An Unusual Extender Unit Is Incorporated into the Modular Polyketide Synthase of Scopranones Biosynthesis.,Biochemistry

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An Unusual Extender Unit Is Incorporated into the Modular Polyketide Synthase of Scopranones Biosynthesis.
Biochemistry ( IF 2.9 ) Pub Date : 2019-12-06 , DOI: 10.1021/acs.biochem.9b00908
Ayumu Demachi ₁ , Ryuji Uchida ₂ , Shiho Arima ₁ , Tohru Nagamitsu ₁ , Junko Hashimoto ₃ , Mamoru Komatsu ₄ , Ikuko Kozone ₃ , Kazuo Shin-Ya ₅ , Hiroshi Tomoda ₁ , Haruo Ikeda ₄

Affiliation

Scopranones, produced by Streptomyces sp. BYK-11038, are the novel bone morphogenetic protein inhibitors characterized by atypical two scoop-like moieties and a 3-furanone moiety. Two scoop-like moieties connected to a 3-furanone have not previously been reported in natural products, and their biosynthesis must occur via a unique pathway. Feeding experiments using 13C-labeled precursors indicated that scopranones were synthesized from three acetates and three butyrates in polyketide-type biosynthesis. Genome mining of Streptomyces sp. BYK-11038 revealed that the candidate biosynthetic gene cluster contains 21 open reading frames (ORFs), including three modular polyketide synthases (PKSs; SprA, SprB, and SprC), which were composed of 4 modules with one loading module and 18 additional ORFs (SprD to SprU) spanning a distance of 55 kbp. The characterization of in-frame deletion mutants and feeding experiments with the predicted extender units indicated that two genes, sprP and sprR, encoding discrete 3-oxoacyl-ACP synthases, and a gene, sprO, encoding crotonyl-CoA reductase, were involved in assembling an unusual C8 branched extender unit, 2-(2-ethylbutyl)malonyl-CoA. Additionally, three ORFs, sprM, sprN, and sprT, encoding cytochrome P450s and a monooxygenase, are important tailoring enzymes in post-PKS modification. SprT is an essential enzyme for decarboxylative ring contraction via oxidation, which converts the 2-pyranone to a 3-furanone.

中文翻译：

一个不寻常的扩展单元被合并到Scopranones生物合成的模块化聚酮化合物合酶中。

Scopranones，由链霉菌属（Streptomyces sp。）产生。BYK-11038是新型骨形态发生蛋白抑制剂，其特征在于非典型的两个勺状部分和一个3-呋喃酮部分。天然产物以前没有报道过两个与3-呋喃酮连接的勺状部分，它们的生物合成必须通过独特的途径发生。使用13C标记前体的进料实验表明，在聚酮化合物型生物合成中，由3种乙酸酯和3种丁酸酯合成了scopranones。链霉菌（Streptomyces sp。）的基因组挖掘。BYK-11038显示，候选生物合成基因簇包含21个开放阅读框（ORF），包括3个模块化聚酮化合物合酶（PKS，SprA，SprB和SprC），由4个模块组成，一个加载模块和18个其他ORF（ SprD到SprU），跨度为55 kbp。框内缺失突变体的表征和带有预测的扩展单元的进料实验表明，编码离散的3-氧代酰基-ACP合酶的两个基因sprP和sprR和编码巴豆酰基-CoA还原酶的基因sprO参与了组装。不常见的C8支链增量剂单元2-（2-乙基丁基）丙二酰-CoA。此外，编码细胞色素P450和单加氧酶的三种ORF，sprM，sprN和sprT是在PKS后修饰中重要的定制酶。SprT是通过氧化作用使脱羧环收缩的必不可少的酶，它可以将2-吡喃酮转化为3-呋喃酮。参与组装一个不寻常的C8支链增量剂单元2-（2-乙基丁基）丙二酰-CoA。此外，编码细胞色素P450和单加氧酶的三种ORF，sprM，sprN和sprT是在PKS后修饰中重要的定制酶。SprT是通过氧化作用使脱羧环收缩的必不可少的酶，它可以将2-吡喃酮转化为3-呋喃酮。参与组装一个不寻常的C8支链增量剂单元2-（2-乙基丁基）丙二酰-CoA。此外，编码细胞色素P450和单加氧酶的三种ORF，sprM，sprN和sprT是在PKS后修饰中重要的定制酶。SprT是通过氧化作用使脱羧环收缩的必不可少的酶，它可以将2-吡喃酮转化为3-呋喃酮。

更新日期：2019-12-07

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