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Substrate‐Tuned Catalysis of the Radical S‐Adenosyl‐L‐Methionine Enzyme NosL Involved in Nosiheptide Biosynthesis
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Xinjian Ji Dr. Yongzhen Li Prof. Dr. Wei Ding Prof. Dr. Qi Zhang 《Angewandte Chemie (International ed. in English)》2015,54(31):9021-9024
NosL is a radical S‐adenosyl‐L ‐methionine (SAM) enzyme that converts L ‐Trp to 3‐methyl‐2‐indolic acid, a key intermediate in the biosynthesis of a thiopeptide antibiotic nosiheptide. In this work we investigated NosL catalysis by using a series of Trp analogues as the molecular probes. Using a benzofuran substrate 2‐amino‐3‐(benzofuran‐3‐yl)propanoic acid (ABPA), we clearly demonstrated that the 5′‐deoxyadenosyl (dAdo) radical‐mediated hydrogen abstraction in NosL catalysis is not from the indole nitrogen but likely from the amino group of L ‐Trp. Unexpectedly, the major product of ABPA is a decarboxylated compound, indicating that NosL was transformed to a novel decarboxylase by an unnatural substrate. Furthermore, we showed that, for the first time to our knowledge, the dAdo radical‐mediated hydrogen abstraction can occur from an alcohol hydroxy group. Our study demonstrates the intriguing promiscuity of NosL catalysis and highlights the potential of engineering radical SAM enzymes for novel activities. 相似文献
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Xinjian Ji Dr. Yongzhen Li Dr. Liqi Xie Prof. Dr. Haojie Lu Prof. Dr. Wei Ding Prof. Dr. Qi Zhang 《Angewandte Chemie (International ed. in English)》2016,55(39):11845-11848
Radical S‐adenosyl‐l ‐methionine (SAM) enzymes utilize a [4Fe‐4S] cluster to bind SAM and reductively cleave its carbon–sulfur bond to produce a highly reactive 5′‐deoxyadenosyl (dAdo) radical. In almost all cases, the dAdo radical abstracts a hydrogen atom from the substrates or from enzymes, thereby initiating a highly diverse array of reactions. Herein, we report a change of the dAdo radical‐based chemistry from hydrogen abstraction to radical addition in the reaction of the radical SAM enzyme NosL. This change was achieved by using a substrate analogue containing an olefin moiety. We also showed that two SAM analogues containing different nucleoside functionalities initiate the radical‐based reactions with high efficiencies. The radical adduct with the olefin produced in the reaction was found to undergo two divergent reactions, and the mechanistic insights into this process were investigated in detail. Our study demonstrates a promising strategy in expanding radical SAM chemistry, providing an effective way to access nucleoside‐containing compounds by using radical SAM‐dependent reactions. 相似文献
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Takuji Magata Yoshimi Hirokawa Yusuke Moriguchi Ryosuke Yokoi Shotaro Nojiri Ryota Miyazaki Sayuri Akasako Rina Takahashi Munetaka Nishida Junya Hakoda Ryota Nakayama Aya Tanaka Naoyoshi Maezaki 《Tetrahedron letters》2019,60(10):718-720
A concise, highly stereoselective synthesis of 2,4- and 2,5-disubstituted thiazole amino acids was developed. These are important building blocks for various biologically active thiazole-containing natural peptides and their regioisomeric analogues. The fundamental reactions are diastereoselective addition of (4- or 5-bromothiazol-2-yl)lithium to N-tert-butanesulfinyl imine with subsequent Pd-catalyzed phenoxycarbonylation. 相似文献
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Reinder H. de Vries Jakob H. Viel Ruben Oudshoorn Prof. Dr. Oscar P. Kuipers Prof. Dr. Gerard Roelfes 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(55):12698-12702
We report the late-stage chemical modification of ribosomally synthesized and post-translationally modified peptides (RIPPs) by Diels–Alder cycloadditions to naturally occurring dehydroalanines. The tail region of the thiopeptide thiostrepton could be modified selectively and efficiently under microwave heating and transition-metal-free conditions. The Diels–Alder adducts were isolated and the different site- and endo/exo isomers were identified by 1D/2D 1H NMR. Via efficient modification of the thiopeptide nosiheptide and the lanthipeptide nisin Z the generality of the method was established. Minimum inhibitory concentration (MIC) assays of the purified thiostrepton Diels–Alder products against thiostrepton-susceptible strains displayed high activities comparable to that of native thiostrepton. These Diels–Alder products were also subjected successfully to inverse-electron-demand Diels–Alder reactions with a variety of functionalized tetrazines, demonstrating the utility of this method for labeling of RiPPs. 相似文献
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Mechanistic Insights into the Radical S‐adenosyl‐l‐methionine Enzyme NosL From a Substrate Analogue and the Shunt Products
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Xinjian Ji Dr. Yongzhen Li Youli Jia Prof. Dr. Wei Ding Prof. Dr. Qi Zhang 《Angewandte Chemie (International ed. in English)》2016,55(10):3334-3337
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. 相似文献
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K. C. Nicolaou 《Angewandte Chemie (International ed. in English)》2012,51(50):12414-12436
Thiostrepton, a powerful antibiotic belonging to the thiopeptide class, was synthesized in the laboratory for the first time in 2004 through an arduous campaign involving novel strategies and tactics, scenic detours, and unexpected roadblocks. In this Review the author narrates the long journey to success, not so dissimilar to Odysseus’ return voyage to Ithaca, full of adventure, knowledge, and wisdom. 1 Inspired by the writing form of Mahaffy, 1 the author has taken liberties with the style in which this Review is written. 相似文献