6254-48-4Relevant articles and documents
Total Synthesis and Antimycobacterial Activity of Ohmyungsamycin A, Deoxyecumicin, and Ecumicin
Hawkins, Paige M. E.,Tran, Wendy,Nagalingam, Gayathri,Cheung, Chen-Yi,Giltrap, Andrew M.,Cook, Gregory M.,Britton, Warwick J.,Payne, Richard J.
supporting information, p. 15200 - 15205 (2020/10/23)
The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid-phase strategy to assemble the linear peptide precursor, involving a key on-resin esterification and an optional on-resin dimethylation step, before a final solution-phase macrolactamization between the non-proteinogenic N-methyl-4-methoxy-l-tryptophan amino acid and a bulky N-methyl-l-valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC90’s ranging from 110–360 nm and retained activity against Mtb in Mtb-infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing against Mtb, sterilizing cultures after 21 days.
Improving and Inverting Cβ-Stereoselectivity of Threonine Aldolase via Substrate-Binding-Guided Mutagenesis and a Stepwise Visual Screening
Chen, Qijia,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming,Ma, Yanhe
, p. 4462 - 4469 (2019/05/10)
Threonine aldolase (TA)-catalyzed aldol condensation is a powerful tool for C-C bond formation under mild conditions, but the low Cβ-stereoselectivity has hampered its wide application. A stepwise visual screening method was developed to measure the activity and stereoselectivity of threonine aldolase-catalyzed aldol condensation by employing a stereoselective phenylserine dehydratase, enabling direct selection of mutants with higher Cβ-stereoselectivity. Mutants of l-PsTA from Pseudomonas sp. with improved or inverted stereoselectivity toward aromatic aldehydes were obtained by simultaneously mutating amino acid residues which interact with the amino and hydroxyl groups of the substrate and screening the resulting mutant libraries with this method. The mutation and enzyme-substrate docking studies provided some insights into the regulation of the Cβ-stereoselectivity by the enzyme-substrate interactions. This study offers a tool and useful guidance for further engineering of TAs to address the Cβ-stereoselectivity problem.
Characteristics of l-threonine transaldolase for asymmetric synthesis of β-hydroxy-α-amino acids
Xu, Lian,Wang, Li-Chao,Xu, Xin-Qi,Lin, Juan
, p. 5943 - 5952 (2019/11/14)
l-Threonine transaldolase (LTTA) is a putative serine hydroxymethyltransferase (SHMT) that can catalyze the trans-aldehyde reaction of l-threonine and aldehyde to produce l-threo-β-hydroxy-α-amino acids with excellent stereoselectivity. In the present study, an l-threonine transaldolase from Pseudomonas sp. (PsLTTA) was mined and expressed in Escherichia coli BL21 (DE3). A substrate spectrum assay indicated that PsLTTA only consumed l-threonine as the donor substrate and could accept a wide range of aromatic aldehydes as acceptor substrates. Among these substrates, PsLTTA could catalyze p-methylsulfonyl benzaldehyde and l-threonine to produce l-threo-p-methylsulfonylphenylserine with a high conversion rate (74.4%) and a high de value (79.9%). The conversion and stereoselectivity of PsLTTA were found to be dramatically influenced by the concentration of the whole cell, the co-solvent and the reaction temperature. Through conditional optimization, l-threo-p-methylsulfonylphenylserine was obtained with 67.1% conversion and a near-perfect de value (94.5%), the highest stereoselectivity for an l-threo-β-hydroxy-α-amino acid so far reported by enzymatic synthesis. Finally, synthesis of l-threo-p-methylsulfonylphenylserine at a 100 mL scale by whole-cell biocatalysis was conducted. This is the first systematic report of l-threonine transaldolase as a robust biocatalyst for preparation of β-hydroxy-α-amino acids, which can provide new insights for β-hydroxy-α-amino acids synthesis.
