NFAT-133 is a Streptomyces-derived aromatic polyketide compound with immunosuppressive, antidiabetic, and antitrypanosomal activities. It inhibits transcription mediated by nuclear factor of activated T cells (NFAT), leading to the suppression of interleukin-2 expression and T cell proliferation. It also activates the AMPK pathway in L6 myotubes and increases glucose uptake. In addition to NFAT-133, a number of its congeners, e.g., panowamycins and benwamycins, have been identified. However, little is known about their modes of formation in the producing organisms. Through genome sequencing of Streptomyces pactum ATCC 27456, gene inactivation, and genetic complementation experiments, the biosynthetic gene cluster of NFAT-133 and its congeners has been identified. The cluster contains a highly disordered genetic organization of type I modular polyketide synthase genes with several genes that are necessary for the formation of the aromatic core unit and tailoring processes. In addition, a number of new analogs of NFAT-133 were isolated and their chemical structures elucidated. It is suggested that the heptaketide NFAT-133 is derived from an octaketide intermediate, TM-123. The current study shows yet another unusual biosynthetic pathway involving a noncanonical polyketide synthase assembly line to produce a group of small molecules with valuable bioactivities.

中文翻译：

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链霉菌中活化 T 细胞抑制剂 NFAT-133 的核因子的生物合成

NFAT-133 是一种源自链霉菌的芳香族聚酮化合物，具有免疫抑制、抗糖尿病和抗锥虫病活性。它抑制由活化 T 细胞 (NFAT) 的核因子介导的转录，从而抑制白细胞介素 2 的表达和 T 细胞增殖。它还激活 L6 肌管中的 AMPK 通路并增加葡萄糖摄取。除 NFAT-133 外，还鉴定了许多其同系物，例如帕诺霉素和本瓦霉素。然而，人们对它们在生产生物中的形成方式知之甚少。通过Streptomyces pactum 的基因组测序ATCC 27456、基因失活和遗传互补实验，NFAT-133 及其同源物的生物合成基因簇已被鉴定。该簇包含 I 型模块化聚酮化合物合酶基因的高度无序遗传组织，其中包含几个基因，这些基因是形成芳香核心单元和定制过程所必需的。此外，还分离了许多新的 NFAT-133 类似物并阐明了它们的化学结构。建议七肽 NFAT-133 衍生自八肽中间体 TM-123。目前的研究显示了另一种不寻常的生物合成途径，该途径涉及非规范的聚酮化合物合酶组装线，以产生一组具有宝贵生物活性的小分子。