دورية أكاديمية
Multiple Complexes of Long AliphaticN-Acyltransferases Lead to Synthesis of 2,6-Diacylated/2-Acyl-Substituted Glycopeptide Antibiotics, Effectively Killing Vancomycin-Resistant Enterococcus
| العنوان: | Multiple Complexes of Long AliphaticN-Acyltransferases Lead to Synthesis of 2,6-Diacylated/2-Acyl-Substituted Glycopeptide Antibiotics, Effectively Killing Vancomycin-Resistant Enterococcus |
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| المؤلفون: | Lyu, Syue-Yi, Liu, Yu-Chen, Chang, Chin-Yuan, Huang, Chuen-Jiuan, Chiu, Ya-Huang, Huang, Chun-Man, Hsu, Ning-Shian, Lin, Kuan-Hung, Wu, Chang-Jer, Tsai, Ming-Daw, Li, Tsung-Lin |
| سنة النشر: | 2014 |
| المجموعة: | National Chung Hsing University Institutional Repository - NCHUIR / 國立中興大學 |
| مصطلحات موضوعية: | Acylation, Acyltransferases, Anti-Bacterial Agents, Biocatalysis, Chemistry Techniques, Synthetic, Glycopeptides, Models, Molecular, Protein Structure, Tertiary, Structure-Activity Relationship, Vancomycin-Resistant Enterococci |
| الوصف: | Teicoplanin A2-2 (Tei)/A40926 is the last-line antibiotic to treat multidrug-resistant Gram-positive bacterial infections, e.g., methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). This class of antibiotics is powered by the N-acyltransferase (NAT) Orf11*/Dbv8 through N-acylation on glucosamine at the central residue of Tei/A40926 pseudoaglycone. The NAT enzyme possesses enormous value in untapped applications ; its advanced development is hampered largely due to a lack of structural information. In this report, we present eight high-resolution X-ray crystallographic unary, binary, and ternary complexes in order to decipher the molecular basis for NAT's functionality. The enzyme undergoes a multistage conformational change upon binding of acyl-CoA, thus allowing the uploading of Tei pseudoaglycone to enable the acyl-transfer reaction to take place in the occlusion between the N- and C-halves of the protein. The acyl moiety of acyl-CoA can be bulky or lengthy, allowing a large extent of diversity in new derivatives that can be formed upon its transfer. Vancomycin/synthetic acyl-N-acetyl cysteamine was not expected to be able to serve as a surrogate for an acyl acceptor/donor, respectively. Most strikingly, NAT can catalyze formation of 2-N,6-O-diacylated or C6→C2 acyl-substituted Tei analogues through an unusual 1,4-migration mechanism under stoichiometric/solvational reaction control, wherein selected representatives showed excellent biological activities, effectively counteracting major types (VanABC) of VRE. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0002-7863 1520-5126 |
| العلاقة: | #PLACEHOLDER_PARENT_METADATA_VALUE#; Journal of the American Chemical Society, Volume 136, Issue 31, Page(s) 10989-10995.; http://hdl.handle.net/11455/86614Test |
| DOI: | 10.1021/ja504125v |
| الإتاحة: | https://doi.org/10.1021/ja504125vTest http://hdl.handle.net/11455/86614Test |
| حقوق: | none |
| رقم الانضمام: | edsbas.C7807A52 |
| قاعدة البيانات: | BASE |
| تدمد: | 00027863 15205126 |
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| DOI: | 10.1021/ja504125v |