The relative basicity of sulfur containing esters

Grunwell, John R.; Foerst, Denis L.; Kaplan, Fred; Siddigui, J.

doi:10.1016/0040-4020(77)80268-8

Cited by 8 publications

(5 citation statements)

References 22 publications

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“…Quantitative data on the relationship between the ν CdO shift and the enthalpy of hydrogen bonding are not yet available for R,β-unsaturated thiolesters, but for R,β-unsaturated esters a shift in ν CdO of 12 cm -1 corresponds to a change in hydrogen-bonding strength of approximately 10 kJ mol -1 (Dulce et al, 1991). On the basis of literature comparisons of simple esters and thiolesters (Grunwell et al, 1977;Smolders et al, 1988) we expect a similar value for the strength of the hydrogen bond-(s) to the acyl CdO in the active-site thiolester. Undoubtedly, the carbonyl oxygen is hydrogen-bonded only weakly.…”

Section: Resultsmentioning

confidence: 78%

“…Overall, it was possible to develop relationships between the rate, the carbonyl bond length, and the hydrogen bonds in the active site between the CdO group and the oxyanion hole (Tonge & Carey, 1992). There are several known differences between the properties of acyl serine and acyl cysteine proteases, including the differences in chemistry between esters and thiolesters (Grunwell et al, 1977;Smolders et al, 1988), the differences in efficacy of the oxyanion holes in the two classes of proteases (Me ´nard et al, 1995), and the existence of strong electrostatic polarizing forces in the active site of members of the papain superfamily which appear to be absent in the serine proteases (Carey et al, 1978). In order to investigate how these differences might affect spectra-structure-reactivity relationships for the papain superfamily, we have combined the kinetic characterization of a series of acyl cysteine proteases, presented in the accompanying paper (Doran et al, 1996), with a Raman and electronic absorption spectroscopic analysis.…”

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confidence: 99%

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α-Helix Dipoles and Catalysis: Absorption and Raman Spectroscopic Studies of Acyl Cysteine Proteases

Doran

Carey

1996

Biochemistry

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Raman and absorption spectroscopic data are combined with the deacylation rate constants for a series of acyl cysteine proteases to provide insight into the role of alpha-helix dipoles in rate acceleration. The Raman spectra, obtained by Raman difference spectroscopy, of (5-methylthienyl)acryloyl adducts with papain, cathepsins B and L, and two oxyanion hole mutants of cathepsin B (Q23S and Q23A) show that extensive polarization throughout the pai-electron chain occurs for the bound acyl group in the active sites. A similar result is obtained using the specific chromophoric substrate ethyl 2-[(N-acetyl-L-phenylalanyl)amino]-3-(5-methylthienyl)acrylate. By using 13C = O substitution it is possible to detect the acyl C = O stretching frequency, vC = O, for each acyl enzyme. A correlation between vC = O and log k3, where k3 is the deacylation rate constant, is found where vC = O increases with increasing reactivity. This is exactly the opposite sense to the relationship found for a series of acyl serine proteases [Carey & Tonge (1995) Acc. Chem. Res. 28, 8]. The opposite trend in the direction of the correlation for the acyl cysteine proteases is ascribed to the strong electron polarizing forces in the active site, due principally to the active-site alpha-helix dipole, giving rise to canonical (valence bond) forms of the acyl group which change the hybridization about the C = O carbon atom. A correlation is also observed between the absorption maximum, lambda max, and log k3 for each acyl cysteine protease. As the deacylation rate increases, 214-fold across the series, lambda max red-shifts from 367 to 384 nm. It is proposed that differential interactions between the active site's alpha-helix dipole and the acyl chromophore give rise to the observed changes in lambda max, with the red shift being caused principally by interactions with the excited electronic state, which has a high degree of charge separation, and the dipole. Similar interactions between the dipole and the negatively charged tetrahedral intermediate, which resembles the transition state, are proposed as the source of differential rates in deacylation. It is interesting to note that similar energies are operating in both cases. A shift in lambda max from 367 to 384 nm corresponds to a change in electronic absorption transition energies of 3.2 kcal/mol and a change of deacylation rate constants of 214-fold also corresponds to a change of activation energies of 3.2 kcal/mol.

