title: Structure and biosynthesis of fumosorinone, a new protein tyrosine phosphatase 1B inhibitor firstly isolated from the entomogenous fungus Isaria fumosorosea.
abstract: Fumosorinone, isolated from the entomogenous fungus Isaria fumosorosea, is a new 2-pyridone alkaloid which is elucidated by HRESIMS 1D and 2DNMR. Fumosorinone is structurally similar to tenellin and desmethylbassianin but it differs in chain length and degree of methylation. It is characterized by a classic noncompetitive inhibitor of protein tyrosine phosphatase 1B (IC50 14.04μM) which was implicated as a negative regulator of insulin receptor signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. For further study, we identified the biosynthetic gene cluster of fumosorinone from ongoing genome sequencing project, and it was verified by a direct knock-out strategy, reported for the first time in I. fumosorosea, using the Agrobacterium-mediated transformation in conjunction with linear deletion cassettes. The biosynthetic gene cluster includes a hybrid polyketide synthase-nonribosomal peptide synthetase gene, two cytochrome P450 enzyme genes, a trans-enoyl reductase gene, and other two transcription regulatory genes. Comparison of fumosorinone biosynthetic cluster with known gene clusters gives further insight into biosynthesis of pyridone alkaloids and provides the foundation for combinatorial biosynthesis for new fumosorinone derivatives.
authors: Hebei University, College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Baoding 071002, China.
authors: Linxia
authors: L
authors: Liu
authors: Hebei University, College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Baoding 071002, China.
authors: Jun
authors: J
authors: Zhang
authors: Hebei University, College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Baoding 071002, China.
authors: Chuan
authors: C
authors: Chen
authors: Hebei University, College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Baoding 071002, China.
authors: Jitao
authors: J
authors: Teng
authors: Chinese Academy of Sciences, Shanghai Institutes for Biological Sciences, Key Laboratory of Insect Developmental and Evolutionary Biology, Institute of Plant Physiology and Ecology, Shanghai 200032, China. Electronic address: cswang@sibs.ac.cn.
authors: Chengshu
authors: C
authors: Wang
authors: Hebei University, College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Baoding 071002, China. Electronic address: duqiangluo@126.com.
authors: Duqiang
authors: D
authors: Luo
mesh_terms: D053898:Biosynthetic Pathways / Q000235:genetics*; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000378:metabolism*; D006999:Hypocreales / Q000235:genetics / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004271:DNA, Fungal; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011728:Pyridones; C000599091:fumosorinone; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Biosynthesis; Fumosorinone; Isaria fumosorosea; Natural product; PKS–NPRS; Protein tyrosine phosphatase 1B inhibitor