Details:

Alternative Title:
Angew Chem Int Ed Engl
Publisher's site:
http://dx.doi.org/10.1002/anie.201509345
Personal Author:
Cochrane, Rachel V. K. ; Sanichar, Randy ; Lambkin, Gareth R. ; Reiz, Béla ; Xu, Wei ; ... More +
Cochrane, Rachel V. K. ; Sanichar, Randy ; Lambkin, Gareth R. ; Reiz, Béla ; Xu, Wei ; Tang, Yi ; Vederas, John C. Less -
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.
Subject:
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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 HHS/United States ; R01 GM085128/GM/NIGMS NIH HHS/United States ; 1DP1 GM106413/DP/NCCDPHP CDC HHS/United States ; 1R01 GM085128/GM/NIGMS NIH HHS/United States
DP1 GM106413/GM/NIGMS NIH HHS/United States ; R01 GM085128/GM/NIGMS NIH HHS/United States ; 1DP1 GM106413/DP/NCCDPHP CDC HHS/United States ; 1R01 GM085128/GM/NIGMS NIH HHS/United States Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:b347c05d852e964c56e335c3acccb6e83597664c207fa676a19c17d23e6b50c8
File Type:

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