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Section: Resultsmentioning

confidence: 78%

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confidence: 99%

α-Helix Dipoles and Catalysis: Absorption and Raman Spectroscopic Studies of Acyl Cysteine Proteases

Doran

Carey

1996

Biochemistry

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“…It has the largest .n-charge delocalization indicated by the largest n z O t n X charge transfer, accompanied by the largest charge separation between the atoms of the carbonyl group. In fact, in the 0-protonated derivatives of amides and (S-alkyl thio)esters, the charge at the oxygen atom increases with respect to the neutral molecules by = 0.40.5 e. 40 This charge derives mainly from the carbonyl atom in the oxygen and sulfur derivatives, but mainly from the X atom in the nitrogen derivatives. The lower n, , Ei value of 1 relative to 2 probably derives from the higher polarizability of this compound.…”

Section: Uv Pe and Et Spectra Of Compounds 1-8-a Comparisonmentioning

confidence: 99%

“…The charge distribution in 3a seems to indicate that the largest difference with respect to the alkyl derivative 2a is the + I effect of the substituent which increases charge density at the carbonyl C atom. 40 In the gauche rotamers, the CH,SMe group in 6a bears a positive charge. However, when X is a good donor, the CH,SMe group is nearly neutral.…”

Section: Uv Pe and Et Spectra Of Compounds 1-8-a Comparisonmentioning

confidence: 99%

Ab initio and electron spectroscopy study of carbonyl derivatives

Jones¹,

Modelli²,

Olivato³

et al. 1994

J. Chem. Soc., Perkin Trans. 2

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“…A linear relationship was established between the length of the acyl CdO bond and the logarithm of the deacylation rate constant, and it was possible to use resonance Raman data to establish the strength of the oxyanion hole-to-CdO hydrogen bonds throughout the series (Tonge & Carey, 1992). There are several marked differences in the properties of serine and cysteine acyl enzymes; in the relative importance of the oxyanion hole (Me ´nard et al, 1995), in the intrinsic chemical differences between esters and thiol esters (Grunwell et al, 1977;Smolders & Zeegers-Huyskens, 1988), and in the presence of strong electron polarization forces in cysteine protease active sites which appear to be absent in serine proteases (Carey et al, 1978). It is these differences which motivated us to explore structure-reactivity relationships for cysteine protease acyl enzymes in the present work.…”

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confidence: 99%

Deacylation and Reacylation for a Series of Acyl Cysteine Proteases, Including Acyl Groups Derived from Novel Chromophoric Substrates

et al. 1996

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In order to investigate structure-reactivity relationships within a series of acyl cysteine proteases [Doran, J. D., & Carey, P. R. (1996) Biochemistry 35, 12495-12502], deacylation kinetics have been measured for a number of acyl intermediates involving members of the papain superfamily. Derivatives of the "simple" chromophoric ligand (5-methylthienyl)acrylate (5MTA) and those based on two chromophorically labeled derivatives of peptidyl substrates, viz., 2-[(N-acetyl-L-phenylalanyl)amino]-3-(5-methylthienyl)acrylate (Phe5MTA) and 2-[(N-acetyl-L-alanyl)amino]-3-(5-methylthienyl)acrylate (Ala5MTA), were used to create acyl enzyme adducts with papain, cathepsin B, and cathepsin L. The chromophoric specific substrates were designed to utilize hydrogen-bonding and hydrophobic interactions which are known to be important in promoting catalysis by papain. For cathepsins B and L, removing one of the hydrogen-bonding donors making up the putative oxyanion hole retards deacylation by 3-25-fold, demonstrating that the oxyanion hole has a modest effect on catalysis for these substrates. With the above substrates and the wild-type and oxyanion hole mutants, the values of the deacylation rate constants stretch over a 214-fold range, from 0.07 to 15 x 10(-3) s-1. The pKa for deacylation of [(5-methylthienyl)-acryloyl]papain is 4.9, close to that reported for similar papain intermediates, while that for Ala5MTA-papain is at 3.5, which in the latter likely represents the effect of the P1-S1 and P2-S2 interactions on the environment of histidine-159. For the Phe5MTA-papain the extent of deacylation was found to depend on the pH and the starting acyl enzyme concentration. A simple model has been derived which accounts quantitatively for this behavior, using the assumptions that the protonated form of the acyl product reacylates the enzyme and that in the pH range 5.0-7.5 the ionization of active-site groups has no effect on reacylation. The validity of the first assumption was demonstrated by following the deacylation of Phe5MTA-papain in the presence of the potent inhibitor E-64 [1-(L-trans-epoxysuccinyl-L-leucylamino)-4-guanidinobutane], whereupon complete deacylation occurred at all pHs with a pKa identical to that for Ala5MTA-papain, viz., 3.5.

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The relative basicity of sulfur containing esters

Cited by 8 publications

References 22 publications

α-Helix Dipoles and Catalysis: Absorption and Raman Spectroscopic Studies of Acyl Cysteine Proteases

α-Helix Dipoles and Catalysis: Absorption and Raman Spectroscopic Studies of Acyl Cysteine Proteases

Ab initio and electron spectroscopy study of carbonyl derivatives

Deacylation and Reacylation for a Series of Acyl Cysteine Proteases, Including Acyl Groups Derived from Novel Chromophoric Substrates

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