J. Chem. 72,86 (1994). The biosynthesis of the phytotoxin coronatine has been investigated by administration of isotopically labeled precursors to Pseudomonas syrirlgae pv. glycinea. The structure of coronatine contains two moieties of distinct biosynthetic origin, a bicyclic, hydrindanone carboxylic acid (coronafacic acid) and a cyclopropyl a-amino acid (coronamic acid). Investigations of coronafacic acid biosynthesis have shown that this compound is a polyketide derived from three acetate units, one butyrate unit, and one pyruvate unit. The two carbonyl oxygen atoms of coronafacic acid were found to be derived from the oxygen atoms of acetate. Additional experiments are described that rule out some possible modes for assembly of the polyketide chain. Coronamic acid is shown to be derived from L-isoleucine via the intermediacy of L-alloisoleucine. Examination of the mechanism of the cyclization of L-alloisoleucine to coronamic acid revealed that the formation of the cyclopropane ring takes place with the removal of only two hydrogen atoms from the amino acid, one at C-2 and the other at C-6. The nitrogen atom at C-2 of L-alloisoleucine is shown to be retained. On the basis of these observations, a mechanism is postulated for the cyclization reaction that involves the diversion of an enzymatic hydroxylation reaction into an oxidative cyclization. Finally, a precursor incorporation experiment with deuterium-labeled coronamic acid demonstrated that free coronamic acid can be efficiently incorporated into coronatine. This observation indicates that the cyclization of L-alloisoleucine to coronamic acid can occur before formation of the amide bond between coronafacic acid and coronamic acid. Can. J. Chem. 72,86 (1994). On a ktudik la biosynthkse de la phytotoxine coronatine en administrant des prtcurseurs marquks au Pseudort~onas syringae pv. glycinea. La structure de la coronatine contient deux portions d'origines biosynthktiques diffkrentes : un acide hydrindanone carboxylique bicyclique (l'acide coronafacique) et un acide cyclopropylique a-amink (I'acide coronamique). Des ktudes sur la biosynthkse de l'acide coronafacique ont montrk que ce composk est un polycktide dkrivk de trois unitks acktique, d'une unit6 butyrique et d'une unitt pyruvique. On a trouvk que les deux atomes d'oxygene carbonyles de I'acide coronafacique sont dtrivks des atomes d'oxygkne de l'acide acktique. On dkcrit des expkriences additionnelles qui permettent d'tliminer un certain nombre de modes d'assemblage de la chaine polycktide. On dkmontre que l'acide coronamique est dkrivk de la L-isoleucine par le biais de la L-alloisoleucine comme intermkdiaire. L'examen du mkcanisme de cyclisation de la L-alloisoleucine en acide coronamique a rkvklt que la formation du cyclopropane se produit avec l'enlkvement de seulement deux atomes d'hydrogene B partir de l'acide amink, I'un en C-2 et I'autre en C-6. On a dkmontrk que l'atome d'azote en C-2 de la L-alloisoleucine est conservk. Sur la base de ces observations, on propose un mkcanisme pour la r...

No abstract

When tested as a microbial model for mammalian drug metabolism, the filamentous fungus Cunninghamella elegans metabolized chlorpromazine and methdilazine within 72 h. The metabolites were extracted by chloroform, separated by high-performance liquid chromatography, and characterized by proton nuclear magnetic resonance, mass, and UV spectroscopic analyses. The major metabolites of chlorpromazine were chlorpromazine sulfoxide (36%), N-desmethylchlorpromazine (11%), N-desmethyl-7-hydroxychlorpromazine (6%), 7-hydroxychlorpromazine sulfoxide (5%), and chlorpromazine N-oxide (2%), all of which have been found in animal studies. The major metabolites of methdilazine were 3-hydroxymethdilazine (35%), methdilazine sulfoxide (30%), methdilazine N-oxide (4%), phenothiazine (3%), and 2-hydroxymethdilazine (3%). 18 O 2 labeling experiments indicated that the oxygen atoms in methdilazine sulfoxide, methdilazine N-oxide, and 3-hydroxymethdilazine were all derived from molecular oxygen. The production of methdilazine sulfoxide and 3-hydroxymethdilazine was inhibited by the cytochrome P-450 inhibitors metyrapone and proadifen. An enzyme activity for the sulfoxidation of methdilazine was found in microsomal preparations of C. elegans. These experiments suggest that the sulfoxidation and hydroxylation of methdilazine and chlorpromazine by C. elegans are catalyzed by cytochrome P-450.

No abstract