Han Yi, Guo Yaojie, Zhang Nan, Xu Fan, Limwachiranon Jarukitt, Xiong Zhenzhen, Xu Liru, Mao Xu-Ming, Scharf Daniel H
Department of Microbiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China.
The Fourth Affiliated Hospital, International School of Medicine, Zhejiang University School of Medicine, Yiwu, China.
Commun Chem. 2024 Sep 30;7(1):221. doi: 10.1038/s42004-024-01311-2.
Fungal natural products from various species often feature hydroxamic acid motifs that have the ability to chelate iron. These compounds have an array of medicinally and ecologically relevant activities. Through genome mining, gene deletion in the host Aspergillus terreus, and heterologous expression experiments, this study has revealed that a nonribosomal peptide synthetase (NRPS) TamA and a specialized cytochrome P450 monooxygenase TamB catalyze the sequential biosynthetic reactions in the formation of terramides A-C, a series of diketopiperazines (DKPs) with hydroxamic acid motifs. Feeding experiments showed that TamB catalyzes an unprecedented di-hydroxylation of the amide nitrogens in the diketopiperazine core. This tailoring reaction led to the formation of two bidentate iron-binding sites per molecule with an unusual iron-binding stoichiometry. The structure of the terramide A-Fe complex was characterized by liquid chromatography-mass spectrometry (LC-MS), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy and electron paramagnetic resonance spectroscopy (EPR). Antimicrobial assays showed that the iron-binding motifs are crucial for the activity against bacteria and fungi. Murine infection experiments indicated that terramide production is crucial for the virulence of A. terreus and could be a potential antifungal drug target.
来自不同物种的真菌天然产物通常具有能螯合铁的异羟肟酸基序。这些化合物具有一系列与医学和生态相关的活性。通过基因组挖掘、宿主土曲霉中的基因缺失以及异源表达实验，本研究揭示了一种非核糖体肽合成酶（NRPS）TamA和一种特殊的细胞色素P450单加氧酶TamB催化了terramides A - C（一系列具有异羟肟酸基序的二酮哌嗪（DKPs））形成过程中的连续生物合成反应。饲喂实验表明，TamB催化了二酮哌嗪核心中酰胺氮前所未有的双羟基化反应。这种修饰反应导致每个分子形成两个具有不寻常铁结合化学计量的双齿铁结合位点。通过液相色谱 - 质谱联用（LC - MS）、傅里叶变换红外光谱（FT - IR）、拉曼光谱和电子顺磁共振光谱（EPR）对terramide A - Fe复合物的结构进行了表征。抗菌试验表明，铁结合基序对于抗细菌和真菌活性至关重要。小鼠感染实验表明，terramide的产生对于土曲霉的毒力至关重要，并且可能是一个潜在的抗真菌药物靶点。
