Ab initio and density functional theory studies of the catalytic mechanism for ester hydrolysis in serine hydrolases

Hu, Ching‐Han; Brinck, Tore; Hult, Karl

doi:10.1002/(sici)1097-461x(1998)69:1<89::aid-qua11>3.0.co;2-0

Cited by 56 publications

(46 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Quantum-chemical methods [18,19] have identified the first tetrahedral substrate-lipase complex and the distance d(H Nε -O alc ) as critical parameter of catalytic activity. Since differences of lipase activity [20,21] toward two enantiomers and diastereomers results in experimentally observable enantioselectivity (…”

Section: å)mentioning

confidence: 99%

Structural basis of stereoselectivity in Candida rugosa lipase-catalyzed hydrolysis of secondary alcohols

Schulz¹,

Schmid²,

Pleiss³

2001

J Mol Model

View full text Add to dashboard Cite

Lipases are widely applied catalysts for highly enantioselective resolution of chiral secondary alcohols. While stereopreference is determined predominantly by the substrate structure, stereoselectivity (enantioselectivity and diastereoselectivity) depends on atomic details of interactions between substrate and lipase. Experimentally (≤ 1.8 Å) for RR stereo isomers, which were also experimentally found to be hydrolyzed most rapidly; distances d(H Nε -O alc ) were about 2 Å for SS and SR stereo isomers, which were converted at similar rates but at lower rate than RR stereo isomers; finally, distances d(H Nε -O alc ) for SR stereo isomers were greater than 4 Å, in accordance with very slow conversion of SR stereo isomers.

show abstract

Section: å)mentioning

confidence: 99%

Structural basis of stereoselectivity in Candida rugosa lipase-catalyzed hydrolysis of secondary alcohols

Schulz¹,

Schmid²,

Pleiss³

2001

J Mol Model

View full text Add to dashboard Cite

show abstract

“…The difference in activation energy for the enantiomers can therefore be approximated to the energy difference between the corresponding two tetrahedral intermediates since the ground-state free energy of the two enantiomers is the same. [7] OR Large Medium R = H, Ac Figure 1. The preferred enantiomer in a lipase catalyzed transesterification or hydrolysis involving sec-alcohols and sec-acetate can be predicted by Kazlauskas´ rule.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Impact of Water on the Enantioselectivity Displayed by CALB in the Kinetic Resolution of δ‐Functionalized Alkan‐2‐ol Derivatives

Yang

Lihammar

Bäckvall

2014

Chemistry A European J

View full text Add to dashboard Cite

It is shown that the low enantioselectivity of Candida antarctica lipase B (CALB)‐catalyzed transesterification of a δ‐functionalized alkan‐2‐ol to its acetate does not correlate at all with the high enantioselectivity of the CALB‐catalyzed hydrolysis of the corresponding acetate in water. This lack of correlation is unusual and for unfunctionalized alkan‐2‐ol derivatives there is a very good correlation between the enantioselectivity of transesterification of the alcohol and hydrolysis of the corresponding acetate (E>200 in both cases). The results confirm previous predictions from molecular modeling. The water effect was mimicked by CALB variant Ala281Ser, which showed an enhanced enantioselectivity in transesterification of δ‐functionalized alkan‐2‐ols compared to wild‐type CALB.

show abstract

“…This difference could cause a difference in hydrogen bonding, electrostatic, and van der Waals interactions during the catalytic process, and result in a significant difference in free energies of activation. Nevertheless, the basic BChE mechanism for both enantiomers may resemble the common catalytic mechanism for ester hydrolysis in other serine hydrolases [32,39], including the thoroughly investigated AChE [40,41,42,43,44].…”

Section: Fundamental Reaction Pathway For Bche-catalyzed Hydrolysis Omentioning

confidence: 99%

Rational design of an enzyme mutant for anti-cocaine therapeutics

Zheng

Chen

2007

J Comput Aided Mol Des

View full text Add to dashboard Cite

Summary(−)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (−)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the stateof-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (−)-cocaine. The computational design of BChE mutants has been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (−)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design highactivity mutants of human BChE for hydrolysis of (−)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (−)-cocaine. One of the discovered BChE mutants (i.e. A199S/S287G/A328W/Y332G) has a ~456-fold improved catalytic efficiency against (−)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.

show abstract

Ab initio and density functional theory studies of the catalytic mechanism for ester hydrolysis in serine hydrolases

Cited by 56 publications

References 39 publications

Structural basis of stereoselectivity in Candida rugosa lipase-catalyzed hydrolysis of secondary alcohols

Structural basis of stereoselectivity in Candida rugosa lipase-catalyzed hydrolysis of secondary alcohols

Investigation of the Impact of Water on the Enantioselectivity Displayed by CALB in the Kinetic Resolution of δ‐Functionalized Alkan‐2‐ol Derivatives

Rational design of an enzyme mutant for anti-cocaine therapeutics

Contact Info

Product

Resources

About