Jun Luo1, Dong Yang1,2, Ajeeth Adhikari1,3, Liao-Bin Dong1, Fei Ye1, Xiaohui Yan1, Christoph Rader3, Ben Shen1,2,4. 1. Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA. 2. Natural Products Discovery Center at Scripps Research, The Scripps Research Institute, Jupiter, FL 33458, USA. 3. Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USA. 4. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA.
Abstract
The ammosamides (AMMs) are a family of pyrroloquinoline alkaloids that exhibits a wide variety of bioactivities. A biosynthetic gene cluster (BGC) that is highly homologous in both gene content and genetic organization to the amm BGC was identified by mining the Streptomyces uncialis DCA2648 genome, leading to the discovery of a sub-family of new AMM congeners, named ammosesters (AMEs). The AMEs feature a C-4a methyl ester, differing from the C-4a amide functional group characteristic to AMMs, and exhibit modest cytotoxicity against a broad spectrum of human cancer cell lines, expanding the structure-activity relationship for the pyrroloquinoline family of natural products. Comparative analysis of the ame and amm BGCs supports the use of a scaffold peptide as an emerging paradigm for the biosynthesis of the pyrroloquinoline family of natural products. AME and AMM biosynthesis diverges from a common intermediate by evolving the pathway-specific Ame24 O-methyltransferase and Amm20 amide synthetase, respectively. These findings will surely inspire future efforts to mimic Nature's combinatorial biosynthetic strategies for natural product structural diversity.
The ammosamides (n class="Chemical">AMMs) are a family of pyrroloquinoline alkaloids that exhibits a wide variety of bioactivities. A biosynthetic gene cluster (BGC) that is highly homologous in both gene content and genetic organization to the amm BGC was identified by mining the Streptomyces uncialisDCA2648 genome, leading to the discovery of a sub-family of new AMM congeners, named ammosesters (AMEs). The AMEs feature a C-4a methyl ester, differing from the C-4aamide functional group characteristic to AMMs, and exhibit modest cytotoxicity against a broad spectrum of humancancer cell lines, expanding the structure-activity relationship for the pyrroloquinoline family of natural products. Comparative analysis of the ame and amm BGCs supports the use of a scaffold peptide as an emerging paradigm for the biosynthesis of the pyrroloquinoline family of natural products. AME and AMM biosynthesis diverges from a common intermediate by evolving the pathway-specific Ame24 O-methyltransferase and Amm20 amide synthetase, respectively. These findings will surely inspire future efforts to mimic Nature's combinatorial biosynthetic strategies for natural product structural diversity.
Authors: Page N Daniels; Hyunji Lee; Rebecca A Splain; Chi P Ting; Lingyang Zhu; Xiling Zhao; Bradley S Moore; Wilfred A van der Donk Journal: Nat Chem Date: 2021-11-01 Impact factor: 24.427