Probable Role of Clavaminic Acid as the Terminal Intermediate in the Common Pathway to Clavulanic Acid and the Antipodal Clavam Metabolites
详细信息 查看全文
- 作者：Laura A. Egan ; Robert W. Busby ; Dirk Iwata-Reuyl ; and Craig A. Townsend
- 刊名：Journal of the American Chemical Society
- 出版年：1997
- 出版时间：March 12, 1997
- 年：1997
- 卷：119
- 期：10
- 页码：2348 - 2355
- 全文大小：306K
- 年卷期：v.119,no.10(March 12, 1997)
- ISSN：1520-5126
文摘
Emerging chemical and genetic evidence suggests that separatebiochemical solutions have evolved tosynthesize the four known classes of 
-lactam antibiotics. Oneof these classes contains clavulanic acid (1) andafamily of structurally related but antipodal clavam metabolites2-5, 7, and 8 which lacka carboxylate at C-3, havea different oxidation state, and exhibit stereochemical features atC-2. Previous work has demonstrated theincorporation of ornithine/arginine in the identical regiochemicalsense in all of these natural products, and hasestablished the common intermediacy of the monocyclic -lactamproclavaminic acid (12) as well. In this paperthequite advanced bicyclic intermediate clavaminic acid (14)has been synthesized in doubly 13C-labeled formbypreparative incubation of recombinant clavaminate synthase. Theintact and equally efficient incorporation of14into valclavam (7) and 2-(2-hydroxyethyl)clavam(8), together with18O2-incorporation experiments, has beeninterpretedto define clavaminic acid as the final intermediate shared in thebiosynthesis of clavulanic acid and the antipodalclavams. A mechanistic rationale of this interrelationship and thelate stages of the respective biosyntheses is proposed.
-lactam antibiotics. Oneof these classes contains clavulanic acid (1) andafamily of structurally related but antipodal clavam metabolites2-5, 7, and 8 which lacka carboxylate at C-3, havea different oxidation state, and exhibit stereochemical features atC-2. Previous work has demonstrated theincorporation of ornithine/arginine in the identical regiochemicalsense in all of these natural products, and hasestablished the common intermediacy of the monocyclic -lactamproclavaminic acid (12) as well. In this paperthequite advanced bicyclic intermediate clavaminic acid (14)has been synthesized in doubly 13C-labeled formbypreparative incubation of recombinant clavaminate synthase. Theintact and equally efficient incorporation of14into valclavam (7) and 2-(2-hydroxyethyl)clavam(8), together with18O2-incorporation experiments, has beeninterpretedto define clavaminic acid as the final intermediate shared in thebiosynthesis of clavulanic acid and the antipodalclavams. A mechanistic rationale of this interrelationship and thelate stages of the respective biosyntheses is proposed.