Nocardicin D
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| Category | Antibiotics |
| Catalog number | BBF-03692 |
| CAS | 61425-17-0 |
| Molecular Weight | 485.44 |
| Molecular Formula | C23H23N3O9 |
| Purity | 95% |
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Description
It is a β-lactam antibiotic originally isolated from Nocardia uniformis subsp. tsuyamanensis. It has similar antibacterial activity to FR-29038.
Specification
| Synonyms | Antibiotic FR 29055; BRN 3578368; FR-29055 |
| IUPAC Name | (2R)-2-amino-4-[4-[2-[[(3S)-1-[(R)-carboxy-(4-hydroxyphenyl)methyl]-2-oxoazetidin-3-yl]amino]-2-oxoacetyl]phenoxy]butanoic acid |
| Canonical SMILES | C1C(C(=O)N1C(C2=CC=C(C=C2)O)C(=O)O)NC(=O)C(=O)C3=CC=C(C=C3)OCCC(C(=O)O)N |
| InChI | InChI=1S/C23H23N3O9/c24-16(22(31)32)9-10-35-15-7-3-13(4-8-15)19(28)20(29)25-17-11-26(21(17)30)18(23(33)34)12-1-5-14(27)6-2-12/h1-8,16-18,27H,9-11,24H2,(H,25,29)(H,31,32)(H,33,34)/t16-,17+,18-/m1/s1 |
| InChI Key | QJZHIGKJGFPGRN-FGTMMUONSA-N |
Properties
| Appearance | Colorless Crystalline |
| Application | A β-lactam antibiotic. |
| Antibiotic Activity Spectrum | Gram-positive bacteria; Gram-negative bacteria |
| Density | 1.6±0.1 g/cm3 |
Reference Reading
1. Acyl Donor Stringency and Dehydroaminoacyl Intermediates in β-Lactam Formation by a Non-ribosomal Peptide Synthetase
Darcie H Long, Craig A Townsend ACS Chem Biol. 2021 May 21;16(5):806-812. doi: 10.1021/acschembio.1c00117. Epub 2021 Apr 13.
Condensation (C) domains in non-ribosomal peptide synthetases catalyze peptide elongation steps whereby activated amino acid or peptidyl acyl donors are coupled with specific amino acid acceptors. In the biosynthesis of the β-lactam antibiotic nocardicin A, an unusual C domain converts a seryl tetrapeptide into its pentapeptide product containing an integrated β-lactam ring. While indirect evidence for the intermediacy of a dehydroalanyl species has been reported, here we describe observation of the elusive enzyme-bound dehydroamino acyl intermediate generated from the corresponding allo-threonyl tetrapeptide and partitioned into pentapeptide products containing either a dehydrobutyrine residue or an embedded β-lactam. Contrary to trends in the literature where condensation domains have been deemed flexible as to acyl donor structure, this β-lactam synthesizing domain is highly discriminating. The observation of dehydrobutyrine formation links this C domain to related clades associated with natural products containing dehydroamino acid and d-configured residues, suggesting a common mechanistic link.
2. Exploring the Molecular Basis of Substrate and Product Selectivities of Nocardicin Bifunctional Thioesterase
Qian Yu, Lefan Xie, Yilu Li, Linquan Bai, Yi-Lei Zhao, Dongqing Wei, Ting Shi Interdiscip Sci. 2022 Mar;14(1):233-244. doi: 10.1007/s12539-021-00482-z. Epub 2021 Oct 26.
D-amino acid introduction in peptides can enrich their biological activities and pharmacological properties as potential drugs. This achievement of stereochemical inversion usually owes to an epimerase or racemase. Interestingly, a unique bifunctional thioesterase (NocTE), which is incorporated in nonribosomal peptide synthetase (NRPS) NocA-NocB assembly line for the biosynthesis of monocyclic β-lactam antibiotic nocardicin A, can control the generation of D-products with high stereochemical purity. However, the molecular basis of NocTE selectivity on substrates and products is still unclear. Herein, we constructed a series of systems with different peptides varying in stereochemistry, length, and composition to investigate the substrate selectivity. The studies on binding affinities and loading conformations elucidated the important roles of peptide length and β-lactam ring in substrate selectivity. Through energy decomposition and interaction analyses, some key residues involved in substrate selectivity were captured. On the other hand, natural product undergoing epimerization was found to be liberated from the active pocket more easily in comparison with its diastereomer (epi-nocardicin G), explaining the superiority of nocardicin G. These results provide detailed molecular insights into the exquisite control of substrate and product scopes for NocTE, and encourage to diversification of substrates and final products for NRPS assembly line. The molecular insights into substrate and product selectivities of unique bifunctional thioesterase NocTE were illustrated via several molecular simulations and free energy calculations, contributing to expanding substrate and product scopes of nonribosomal peptide synthetases.
3. Insight into substrate-assisted catalytic mechanism and stereoselectivity of bifunctional nocardicin thioesterase
Qian Yu, Wei Lu, Daixi Li, Ting Shi Proteins. 2022 Dec;90(12):2035-2044. doi: 10.1002/prot.26395. Epub 2022 Jul 18.
The inversion from L- to D-stereochemistry endows peptides improved bioactivity and enhanced resistance to many proteases and peptidases. To strengthen the biostability and bioavailability of peptide drugs, enzymatic epimerization becomes an important way to incorporate D-amino acid into peptide backbones. Recently, a bifunctional thioesterase NocTE, which is responsible for the epimerization and hydrolysis of the C-terminal (p-hydroxyphenyl)glycine residue of β-lactam antibiotic nocardicin A, exclusively directs to the generation of D-diastereomers. Different from other epimerases, NocTE exhibits unique stereochemical selectivity. Herein, we investigated the catalytic mechanism of NocTE via molecular dynamic (MD) simulations and quantum mechanical/molecular mechanics (QM/MM) calculations. Through structural analyses, two key water molecules around the reaction site were found to serve as proton mediators in epimerization. The structural characteristics inspired us to propose a substrate-assisted mechanism for the epimerization, where multi-step proton transfers were mediated by water molecules and β-lactam ring, and the free energy barrier was calculated to be 20.3 kcal/mol. After that, the hydrolysis of D-configured substrate was energetically feasible with the energy barrier of 14.3 kcal/mol. As a comparison, the energy barrier for the direct hydrolysis of L-configured substrate was obtained to be 24.0 kcal/mol. Our study provides mechanistic insights into catalytic activities of bifunctional thioesterase NocTE, uncovers more clues to the molecular basis for stereochemical selectivity and paves the way for the directed biosynthesis of novel peptide drugs with various stereostructural characteristics by enzyme rational design.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
