Biosynthesis of benzylpenicillin (G), phenoxymethylpenicillin (V) and octanoylpenicillin (K) from glutathione S-derivatives.
"In vitro" synthesis of benzylpenicillin and phenoxymethylpenicillin has been carried out by direct N-acylation of 6-aminopenicillanic acid (6-APA) with S-phenylacetyl- and (S-phenoxyacetyl)glutathione. The reactions were catalyzed by the enzyme acyl-CoA: 6-APA acyltransferase (AT) from Penicillium chrysogenum and in both cases the synthesis of antibiotics was enhanced by CoA. Penicillin K, a natural penicillin, was also synthesized "in vitro" by incubating (S-octanoyl)glutathione, 6-APA and AT, but in this case the formation of antibiotic required the presence of CoA. Furthermore, benzylpenicillin was obtained from (S-phenylacetyl)cysteinylglycine and 6-APA, suggesting that some intermediates of the gamma-glutamyl cycle are directly involved in the biosynthesis of penicillins. To explain "in vivo" formation of this beta-lactam antibiotic, a biosynthetic pathway which includes several glutathione-S-derivatives and a non-enzymatic reaction, is proposed.
Ferrero
M A
MA
Departmento de Bioquímica y Biología Molecular, Universidad de León, España.
Reglero
A
A
Martín-Villacorta
J
J
Fernández-Cañón
J M
JM
Luengo
J M
JM
D000217:Acyltransferases / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000378:metabolism*; D008837:Micrococcus / Q000187:drug effects; D010397:Penicillanic Acid / Q000378:metabolism / Q000031:analogs & derivatives; D010400:Penicillin G / Q000378:metabolism* / Q000494:pharmacology; D010404:Penicillin V / Q000378:metabolism* / Q000494:pharmacology; D046915:Penicillin-Binding Proteins; D010406:Penicillins / Q000096:biosynthesis* / Q000097:blood* / Q000494:pharmacology; D010407:Penicillium / Q000378:metabolism*; D010408:Penicillium chrysogenum / Q000201:enzymology / Q000378:metabolism*
D046915:Penicillin-Binding Proteins; D010406:Penicillins; C065221:penicillin K; D010397:Penicillanic Acid; D000217:Acyltransferases; C018756:acyl-CoA-6-aminopenicillanic acid acyltransferase; D005978:Glutathione; D010400:Penicillin G; C004408:aminopenicillanic acid; D010404:Penicillin V