The modelling and kinetic investigation of the lipase-catalysed acetylation of stereoisomeric prostaglandins

Vallikivi, Imre; Fransson, Linda; Hult, Karl; Järving, Ivar; Pehk, Tõnis; Samel, Nigulas; Tõugu, Vello; Villo, Ly; Parve, Omar

doi:10.1016/j.molcatb.2005.05.008

Cited by 14 publications

(7 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, it may be that the terminal [ R ]−[ R ] configuration of d -mannitol is a key factor that led to rapid formation of d -mannitol polyol−polyesters of high M w . This agrees with studies by Hult and co-workers on the selective for [ R ]-alcohols in CALB-catalyzed transesterification reactions. , …”

supporting

confidence: 92%

“…These 6-carbon alditols have 2, 3, and 4 [ R ]-secondary hydroxyl groups, respectively. Previous studies showed that CALB more rapidly acylates [ R ]-secondary hydroxyl groups. , Assuming reactivity at primary hydroxyl groups remains high, increased reactivity at [ R ]-secondary hydroxyl groups will lead to branching. Therefore, larger molecular weight chains formed by d -mannitol may be due to high reactivity at [ R ]-primary hydroxyl groups in addition to reactivity at [ R ]-secondary hydroxyl groups leading to higher molecular weight chains through branching.…”

mentioning

confidence: 99%

See 1 more Smart Citation

“Sweet Polyesters”: Lipase-Catalyzed Condensation−Polymerizations of Alditols

Hu¹,

Gao²,

Kulshrestha³

et al. 2006

Macromolecules

View full text Add to dashboard Cite

Alditol polyols are readily renewable, inexpensive, and harmless to the environment. By incorporation of polyols into aliphatic polyesters, functional linear or hyperbranched polymers can be prepared with specific biological activities and/or that respond to environmental stimuli. 1 Polyesters with carbohydrate or polyol repeat units in chains have been prepared by chemical methods. 2a-d,4a-c,8 In some cases, the reaction conditions led to hyperbranched polymers (HBPs). 4a-c,8 The highly branched architecture of HBPs leads to unusual mechanical, rheological and compatibility properties. [4][5][6][7][8] These distinguishing characteristics have garnered interest for their use in numerous industrial and biomedical fields. 8 Chemical routes to linear polyol-polyesters require elaborate protection-deprotection steps. 2a-d Furthermore, condensation routes to hyperbranched polymers generally require harsh reaction conditions such as temperatures above 150 °C and highly acidic catalysts. 4a-c,8 Single-step chemical routes to HBPs from multifunctional monomers, without protection-deprotection chemistry, leads to randomly branched polymer topologies. To achieve perfectly branched polymers researchers have used stepwise synthetic methods to prepare dendrimers. A need exists for new, simple synthetic methods that do not rely on protection-deprotection methods to prepare both functional linear polymers and polymers with improved control over branching. A promising approach to address these challenges is the use of isolated enzymes as catalysts for polymerization reactions. Lipases are already wellestablished catalysts for regioselective esterification of low molar mass substrates at mild temperatures (30-70 °C). 12 Early work assumed that activation of carboxylic acids by electron withdrawing groups was needed to perform enzyme-catalyzed copolymerizations of polyols. 13a-j Furthermore, since polyols (e.g., glucitol) are generally insoluble in nonpolar organic media, polar solvents were used. 13f-j Unfortunately, these solvents cause large reductions in enzyme activity. 13f-j Recently, our laboratory reported copolymerizations without activation of the diacid or adding solvent. 14a,b The monomers were combined so they formed monophasic mixtures, Candida antarctica Lipase B (CALB), physically immobilized on Lewatit beads (N435), was then added. For example, a hyperbranched copolyester with 18 mol % glycerol-adipate units was formed in 90% yield, with M w ) 75 600 (by SEC-MALLS), M w /M n ) 3.1, and 27 mol % of glycerol units that are branch sites. 14a Also, N435 catalyzed the polymerization of D-glucitol and adipic acid, in-bulk, with high regioselectivity (85 ( 5%) at the primary hydroxyl groups, to give a water-soluble product with M n ) 10 880 and M w /M n ) 1.6. Time-course studies of glycerol copolymerizations showed that, while the reaction is under kinetic control, linear chains (determined by NMR) were formed. Hence, the product formed at 18 h was linear. However, by extending the reaction to 42 h, pendant hydro...

show abstract

supporting

confidence: 92%

mentioning

confidence: 99%

“Sweet Polyesters”: Lipase-Catalyzed Condensation−Polymerizations of Alditols

Hu¹,

Gao²,

Kulshrestha³

et al. 2006

Macromolecules

View full text Add to dashboard Cite

show abstract

“…A structure is considered productive if the observed binding mode can lead to product formation. Two parameters, protein distortion and essential hydrogen bonds in the active site vicinity, were used as criteria for productivity. ,,− The former is estimated from the overall RMSD value as depicted in the work of Vallikivi et al for the noncovalent complexes between AcCalB and prostaglandins. The latter concerns the hydrogen bonds between (i) the carbonyl oxygen of the acyl group of the acylated catalytic serine (oxyanion, SEA:O) and the oxyanion hole, (ii) the protonated His224 and the reactive oxygen atoms (the SEA:Oγ atom and the alcohol oxygen of propranolol (Sub: O) ), and (iii) the residues Asp187 and His224 (see Figure ).…”

