Enantioselective formation and ring-opening of epoxides catalysed by halohydrin dehalogenases

Janssen, Dick B.; Majerić-Elenkov, Maja; Hasnaoui, G.; Hauer, Bernhard; Spelberg, Jeffrey H. Lutje

doi:10.1042/bst0340291

Cited by 41 publications

(9 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, haloalcohol dehalogenases belong to the short chain dehydrogenase/reductase (SDR) superfamily of dinucleotide-binding redox enzymes. However, haloalcohol dehalogenases lack the dinucleotide binding motif, and structural analysis reveals that this domain has been substituted by bulky amino acid residue side chains that compose a halogen binding site. , In addition to dehalogenation, the epoxide cyanolysis and azidolysis side activity of the HDHs have been utilized to generate β-hydroxynitriles and azides in conjunction with site-directed enzyme engineering efforts. − …”

Section: Enzymatic Dehalogenationmentioning

confidence: 99%

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

et al. 2017

View full text Add to dashboard Cite

Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution. Biosynthetic halogenation reactions range from simple aromatic substitutions to stereoselective C-H functionalizations on remote carbon centers and can initiate the formation of simple to complex ring structures. Dehalogenating enzymes, on the other hand, are best known for removing halogen atoms from man-made organohalogens, yet also function naturally, albeit rarely, in metabolic pathways. This review details the scope and mechanism of nature’s halogenation and dehalogenation enzymatic strategies, highlights gaps in our understanding, and posits where new advances in the field might arise in the near future.

show abstract

Section: Enzymatic Dehalogenationmentioning

confidence: 99%

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The dehalogenation reaction is reversible, with the reverse step leading to epoxide-opening . Interestingly, in the epoxide-opening reaction, nucleophiles other than halides, such as NO 2 – , CN – , and N 3 – , are accepted by HheC – . With azide and cyanide, HheC-mediated transformation of epoxides results in the irreversible formation of β-azidoalcohols and β-hydroxynitriles, respectively , .…”

mentioning

confidence: 99%

Cyanolysis and Azidolysis of Epoxides by Haloalcohol Dehalogenase: Theoretical Study of the Reaction Mechanism and Origins of Regioselectivity

Hopmann

Himo

2008

Biochemistry

View full text Add to dashboard Cite

Haloalcohol dehalogenase HheC catalyzes the reversible dehalogenation of vicinal haloalcohols to form epoxides and free halides. In addition, HheC is able to catalyze the irreversible and highly regioselective ring-opening of epoxides with nonhalide nucleophiles, such as CN (-) and N 3 (-). For azidolysis of aromatic epoxides, the regioselectivity observed with HheC is opposite to the regioselectivity of the nonenzymatic epoxide-opening. This, together with a relatively broad substrate specificity, makes HheC a promising tool for biocatalytic applications. We have designed large quantum chemical models of the HheC active site and used density functional theory to study the reaction mechanism of the HheC-catalyzed ring-opening of ( R)-styrene oxide with the nucleophiles CN (-) and N 3 (-). Both the cyanolysis and the azidolysis reactions are shown to take place in a single concerted step. The results support the suggested role of the putative Ser132-Tyr145-Arg149 catalytic triad, where Tyr145 acts as a general acid, donating a proton to the substrate, and Arg149 interacts with Tyr145 and facilitates proton abstraction, while Ser132 positions the substrate and reduces the barrier for epoxide opening through interaction with the emerging oxyanion of the substrate. We have also studied the regioselectivity of ( R)-styrene oxide opening for both the cyanolysis and the azidolysis reactions. The employed active site model was shown to be able to reproduce the experimentally observed beta-regioselectivity of HheC. In silico mutations of various groups in the HheC active site model were performed to elucidate the important factors governing the regioselectivity.

show abstract

“…Overall, the poor organic solvent tolerance of the used HHDHs, HheE and HheE5, turned out to be a main limiting factor regarding product yield in both cascades, but also enantioselectivity in cascade 1. In the future, this could be addressed by enzyme engineering as previously shown for HheC, for which a mutant with high residual activity in 50% (v/v) acetonitrile could be generated [50]. Such a solvent-tolerant HHDH would enable to run the Shi epoxidation reaction at optimal acetonitrile concentration to improve epoxide ee P % and conversion.…”

Section: Chemicalsmentioning

confidence: 99%

Two (Chemo)-Enzymatic Cascades for the Production of Opposite Enantiomers of Chiral Azidoalcohols

Calderini

Süss²,

Hollmann

et al. 2021

Catalysts

View full text Add to dashboard Cite

Multi-step cascade reactions have gained increasing attention in the biocatalysis field in recent years. In particular, multi-enzymatic cascades can achieve high molecular complexity without workup of reaction intermediates thanks to the enzymes’ intrinsic selectivity; and where enzymes fall short, organo- or metal catalysts can further expand the range of possible synthetic routes. Here, we present two enantiocomplementary (chemo)-enzymatic cascades composed of either a styrene monooxygenase (StyAB) or the Shi epoxidation catalyst for enantioselective alkene epoxidation in the first step, coupled with a halohydrin dehalogenase (HHDH)-catalysed regioselective epoxide ring opening in the second step for the synthesis of chiral aliphatic non-terminal azidoalcohols. Through the controlled formation of two new stereocenters, corresponding azidoalcohol products could be obtained with high regioselectivity and excellent enantioselectivity (99% ee) in the StyAB-HHDH cascade, while product enantiomeric excesses in the Shi-HHDH cascade ranged between 56 and 61%.

show abstract

Enantioselective formation and ring-opening of epoxides catalysed by halohydrin dehalogenases

Cited by 41 publications

References 19 publications

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

Cyanolysis and Azidolysis of Epoxides by Haloalcohol Dehalogenase: Theoretical Study of the Reaction Mechanism and Origins of Regioselectivity

Two (Chemo)-Enzymatic Cascades for the Production of Opposite Enantiomers of Chiral Azidoalcohols

Contact Info

Product

Resources

About