Radical Mechanisms of Iron-Sulfur Proteins

Project: Research project

Project Details


PROJECT SUMMARY Elaborations of unactivated carbon centers are among the most demanding reactions that enzymes catalyze. These reactions generally involve radical intermediates, often produced by strategic abstraction of substrate hydrogen atoms (H·). A prevalent strategy to cleave C?H bonds possessing homolytic bond-dissociation energies (BDEs) in excess of 95 kcal/mol involves intermediates derived from the reaction of O2 with transition metal cofactors. A distinct strategy, predominant in the anaerobic world and still important in aerobes, employs a 5'-deoxyadenosyl 5'-radical as the H· abstractor. This radical is generated via the homolysis of adenosylcobalamin (AdoCbl) or the reductive cleavage of S-adenosylmethionine (SAM). Those enzymes employing SAM to catalyze radical-dependent reactions belong to the so-called radical SAM (RS) superfamily, which contains almost 114,000 individual sequences that encompass at least 65 distinct reactions. Moreover, the number of enzymes and reactions catalyzed by members of the superfamily are increasing at an amazing pace as sequences of new genomes become available. The work described herein builds on and advances work from our laboratory on the characterization of some of the most novel reactions within the superfamily, including those involved in tRNA and ribosome modification, lipoic acid biosynthesis, the biosynthesis of several antibiotics, and antibiotic resistance. Specific objectives will be to i) elucidate how methylation of unactivated carbon and phosphorus atoms takes place, and provide rationale for the strategy employed for each type of methyl acceptor; ii) formulate methods to determine substrates for the many unannotated radical SAM methylases; iii) elucidate how iron-sulfur clusters are used as sources of sulfur atoms during sulfur insertion reactions and to determine how they are resynthesized after each turnover; iv) elucidate the pathway for the biosynthesis of the thiopeptide antibiotic, nosiheptide; and v) begin to characterize several radical SAM enzymes from humans that play important roles in health and disease.
Effective start/end date4/1/173/31/18


  • National Institute of General Medical Sciences: $298,493.00
  • National Institute of General Medical Sciences: $298,753.00
  • National Institute of General Medical Sciences: $298,357.00
  • National Institute of General Medical Sciences: $298,625.00
  • National Institute of General Medical Sciences: $298,215.00


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