Section: Resultsmentioning

confidence: 99%

Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B

et al. 2016

View full text Add to dashboard Cite

Classical molecular dynamics (MD) simulations and combined quantum mechanics/molecular mechanics (QM/MM) calculations were used to investigate the origin of the enantioselectivity of the Candida antarctica lipase B (CalB) catalyzed O-acetylation of (R,S)-propranolol. The reaction is a two-step process. The initial step is the formation of a reactive acyl enzyme (AcCalB) via a tetrahedral intermediate (TI-1). The stereoselectivity originates from the second step, when AcCalB reacts with the racemic substrate via a second tetrahedral intermediate (TI-2). Reaction barriers for the conversion of (R)- and (S)-propranolol to O-acetylpropranolol were computed for several distinct conformations of TI-2. In QM/MM geometry optimizations and reaction path calculations the QM region was described by density functional theory (B3LYP/TZVP) and the MM region by the CHARMM force field. The QM/MM calculations show that the formation of TI-2 is the rate-determining step. The energy barrier for transformation of (R)-propranolol to O-acetylpropranolol is 4.5 kcal/mol lower than that of the reaction of (S)-propranolol. Enzyme–substrate interactions were identified that play an important role in the enantioselectivity of the reaction. Our QM/MM calculations reproduce and rationalize the experimentally observed enantioselectivity in favor of (R)-propranolol. Furthermore, in contrast to what is commonly suggested for lipase-catalyzed reactions, our results indicate that the tetrahedral intermediate is not a good approximation of the corresponding transition states

show abstract

“…type has been investigated by using this approach. [35] Characteristics allowing to prognosticate regioselectivity quite precisely are: 1) root mean square deviation (RMSD) of the enzyme geometry along the MD simulation trajectory and 2) energy of the function-based subset of the tetrahedral intermediate. [36] However, the above mentioned strategy cannot be used for modeling of lipase-catalyzed reactions occurring according to a mechanism devoid of the covalent bonding of the substrate to the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Thermomyces lanuginosus Lipase with Closed Lid Catalyzes Elimination of Acetic Acid from 11‐Acetyl‐Prostaglandin E₂

et al. 2014

Self Cite

View full text Add to dashboard Cite

A lipase may catalyze either one or more of the three reactions of 11‐acetyl‐prostaglandin E2 in methanol‐containing reaction medium: esterification, deacetylation, and/or elimination. The catalytic performance depends on the lipase and on the methanol content. An increase in the methanol concentration in benzene from 5 % to 95 % leads to the exclusive switch of reactions from esterification to elimination catalyzed by Thermomyces lanuginosus lipase (TLL). To explain the switch, molecular dynamics simulations of solvation of TLL in benzene and in methanol were performed. Solvation in methanol leads to the closing of the lid. The repositioning of the oxyanion hole towards the catalytic triad blocks the catalysis of ester synthesis whereas enabling TLL to act as an acetyl‐β‐ketol eliminase. In benzene the lid is open, allowing esterification to occur. Docking analysis of 11‐acetyl‐prostaglandin E2 into the active site of the solvated TLL structures suggested the occurrence of reactions in accordance with the experiment.

show abstract

The modelling and kinetic investigation of the lipase-catalysed acetylation of stereoisomeric prostaglandins

Cited by 14 publications

References 26 publications

“Sweet Polyesters”: Lipase-Catalyzed Condensation−Polymerizations of Alditols

“Sweet Polyesters”: Lipase-Catalyzed Condensation−Polymerizations of Alditols

Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B

Thermomyces lanuginosus Lipase with Closed Lid Catalyzes Elimination of Acetic Acid from 11‐Acetyl‐Prostaglandin E₂

Contact Info

Product

Resources

About

The modelling and kinetic investigation of the lipase-catalysed acetylation of stereoisomeric prostaglandins

Cited by 14 publications

References 26 publications

“Sweet Polyesters”: Lipase-Catalyzed Condensation−Polymerizations of Alditols

“Sweet Polyesters”: Lipase-Catalyzed Condensation−Polymerizations of Alditols

Quantum Mechanics/Molecular Mechanics Insights into the Enantioselectivity of the O-Acetylation of (R,S)-Propranolol Catalyzed by Candida antarctica Lipase B

Thermomyces lanuginosus Lipase with Closed Lid Catalyzes Elimination of Acetic Acid from 11‐Acetyl‐Prostaglandin E2

Contact Info

Product

Resources

About

Thermomyces lanuginosus Lipase with Closed Lid Catalyzes Elimination of Acetic Acid from 11‐Acetyl‐Prostaglandin E₂