Efficient preparation of the chiral intermediate of luliconazole with Lactobacillus kefir alcohol dehydrogenase through rational rearrangement of the substrate binding pocket

Zheng, Chenni; Wang, Zhiguo; Wang, Qian; Wang, Shenyong; Lao, Shuhua; He, Jin; Chen, Zhenming

doi:10.1016/j.mcat.2021.111639

Cited by 4 publications

(5 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The synthesis of luliconazole, an antifungal medication, requires ( S )-2-chloro-1-(2,4-dichlorophenyl)ethanol (( S )-TCPE) as a chiral intermediate. 123 Asymmetric reduction of 2,2′,4′-trichloroacetophenone (TCAP, 61 ) to ( S )-TCPE ( 62 ) by the wild type Lactobacillus kefir ketoreductase ( Lk KRED) was highly enantioselective (ee >99%) but displayed poor catalytic activity (Table 1, entry 12). As per the predictions from docking and molecular dynamic simulations on the Lk KRED-TCAP complex, site directed mutagenesis was carried out at A94, then on E145, and finally the best double mutant was used for mutation at S96.…”

Section: Protein Engineering Of Carbonyl Reductasesmentioning

confidence: 99%

Microbial alcohol dehydrogenases: recent developments and applications in asymmetric synthesis

Chadha,

Padhi,

Stella

et al. 2024

Org. Biomol. Chem.

View full text Add to dashboard Cite

show abstract

Section: Protein Engineering Of Carbonyl Reductasesmentioning

confidence: 99%

Microbial alcohol dehydrogenases: recent developments and applications in asymmetric synthesis

Chadha,

Padhi,

Stella

et al. 2024

Org. Biomol. Chem.

View full text Add to dashboard Cite

show abstract

“…Catalytic activity improvement. Recently, Zheng and coworkers reported engineering the ADH from Lactobacillus kefir (LkADH) for improved activity for the synthesis of (S)-2chloro-1-(2,4-dichlorophenyl) ethanol [(S)-TCPE] from the corresponding ketone starting material (Zheng et al, 2021). wt-LkADH showed high enantioselectivity but rather poor catalytic activity.…”

Section: Protein Engineeringmentioning

confidence: 99%

“…Several aryl, benzyl and alkyl chlorohydrins (Hanson et al, 2005;Poessl et al, 2005;Berkessel et al, 2007;Schrittwieser et al, 2009a;Schrittwieser et al, 2009b;Zheng et al, 2021), and, to a lesser extent, bromo- (Mangas-Sánchez et al, 2011) and fluorohydrins (Borzecka et al, 2013) have been synthesised on (semi-)preparative scale.…”

Section: Adh-catalysed Reduction Reactionsmentioning

confidence: 99%

“…The large repertoire of halohydrins derived from ADHcatalysed reduction of the corresponding ketones (Figure 12) also includes propargylic chlorohydrins (Schubert et al, 2002) and compounds bearing functional groups such as esters (Yang et al, 2020), amino-protected groups (Patel, 2001;de Miranda et al, 2015) and heteroaryl moieties (Borzecka et al, 2013). Importantly, some relevant chlorohydrins have been produced by ADH in practical scale, such as the enantiopure ethyl (S)-chloroacetoacetate (Yang et al, 2020), a chiral synthetic intermediate of the "blockbuster" drug atorvastatin, and (S)-2chloro-1-(2,4-dichlorophenyl) ethanol (Zheng et al, 2021), an intermediate of the antifungal agent luliconazole.…”

Section: Adh-catalysed Reduction Reactionsmentioning

confidence: 99%

See 1 more Smart Citation

Alcohol Dehydrogenases as Catalysts in Organic Synthesis

2022

View full text Add to dashboard Cite

Alcohol dehydrogenases (ADHs) have become important catalysts for stereoselective oxidation and reduction reactions of alcohols, aldehydes and ketones. The aim of this contribution is to provide the reader with a timely update on the state-of-the-art of ADH-catalysis. Mechanistic basics are presented together with practical information about the use of ADHs. Current concepts of ADH engineering and ADH reactions are critically discussed. Finally, this contribution highlights some prominent examples and future-pointing concepts.

show abstract

“…These processes often involve harsh reaction conditions, complex protection and deprotection steps, and substantial environmental pollution. Biocatalysts, on the contrary, eliminate the need for functional group protection and deprotection and reduce the reliance on precious metal catalysts and can be used under mild conditions. − The utilization of biocatalysts in the synthesis of chiral alcohols has the potential to significantly mitigate the environmental impact of chemical synthesis and promote the advancement of sustainable chemistry.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Analysis of Selectivity Differences in Ketoreductases toward Aldehyde and Ketone Carbonyl Groups

Lin,

Xing,

et al. 2024

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Lactobacillus kef ir alcohol dehydrogenase (LkADH) and ketoreductase from Chryseobacterium sp. CA49 (ChKRED12) exhibit different chemoselectivity and stereoselectivity toward a substrate with both keto and aldehyde carbonyl groups. LkADH selectively reduces the keto carbonyl group while retaining the aldehyde carbonyl group, producing optically pure R-alcohols. In contrast, ChKRED12 selectively reduces the aldehyde group and exhibits low reactivity toward ketone carbonyls. This study investigated the structural basis for these differences and the role of specific residues in the active site. Molecular dynamics (MD) simulations and quantum chemical calculations were used to investigate the interactions between the substrate and the enzymes and the essential cause of this phenomenon. The present study has revealed that LkADH and ChKRED12 exhibit significant differences in the structure of their respective active pockets, which is a crucial determinant of their distinct chemoselectivity toward the same substrate. Moreover, residues N89, N113, and E144 within LkADH as well as Q151 and D190 within ChKRED12 have been identified as key contributors to substrate stabilization within the active pocket through electrostatic interactions and van der Waals forces, followed by hydride transfer utilizing the coenzyme NADPH. Furthermore, the enantioselectivity mechanism of LkADH has been elucidated using quantum chemical methods. Overall, these findings not only provide fundamental insights into the underlying reasons for the observed differences in selectivity but also offer a detailed mechanistic understanding of the catalytic reaction.

show abstract

Efficient preparation of the chiral intermediate of luliconazole with Lactobacillus kefir alcohol dehydrogenase through rational rearrangement of the substrate binding pocket

Cited by 4 publications

References 35 publications

Microbial alcohol dehydrogenases: recent developments and applications in asymmetric synthesis

Microbial alcohol dehydrogenases: recent developments and applications in asymmetric synthesis

Alcohol Dehydrogenases as Catalysts in Organic Synthesis

Theoretical Analysis of Selectivity Differences in Ketoreductases toward Aldehyde and Ketone Carbonyl Groups

Contact Info

Product

Resources

About