Identification of the First Diketomorpholine Biosynthetic Pathway Using FAC-MS Technology,ACS Chemical Biology

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Identification of the First Diketomorpholine Biosynthetic Pathway Using FAC-MS Technology
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-04-09 00:00:00 , DOI: 10.1021/acschembio.8b00024
Matthew T. Robey ₁ , Rosa Ye ₂ , Jin Woo Bok ₃ , Kenneth D. Clevenger ₄ , Md Nurul Islam ₂ , Cynthia Chen ₂ , Raveena Gupta ₃ , Michael Swyers ₂ , Edward Wu ₂ , Peng Gao ₄ , Paul M. Thomas _{1,

4} , Chengcang C. Wu ₂ , Nancy P. Keller ₃ , Neil L. Kelleher _{1,

4,

5}

Affiliation

Filamentous fungi are prolific producers of secondary metabolites with drug-like properties, and their genome sequences have revealed an untapped wealth of potential therapeutic leads. To better access these secondary metabolites and characterize their biosynthetic gene clusters, we applied a new platform for screening and heterologous expression of intact gene clusters that uses fungal artificial chromosomes and metabolomic scoring (FAC-MS). We leverage FAC-MS technology to identify the biosynthetic machinery responsible for production of acu-dioxomorpholine, a metabolite produced by the fungus, Aspergilllus aculeatus. The acu-dioxomorpholine nonribosomal peptide synthetase features a new type of condensation domain (designated C_R) proposed to use a noncanonical arginine active site for ester bond formation. Using stable isotope labeling and MS, we determine that a phenyllactate monomer deriving from phenylalanine is incorporated into the diketomorpholine scaffold. Acu-dioxomorpholine is highly related to orphan inhibitors of P-glycoprotein targets in multidrug-resistant cancers, and identification of the biosynthetic pathway for this compound class enables genome mining for additional derivatives.

中文翻译：

利用FAC-MS技术鉴定第一个二酮吗啉生物合成途径

丝状真菌是具有药物样特性的次生代谢产物的多产者，它们的基因组序列已揭示出许多尚未开发的潜在治疗线索。为了更好地利用这些次生代谢产物并表征其生物合成基因簇，我们应用了一个新平台，该平台使用真菌人工染色体和代谢组学评分（FAC-MS）筛选和异源表达完整基因簇。我们利用FAC-MS技术确定负责生产acu-dioxomorpholine（一种由真菌Aspergilllus aculeatus产生的代谢物）的生物合成机制。acu-二氧代吗啉非核糖体肽合成酶具有新型缩合结构域（称为C _R）建议使用非规范的精氨酸活性位点形成酯键。使用稳定的同位素标记和质谱，我们确定衍生自苯丙氨酸的苯基乳酸单体被并入二酮吗啉支架中。Acu-二氧代吗啉与多药耐药性癌症中P-糖蛋白靶标的孤儿抑制剂高度相关，并且针对该化合物类别的生物合成途径的鉴定使得能够进行其他衍生物的基因组挖掘。

更新日期：2018-04-09

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