The enhancement of enantioselectivities for lipase-catalyzed reactions by using carbamates

Gao, Lin; Lin, Wen‐Yuan; Shieh, Chuen-Tzwu

doi:10.1016/s0040-4039(98)02021-8

Cited by 14 publications

(2 citation statements)

References 21 publications

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“…These carbon atoms fold between and make extensive van der Waals contacts with the phenyl rings of Phe344 and Phe448. That partial blocking of the active site of porcine pancreatic lipase by a carbamate inhibitor causes the enhancement of enantioselectivity for the resolution of 1-indanol (38), strongly supporting two binding sites for the alkyl groups in PSL and CEase. Thus, the overall binding site shape for all three alkyl chains of triacylglyceride in the enzyme looks like a tuning fork, which either the sn-1,3 or sn-2 fatty acyl chain binds to ACS, another fatty acyl chain binds to SACS, and the third fatty acid acyl chain extends into the solvent, binds to the third alkyl chain binding site, and has room to adopt many different conformations (Figure 2B) (32).…”

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confidence: 86%

Structure−Reactivity Relationships for the Inhibition Mechanism at the Second Alkyl-Chain-Binding Site of Cholesterol Esterase and Lipase

Gao

Shieh

et al. 1999

Biochemistry

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Alkyl-N-phenyl carbamates (2-8) (see Figure 1), alkyl-N-phenyl thiocarbamates (9-15), 2,2'-biphenyl-2-ol-2'-N-substituted carbamates (16-23), and 2, 2'-biphenyl-2-N-octadecylcarbamate-2'-N-substituted carbamates (24-31) are prepared and evaluated for their inhibition effects on porcine pancreatic cholesterol esterase and Pseudomona species lipase. All inhibitors are characterized as transient or pseudo substrate inhibitors for both enzymes. Both enzymes are not protected from inhibition and further inactivated by carbamates 2-8 and thiocarbamates 9-15 in the presence of trifluoroacetophenone. Therefore, carbamates 2-8 and thiocarbamates 9-15 are exceptions for active site binding inhibitors and are probably the second alkyl-chain binding-site-directed inhibitors for both enzymes. The inhibition data for carbamates 2-8 and thiocarbamates 9-15 are correlated with the steric constant, E(s), and the hydrophobicity constant, pi; however, the inhibition data are not correlated with the Taft substituent constant, sigma. A comparison of the inhibition data for carbamates 2-8 and thiocarbamates 9-15 toward both enzymes indicates that thiocarbamates 9-15 are more potent inhibitors than carbamates 2-8. A comparison of the inhibition data for cholesterol esterase and Pseudomona species lipase by carbamates 2-8 or thiocarbamates 9-15 indicates that cholesterol esterase is more sensitive to the E(s) and pi values than Pseudomona species lipase. The negative slope values for the logarithms of inhibition data for Pseudomona species lipase by carbamates 2-8 and thiocarbamates 9-15 versus E(s) and pi indicate that the second alkyl-chain-binding site of Pseudomona species lipase is huge, hydrophilic, compared to that of cholesterol esterase, and prefers to interact with a bulky, hydrophilic inhibitor rather than a small, hydrophobic one. On the contrary, the second alkyl-chain-binding site of cholesterol esterase prefers to bind to a small, hydrophobic inhibitor. Both enzymes are protected from inhibition by carbamates 16-23 in the presence of trifluoroacetophenone. Therefore, carbamates 16-23 are characterized as the alkyl chain binding site, esteratic site oxyanion active site directed pseudo substrate inhibitors for both enzymes. Both enzyme inhibition data for carbamates 16-22 are well-correlated with sigma alone. The negative rho values for these correlations indicate that the serine residue of both enzymes and carbamates 16-22 forms the tetrahedral species with more positive charges than inhibitors and the enzymes and follow the formation of the carbamyl enzymes with more positive charges than the tetrahedral species. Carbamates 24-31 are also exceptions for active site binding inhibitors and probably the second alkyl chain binding site-directed inhibitors for both enzymes. However, the enzyme inhibition constants for carbamates 24-31 are correlated with values of sigma, E(s), and pi. The negative rho values for these correlations indicate that both enzymes and carbamates 24-31 form the tetrahedral species with more positive ...

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Structure−Reactivity Relationships for the Inhibition Mechanism at the Second Alkyl-Chain-Binding Site of Cholesterol Esterase and Lipase

Gao

Shieh

et al. 1999

Biochemistry

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“…It is recommended that the inhibitor and the enzyme are mixed 10 h prior to the biotransformation; it is believed that the carbonate covalently binds to the protein, modifying the active site. 43 The closely related ketoester 22 is hydrolysed using Amano PS lipase in acetonitrile-pH 7 buffer to furnish the (R)-alcohol (45%, 94% ee) and recovered (S)-acetate (47%, 96% ee). 44 The diester 23 was converted into the (R,R)-diol (49% yield, >99.5% ee) using Candida rugosa lipase at pH 7, with the (S,S)-diester being recovered in almost the same yield and having the same very high optical purity.…”

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confidence: 99%