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Dr. Jesko Koehnke Andrew F. Bent David Zollman Kieran Smith Dr. Wael E. Houssen Dr. Xiaofeng Zhu Greg Mann Dr. Tomas Lebl Richard Scharff Dr. Sally Shirran Dr. Catherine H. Botting Prof. Marcel Jaspars Dr. Ulrich Schwarz‐Linek Prof. James H. Naismith 《Angewandte Chemie (International ed. in English)》2013,52(52):13991-13996
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The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides 下载免费PDF全文
Mark Petchey Anibal Cuetos Benjamin Rowlinson Stephanie Dannevald Amina Frese Peter W. Sutton Sarah Lovelock Richard C. Lloyd Ian J. S. Fairlamb Gideon Grogan 《Angewandte Chemie (International ed. in English)》2018,57(36):11584-11588
Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides. 相似文献
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Dr. Hajo Kries Rudolf Wachtel Anja Pabst Benedikt Wanner David Niquille Prof. Dr. Donald Hilvert 《Angewandte Chemie (International ed. in English)》2014,53(38):10105-10108
Nonribosomal peptide synthetases (NRPSs) are multifunctional enzymes that produce a wide array of bioactive peptides. Here we show that a single tryptophan‐to‐serine mutation in phenylalanine‐specific NRPS adenylation domains enables the efficient activation of non‐natural aromatic amino acids functionalized with azide and alkyne groups. The resulting 105‐fold switch in substrate specificity was achieved without appreciable loss of catalytic efficiency. Moreover, the effective communication of the modified A domains with downstream modules in dipeptide synthetases permitted incorporation of O‐propargyl‐L ‐tyrosine into diketopiperazines both in vitro and in vivo, even in the presence of competing phenylalanine. Because azides and alkynes readily undergo bioorthogonal click reactions, reprogramming NRPSs to accept non‐natural amino acids that contain these groups provides a potentially powerful means of isolating, labeling, and modifying biologically active peptides. 相似文献
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Structural Elucidation of the Bispecificity of A Domains as a Basis for Activating Non‐natural Amino Acids 下载免费PDF全文
Heidi Kaljunen Stephan H. H. Schiefelbein Dr. Daniela Stummer Sandra Kozak Dr. Rob Meijers Dr. Guntram Christiansen Prof. Dr. Andrea Rentmeister 《Angewandte Chemie (International ed. in English)》2015,54(30):8833-8836
Many biologically active peptide secondary metabolites of bacteria are produced by modular enzyme complexes, the non‐ribosomal peptide synthetases. Substrate selection occurs through an adenylation (A) domain, which activates the cognate amino acid with high fidelity. The recently discovered A domain of an Anabaenopeptin synthetase from Planktothrix agardhii (ApnA A1) is capable of activating two chemically distinct amino acids (Arg and Tyr). Crystal structures of the A domain reveal how both substrates fit into to binding pocket of the enzyme. Analysis of the binding pocket led to the identification of three residues that are critical for substrate recognition. Systematic mutagenesis of these residues created A domains that were monospecific, or changed the substrate specificity to tryptophan. The non‐natural amino acid 4‐azidophenylalanine is also efficiently activated by a mutant A domain, thus enabling the production of diversified non‐ribosomal peptides for bioorthogonal labeling. 相似文献
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Thirlway J Lewis R Nunns L Al Nakeeb M Styles M Struck AW Smith CP Micklefield J 《Angewandte Chemie (International ed. in English)》2012,51(29):7181-7184
Calcium-dependent antibiotics (CDA) are cyclic lipopeptides assembled by nonribosomal peptide synthetase (NRPS) enzymes. Active site modification of the 3-methyl glutamate activating adenylation (A) domain of the CDA NRPS enables the incorporation of synthetic 3-methyl glutamine into CDA. This provides the first example of how A-domains can be engineered to introduce synthetic "non-natural" amino acids into nonribosomal peptides. 相似文献
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