Identification and reconstitution of the polyketide synthases responsible for biosynthesis of the anti-malarial agent, cladosporin

Details

• Alternative Title:
  Angew Chem Int Ed Engl
• Personal Author:
  Cochrane, Rachel V. K. ; Sanichar, Randy ; Lambkin, Gareth R. ; Reiz, Béla ; Xu, Wei ; Tang, Yi ; Vederas, John C.
• Description:
  The antimalarial agent cladosporin is a nanomolar inhibitor of the Plasmodium falciparum lysyl-tRNA synthetase, and exhibits activity against both blood- and liver-stage infection. Cladosporin can be isolated from the fungus Cladosporium cladosporioides, where it is biosynthesized by a highly reducing (HR) and a non-reducing (NR) iterative type I polyketide synthase (PKS) pair. Genome sequencing of the host organism and subsequent heterologous expression of these enzymes in Saccharomyces cerevisiae produced cladosporin, confirming the identity of the putative gene cluster. Incorporation of a pentaketide intermediate analogue indicated a 5+3 assembly by the HR PKS Cla2 and the NR PKS Cla3 during cladosporin biosynthesis. Advanced-intermediate analogues were synthesized and incorporated by Cla3 to furnish new cladosporin analogues. A putative lysyl-tRNA synthetase resistance gene was identified in the cladosporin gene cluster. Analysis of the active site emphasizes key structural features thought to be important in resistance to cladosporin.
• Subjects:
  Antimalarials Article Isocoumarins Polyketide Synthases
• Source:
  Angew Chem Int Ed Engl. 55(2):664-668
• Pubmed ID:
  26783060
• Pubmed Central ID:
  PMC4906947
• Document Type:
  Journal Article
• Funding:
  DP1 GM106413/GM/NIGMS NIH HHSUnited States/ ; R01 GM085128/GM/NIGMS NIH HHSUnited States/ ; 1DP1 GM106413/DP/NCCDPHP CDC HHSUnited States/ ; 1R01 GM085128/GM/NIGMS NIH HHSUnited States/
• Volume:
  55
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:b347c05d852e964c56e335c3acccb6e83597664c207fa676a19c17d23e6b50c8
• Download URL:
  https://stacks.cdc.gov/view/cdc/39904/cdc_39904_DS1.pdf
• File Type:
  [PDF - 1.19 MB ]