10.1021/acs.biomac.0c00593.s001
Hubert Casajus
Hubert
Casajus
Eric Dubreucq
Eric
Dubreucq
Sylvain Tranchimand
Sylvain
Tranchimand
Véronique Perrier
Véronique
Perrier
Caroline Nugier-Chauvin
Caroline
Nugier-Chauvin
Sandrine Cammas-Marion
Sandrine
Cammas-Marion
Lipase-Catalyzed Ring-Opening Polymerization of Benzyl
Malolactonate: An Unusual Mechanism?
American Chemical Society
2020
DFT quantum-chemical calculations
ring opening polymerization
enzyme
histidine
proton
acidic
monobenzyl fumarate group
KO
Lipase-Catalyzed Ring-Opening Polym...
ROP
lactone
monomer
presence
serine
weight-average molar mass
CpLip 2
MLABe
2020-06-30 11:35:12
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Lipase-Catalyzed_Ring-Opening_Polymerization_of_Benzyl_Malolactonate_An_Unusual_Mechanism_/12588143
The
use of safe natural catalyst such as enzymes for ring opening
polymerization (ROP) of β-substituted β-lactones such
as benzyl malolactonate (MLABe) is an important objective considering
the biomedical applications of the resulting (co)polymers. However,
the preparation of well-defined polymeric materials using such systems
requires an understanding of enzyme–substrate interactions.
In this context, we investigated the mechanism of lipase-catalyzed
ROP of MLABe, because it appears that it is probably not the same
as the one widely described for other lactones such ε-caprolactone,
propiolactone. and lactide. Enzymatic-catalyzed ROPs of MLABe in the
presence of the lipase/acyltransferase CpLip2 and its serine knockout
(serine KO) mutant (CpLip2_180A) have led to poly(benzyl malate) (PMLABe)
terminated by a monobenzyl fumarate group with monomer conversion
higher than 70% and weight-average molar mass of about 3600 g/mol
(<i>Đ</i> = 1.42). On the other hand, only less than
7% of MLABe conversion and no polymer formation were observed when
the polymerization reaction was conducted in the presence of inactivated
CpLip2 (heated at 100 °C). Moreover, the ROP of MLABe in the
presence of imidazole, a synthetic mimic of the catalytic histidine,
led to a PMLABe terminated by a monobenzyl fumarate group. On the
contrary, neither the enzymatic-catalyzed ROP of benzyl dimethylmalolactonate
(diMeMLABe), a MLABe with two methyl groups instead of the two “acidic”
protons on the lactone’s ring, in the presence of CpLip2 and
CpLip2_180A nor its chemical ROP in the presence of imidazole were
successful. Together, all these results suggested that the lipase-catalyzed
polymerization of malolactonates occurred through the abstraction
of one of the two “acidic” protons of the lactone’s
ring by the histidine of the catalytic triad leading to the corresponding
monobenzyl fumarate responsible for the polymerization of the remaining
monomer. Finally, molecular modeling of the positioning of the monomer
into the catalytic site of the CpLip2 and DFT quantum-chemical calculations
highlighted an interaction of (<i>R</i>)- and (<i>S</i>)-MLABe with the catalytic histidine of the enzyme preferentially
to serine, in the form of a strong hydrogen bond with one of the “acidic”
protons of MLABe, thus, supporting the important role of the catalytic
histidine in the polymerization of such cyclic lactones.