Biosynthesis and Structures of Cyclomarins and Cyclomarazines, Prenylated Cyclic Peptides of Marine Actinobacterial Origin
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- 作者：Andrew W. Schultz ; Dong-Chan Oh ; John R. Carney ; R. Thomas Williamson ; Daniel W. Udwary ; Paul R. Jensen ; Steven J. Gould ; William Fenical ; Bradley S. Moore
- 刊名：Journal of the American Chemical Society
- 出版年：2008
- 出版时间：April 2, 2008
- 年：2008
- 卷：130
- 期：13
- 页码：4507 - 4516
- 全文大小：226K
- 年卷期：v.130,no.13(April 2, 2008)
- ISSN：1520-5126
文摘
Two new diketopiperazine dipeptides, cyclomarazines A and B, were isolated and characterizedalong with the new cyclic heptapeptide cyclomarin D from the marine bacterium Salinispora arenicola CNS-205. These structurally related cyclic peptides each contain modified amino acid residues, includingderivatives of N-(1,1-dimethylallyl)-tryptophan and 
-hydroxyleucine, which are common in the di- andheptapeptide series. Stable isotope incorporation studies in Streptomyces sp. CNB-982, which was firstreported to produce the cyclomarin anti-inflammatory agents, illuminated the biosynthetic building blocksassociated with the major metabolite cyclomarin A, signifying that this marine microbial peptide isnonribosomally derived largely from nonproteinogenic amino acid residues. DNA sequence analysis of the5.8 Mb S. arenicola circular genome and PCR-targeted gene inactivation experiments identified the 47 kbcyclomarin/cyclomarazine biosynthetic gene cluster (cym) harboring 23 open reading frames. The cymlocus is dominated by the 23 358 bp cymA, which encodes a 7-module nonribosomal peptide synthetase(NRPS) responsible for assembly of the full-length cyclomarin heptapeptides as well as the truncatedcyclomarazine dipeptides. The unprecedented biosynthetic feature of the megasynthetase CymA tosynthesize differently sized peptides in vivo may be triggered by the level of 
oxidation of the primingtryptophan residue, which is oxidized in the cyclomarin series and unoxidized in the cyclomarazines.Biosynthesis of the N-(1,1-dimethyl-2,3-epoxypropyl)--hydroxytryptophan residue of cyclomarin A wasfurther illuminated through gene inactivation experiments, which suggest that the tryptophan residue isreverse prenylated by CymD prior to release of the cyclic peptide from the CymA megasynthetase, whereasthe cytochrome P450 CymV installs the epoxide group on the isoprene of cyclomarin C post-NRPS assembly.Last, the novel amino acid residue 2-amino-3,5-dimethylhex-4-enoic acid in the cyclomarin series wasshown by bioinformatics and stable isotope experiments to derive from a new pathway involvingcondensation of isobutyraldehyde and pyruvate followed by S-adenosylmethionine methylation. Assemblyof this unsaturated, branched amino acid is unexpectedly related to the degradation of the environmentalpollutant 3-(3-hydroxyphenyl)propionic acid.
-hydroxyleucine, which are common in the di- andheptapeptide series. Stable isotope incorporation studies in Streptomyces sp. CNB-982, which was firstreported to produce the cyclomarin anti-inflammatory agents, illuminated the biosynthetic building blocksassociated with the major metabolite cyclomarin A, signifying that this marine microbial peptide isnonribosomally derived largely from nonproteinogenic amino acid residues. DNA sequence analysis of the5.8 Mb S. arenicola circular genome and PCR-targeted gene inactivation experiments identified the 47 kbcyclomarin/cyclomarazine biosynthetic gene cluster (cym) harboring 23 open reading frames. The cymlocus is dominated by the 23 358 bp cymA, which encodes a 7-module nonribosomal peptide synthetase(NRPS) responsible for assembly of the full-length cyclomarin heptapeptides as well as the truncatedcyclomarazine dipeptides. The unprecedented biosynthetic feature of the megasynthetase CymA tosynthesize differently sized peptides in vivo may be triggered by the level of oxidation of the primingtryptophan residue, which is oxidized in the cyclomarin series and unoxidized in the cyclomarazines.Biosynthesis of the N-(1,1-dimethyl-2,3-epoxypropyl)--hydroxytryptophan residue of cyclomarin A wasfurther illuminated through gene inactivation experiments, which suggest that the tryptophan residue isreverse prenylated by CymD prior to release of the cyclic peptide from the CymA megasynthetase, whereasthe cytochrome P450 CymV installs the epoxide group on the isoprene of cyclomarin C post-NRPS assembly.Last, the novel amino acid residue 2-amino-3,5-dimethylhex-4-enoic acid in the cyclomarin series wasshown by bioinformatics and stable isotope experiments to derive from a new pathway involvingcondensation of isobutyraldehyde and pyruvate followed by S-adenosylmethionine methylation. Assemblyof this unsaturated, branched amino acid is unexpectedly related to the degradation of the environmentalpollutant 3-(3-hydroxyphenyl)propionic acid.