Biosynthesis of Dolastatin 10 in Marine Cyanobacteria, a Prototype for Multiple Approved Cancer Drugs
Dimitris Kallifidas, Dipesh Dhakal, Man‐Yun Chen, Qi-Yin Chen, Sofia Kokkaliari, Nicole A. Colon Rosa, Ranjala Ratnayake, Steven D. Bruner, Valerie J. Paul, Yousong Ding, Hendrik Luesch
Abstract
Dolastatin 10, a potent tubulin-targeting marine anticancer natural product, provided the basis for the development of six FDA-approved antibody–drug conjugates. Through the screening of cyanobacterial Caldora penicillata environmental DNA libraries and metagenome sequencing, we identified its biosynthetic gene cluster. Functional prediction of 10 enzymes encoded in the 39 kb cluster supports the dolastatin 10 biosynthesis. The nonheme diiron monooxygenase DolJ was biochemically characterized to mediate the terminal thiazole formation in dolastatin 10.
Topics & Concepts
Natural productBiosynthesisGene clusterChemistryComputational biologyCyanobacteriaBiochemistryCiguatoxinGeneBiologyGeneticsBacteriaFisheryFish <Actinopterygii>Microbial Natural Products and BiosynthesisMarine Sponges and Natural ProductsSynthesis and Biological Activity