Mechanistic Insights into the Radical S-adenosyl-l-methionine Enzyme NosL From a Substrate Analogue and the Shunt Products
Xinjian Ji
Department of Chemistry, Fudan University, Shanghai, 200433 China
These authors contributed equally to this work.
Search for more papers by this authorDr. Yongzhen Li
Department of Chemistry, Fudan University, Shanghai, 200433 China
These authors contributed equally to this work.
Search for more papers by this authorYouli Jia
Department of Chemistry, Fudan University, Shanghai, 200433 China
Key Laboratory of Extreme Environmental Microbial Resources and Engineering, Gansu Province, Lanzhou, 730000 China
Search for more papers by this authorProf. Dr. Wei Ding
Department of Chemistry, Fudan University, Shanghai, 200433 China
Key Laboratory of Extreme Environmental Microbial Resources and Engineering, Gansu Province, Lanzhou, 730000 China
Search for more papers by this authorCorresponding Author
Prof. Dr. Qi Zhang
Department of Chemistry, Fudan University, Shanghai, 200433 China
Search for more papers by this authorXinjian Ji
Department of Chemistry, Fudan University, Shanghai, 200433 China
These authors contributed equally to this work.
Search for more papers by this authorDr. Yongzhen Li
Department of Chemistry, Fudan University, Shanghai, 200433 China
These authors contributed equally to this work.
Search for more papers by this authorYouli Jia
Department of Chemistry, Fudan University, Shanghai, 200433 China
Key Laboratory of Extreme Environmental Microbial Resources and Engineering, Gansu Province, Lanzhou, 730000 China
Search for more papers by this authorProf. Dr. Wei Ding
Department of Chemistry, Fudan University, Shanghai, 200433 China
Key Laboratory of Extreme Environmental Microbial Resources and Engineering, Gansu Province, Lanzhou, 730000 China
Search for more papers by this authorCorresponding Author
Prof. Dr. Qi Zhang
Department of Chemistry, Fudan University, Shanghai, 200433 China
Search for more papers by this authorAbstract
The radical S-adenosyl-l-methionine (SAM) enzyme NosL catalyzes the transformation of l-tryptophan into 3-methyl-2-indolic acid (MIA), which is a key intermediate in the biosynthesis of a clinically interesting antibiotic nosiheptide. NosL catalysis was investigated by using the substrate analogue 2-methyl-3-(indol-3-yl)propanoic acid (MIPA), which can be converted into MIA by NosL. Biochemical assays with different MIPA isotopomers in D2O and H2O unambiguously indicated that the 5′-deoxyadenosyl (dAdo)-radical-mediated hydrogen abstraction is from the amino group of l-tryptophan and not a protein residue. Surprisingly, the dAdo-radical-mediated hydrogen abstraction occurs at two different sites of MIPA, thereby partitioning the substrate into different reaction pathways. Together with identification of an α,β-unsaturated ketone shunt product, our study provides valuable mechanistic insight into NosL catalysis and highlights the remarkable catalytic flexibility of radical SAM enzymes.
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