Remote Interactions Explain the Unusual Regioselectivity of Lipase from Pseudomonas cepacia toward the Secondary Hydroxyl of 2′‐Deoxynucleosides

Abstract

Abstract. Lipase from

Regioselectivity-reversal in acylation of 6-azauridine catalyzed by Burkholderia cepacia lipase

“…However, PS IM lipase showed good 3 0 -regioselectivity (80%) and excellent substrate conversion (98%) under the reaction conditions examined. Lipase could functionalize its favorable hydroxyl in the regioselective acylation of polyhydroxyl compounds due to the specific structure of its active center and the molecular structure of the substrate (Lavandera et al 2006). Various sources of the lipases differ in the geometry of their active center of the binding sites, which fit exactly to their favorite substrates Effect of organic solvents on enzymatic acylation One of the most impracticable limitations in the acylation of hydrophilic nucleosides is their poor solubility in hydrophobic solvents, which is advantageous to the stabilization of enzyme.…”

“…The change of the superior regioselectivity might be attributed to the interaction between the base moiety and the acyl group. According to the molecular basis demonstrated by Gotor and co-workers, the nucleoside acts as the nucleophile and thus binds in the mediumsized pocket in the acylation of nucleoside catalyzed by Burkholderia cepacia lipase (Lavandera et al 2006). Since the molecular of the nucleoside is much larger than the medium-sized pocket, the base moiety might extend into the large hydrophobic pocket in 5 0 -acylation transition state or the alternate hydrophobic pocket in 3 0 -acylation transition state.…”

Highly Regioselective Synthesis of 3′-O-Acyl-Trifluridines Catalyzed by Pseudomonas cepacia Lipase

“…Recently, Lavandera et al uncovered the binding model of the lipase from P. cepacia via computer-aided molecular modeling [19]. It was proposed that the special recognizing ability of enzymes could be attributed to favorable substrate orientation in the active centers, due to the difference of the enzyme structures.…”

“…It was proposed that the special recognizing ability of enzymes could be attributed to favorable substrate orientation in the active centers, due to the difference of the enzyme structures. X-ray crystal structure investigations have revealed that the active site of the PS IM had a large hydrophobic pocket, where the acyl donor binds, a medium-sized pocket in which the base moiety lies and an alternate hydrophobic pocket which can also bind parts of the alcohol moiety [19,20]. According to the molecular basis of high 3′-regioselectivity of the lipase from P. cepacia proposed by Gotor and co-workers, this kind of special structure can effectively reduce the steric strain of the active center to stabilize the 3′-acylation transition state [18,19].…”

Biocatalysis Applied to the Synthesis of Nucleoside Analogs

“…It is remarkable that, in the case of ribonucleosides (X = OH), it is not possible to achieve high regioselectivities in the 2 ′ or 3 ′ -position with PSL, but CALB again catalyzes the process towards the primary hydroxyl group in the 5 ′ -position. In addition, a theoretic study to explain the abnormal regioselectivity of PSL to the less reactive hydroxyl group has recently been published [12] .…”