Accurate prediction of secondary metabolite gene clusters in filamentous fungi

被引:175
作者
Andersen, Mikael R. [1 ]
Nielsen, Jakob B. [1 ]
Klitgaard, Andreas [1 ]
Petersen, Lene M. [1 ]
Zachariasen, Mia [1 ]
Hansen, Tilde J. [1 ]
Blicher, Lene H. [2 ]
Gotfredsen, Charlotte H. [3 ]
Larsen, Thomas O. [1 ]
Nielsen, Kristian F. [1 ]
Mortensen, Uffe H. [1 ]
机构
[1] Tech Univ Denmark, Dept Syst Biol, Ctr Microbial Biotechnol, DK-2800 Lyngby, Denmark
[2] Tech Univ Denmark, Dept Syst Biol, DTU Multiassay Core, DK-2800 Lyngby, Denmark
[3] Tech Univ Denmark, Dept Chem, DK-2800 Lyngby, Denmark
关键词
aspergilli; natural products; secondary metabolism; polyketide synthases; ASPERGILLUS-NIDULANS; NATURAL-PRODUCT; POLYKETIDE; BIOSYNTHESIS; GENOME; IDENTIFICATION; DEREPLICATION; SYNTHETASE; DISCOVERY; PATHWAY;
D O I
10.1073/pnas.1205532110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Biosynthetic pathways of secondary metabolites from fungi are currently subject to an intense effort to elucidate the genetic basis for these compounds due to their large potential within pharmaceutics and synthetic biochemistry. The preferred method is methodical gene deletions to identify supporting enzymes for key synthases one cluster at a time. In this study, we design and apply a DNA expression array for Aspergillus nidulans in combination with legacy data to form a comprehensive gene expression compendium. We apply a guilt-by-association-based analysis to predict the extent of the biosynthetic clusters for the 58 synthases active in our set of experimental conditions. A comparison with legacy data shows the method to be accurate in 13 of 16 known clusters and nearly accurate for the remaining 3 clusters. Furthermore, we apply a data clustering approach, which identifies cross-chemistry between physically separate gene clusters (superclusters), and validate this both with legacy data and experimentally by prediction and verification of a supercluster consisting of the synthase AN1242 and the prenyltransferase AN11080, as well as identification of the product compound nidulanin A. We have used A. nidulans for our method development and validation due to the wealth of available biochemical data, but the method can be applied to any fungus with a sequenced and assembled genome, thus supporting further secondary metabolite pathway elucidation in the fungal kingdom.
引用
收藏
页码:E99 / E107
页数:9
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