Discovery of Unclustered Fungal Indole Diterpene Biosynthetic Pathways through Combinatorial Pathway Reassembly in Engineered Yeast

Details

• Alternative Title:
  J Am Chem Soc
• Personal Author:
  Tang, Mancheng ; Lin, Hsiao-Ching ; Li, Dehai ; Zou, Yi ; Li, Jian ; Xu, Wei ; Cacho, Ralph A. ; Hillenmeyer, Maureen E. ; Garg, Neil K. ; Tang, Yi
• Description:
  The structural diversity and biological activities of fungal indole diterpenes (IDTs) are generated in large part by the IDT cyclases (IDTCs). Identifying different IDTCs from IDT biosynthetic pathways is therefore important toward understanding how these enzymes introduce chemical diversity from a common linear precursor. However, IDTCs involved in the cyclization of the well-known aflavinine subgroup of IDTs have not been discovered. Here, using Saccharomyces cerevisiae as a heterologous host and a phylogenetically guided enzyme mining approach, we combinatorially assembled IDT biosynthetic pathways using IDTCs homologues identified from different fungal hosts. We identified the genetically standalone IDTCs involved in the cyclization of aflavinine and anominine and produced new IDTs not previously isolated. The cyclization mechanisms of the new IDTCs were proposed based on the yeast reconstitution results. Our studies demonstrate heterologous pathway assembly is a useful tool in the reconstitution of unclustered biosynthetic pathways.
• Subjects:
  Article Biosynthetic Pathways Cyclization Diterpenes Genetic Engineering Indoles Molecular Conformation Phosphorus-Oxygen Lyases Saccharomyces Cerevisiae
• Source:
  J Am Chem Soc. 137(43):13724-13727.
• Pubmed ID:
  26469304
• Pubmed Central ID:
  PMC4732561
• Document Type:
  Journal Article
• Funding:
  DP1 GM106413/GM/NIGMS NIH HHS/United States ; P01 HG000205/HG/NHGRI NIH HHS/United States ; U01 GM110706/GM/NIGMS NIH HHS/United States ; 1DP1GM106413/DP/NCCDPHP CDC HHS/United States ; 1U01GM110706-01/GM/NIGMS NIH HHS/United States
• Volume:
  137
• Issue:
  43
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0829777a2d6758b952661c5c47cecac15713457228e416e671f216630f4dc562
• Download URL:
  https://stacks.cdc.gov/view/cdc/37824/cdc_37824_DS1.pdf
• File Type:
  [PDF - 1.46 MB ]