关键词: 非核糖体肽, 双嵌入家族, 天然产物, 抗肿瘤化合物, 生物合成

Abstract:

Bisintercalator family of natural products are a group of C2-symmetric cyclic non-ribosomal peptides produced by actinobacteria, possessing potent antimicrobial, antitumor and other bioactivities. Bisintercalators can be divided into two groups based on the size of their macrocycles. Those that are constituted of eight amino acid residues are defined as the minor scaffold type, while those with ten residues belong to the major scaffold type. Structure diversity among bisintercalators arises from variations in aromatic heterocycles, amino acids identities and quantities, and post-assembly line modifications. The major scaffold type harbors two structurally rigid six-membered nitrogen heterocycle-containing amino acids, which can further undergo oxidative and acylation tailorings. The minor scaffold type seemingly derives their rigidity from disulfide or thioacetal bridges formed by sulfydryls of two cysteines. Thioacetal bridges allow variable S-alkyl elongation and conversion of S-alkyl sulfur into sulfoxide moiety. Besides, bisintercalators exhibit differences in other amino acid identities, which contribute to their diverse activities, including antimicrobial, antitumor, antifungal, anti-malarial, or antiviral effects. Chemical synthesis of these nonribosomal peptides is complex due to their intricate architecture, making microbial fermentation a more efficient scalable production method. Structural optimization is achievable through combinatorial and precursor-guided biosynthesis. Understanding the biosynthetic pathways of bisintercalators is crucial for yield enhancement via pathway-specific regulation and offers biocatalytic parts for structural innovations. All these necessitate delineation of the biosynthetic pathway of bisintercalators, which paves the way for yield promotion through pathway-specific regulator manipulation and provides basic genetic elements for structural renovation. Deciphering biosynthesis pathways of these compounds has uncovered the biochemical basis for peptide chain assembly, aromatic heterocycle formation, and post-NRPS tailoring. Corresponding to their structural similarity, their biosynthesis involves several shared enzyme machineries. Different types of the key aromatic bicyclic heterocycles are all derived from L-tryptophan, and used as starting unites in respective NRPS assembly lines. Diversified post-NRPS tailoring finally gives bisintercalators. This knowledge will facilitate future discovery and drug development for this promising natural product family.

Key words: nonribosomal peptide, bisintercalator family, natural product, antitumor agent, biosynthesis