Stereoelectronic control in the cleavage of tetrahedral intermediates in the hydrolysis of esters and amides

Deslongchamps, Pierre

doi:10.1016/0040-4020(75)80257-2

Cited by 257 publications

(116 citation statements)

References 60 publications

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“…Presumably stabilized by this hydrogen bond, the same Glu-19 carboxylate oxygen of the complexed Oh4TKY3 is further involved in a hydrogen bond formed with the amide nitrogen of the same residue [5]. A similar intra-residue, but stereochemically likewise unfavourable hydrogen bond is also observed in OMJPQ3 for the homologous aspartate residue 19 and may impair the rehybridization at this P1' amide nitrogen assumed to be stereochemically required for the formation of a tetrahedral intermediate [19]. In fact residue 19 is restricted, in the overwhelming majority of avian ovomucoid third domains sequenced to date, to glutamic and aspartic acid.…”

Section: Omsvp3 and Omtky3mentioning

confidence: 93%

“…It was expected to be different in OMSVP3. The side chains of OMJPQ3 which are not in common with OMSVP3 residues [17][18][19]23, 32, 511 were truncated to alanines. For the calculation of the model Patterson map, structure factors were calculated with the changed OMJPQ3 molecule placed in a large cubic unit cell (a = 5 nm) with P 1 symmetry in order to eliminate intermolecular vectors.…”

Section: Results and Discussion Patterson Searchmentioning

confidence: 99%

“…The sequence of OMSVP3 differs at six positions from OMJPQ3. Three of these changes occur at P2 (17), Pl (18) and Pl' (19) around the reactive site. The P3 to P2' residues run as follows: Cys-16, Thr-17, Met-18, Glu-19, Tyr-20.…”

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confidence: 99%

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The crystal and molecular structure of the third domain of silver pheasant ovomucoid (OMSVP3)

Bode

Epp

Huber

et al. 1985

European Journal of Biochemistry

121

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OMSVP3 and Oh4TKY3 (third domains of silver pheasant and turkey ovomucoid inhibitor) are Kazal-type serine proteinase inhbitors. They have been isomorphously crystallized in the monoclinic space group C2 with cell dimensions of a = 4.429 nm, b = 2.115 nm, c = 4.405 nm, /3 = 107". The asymmetric unit contains one molecule corresponding to an extremely low volume per unit molecular mass of 0.0017 nm3/Da. Data collection was only possible for the OMSVP3 crystals. Orientation and position of the OMSVP3 molecules in the monoclinic unit cells were determined using Patterson search methods and the known structure of the third domain of Japanese quail ovomucoid (OMJPQ3) [Papamokos, E., Weber, E., Bode, W., Huber, R., Empie, M. W., Kato, I. Ovomucoid inhibitors are major constitutents of avian egg white. Generally they consist of three tandem domains, each of which is a strong inhibitor of serine proteases and belongs to the family of Kazal inhibitors. The specificity of the ovomucoid inhibitors is mainly determined by the P1 residue. The nomenclature of Schechter and Berger [l] is used for the numbering of the substrate amino acid residues 'towards the NH2-terminal and the COOH-terminal directions from the scissile bond. The detailed specificity is also affected by single residue changes in positions other than P1. In an attempt to unravel the detailed algorithm for predicting inhibitory specificity from the amino acid sequence the Purdue group has sequenced a large number of avian ovomucoid domains and compared their inhibitory properties. It was found that only changes of residues in contact with the enzyme are important. Such exchanges may affect the packing of the inhibitory enzyme interface but they may also alter the mainchain conformation of the binding segment itself. Structural studies of related inhibitors are required to clarify this problem.The high-resolution crystal structures of three different representatives of the Kazal family have been determined and crystallographically refined : four independent molecules per asymmetric unit of the third domain of Japanese quail ovomucoid inhibitor (OMJPQ3) [2, 31, the third domain of turkey ovomucoid inhibitor (OMTKY3) complexed with the Abbreviations. OMSVP3, third domain of silver pheasant ovomucoid inhibitor; Oh4TKY3, third domain of turkey ovomucoid inhibitor; OMJPQ3, third domain of Japanese quail ovomucoid inhibitor; PSTI, porcine pancreatic trypsin inhibitor; SGPB, Streptomyces griseus protease B; r.m.s., root-mean-square; IFo\, IF& observed and computed structure amplitudes.Streptomyces griseus protease B [4,5], and the porcine pancreatic secretory trypsin inhibitor (PSTI) complexed with bovine trypsinogen [6]. The sequence of OMSVP3 differs at six positions from OMJPQ3. Three of these changes occur at P2(17), Pl(18) and Pl'(19) around the reactive site. The P3 to P2' residues run as follows: Cys-16, Thr-17, Met-18, Glu-19, Tyr-20. Thus, in contrast to OMJPQ3, which is a trypsin inhibitor because of a lysine residue at its PI position, the methionine of OMS...

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Section: Omsvp3 and Omtky3mentioning

confidence: 93%

Section: Results and Discussion Patterson Searchmentioning

confidence: 99%

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The crystal and molecular structure of the third domain of silver pheasant ovomucoid (OMSVP3)

Bode

Epp

Huber

et al. 1985

European Journal of Biochemistry

121

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“…Evidently, the breakdown of the hemiorthoester is subject to stereoelectronic control (Deslongchamps effects), which favors C 22 -O 17 bond cleavage because the hydroxyl oxygen and ester oxygen each have an orbital oriented antiperiplanar to this bond. [34][35][36] The E-ring opened glycinate and E-ring opened glycinamide have the same molecular weight in their neutral forms. Adamovices et al observed that E-ring opened amide derivatives of camptothecin undergo transformation in dilute solution to the parent lactone by 17-hydroxyl attack on the 21-amide bond.…”

Section: Discussionmentioning

confidence: 99%

Kinetics and Mechanisms of Activation of α-Amino Acid Ester Prodrugs of Camptothecins

2006

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The α-amino acid ester prodrugs of the antitumor agent camptothecin and a more potent, lipophilic silatecan analog, DB-67, have been shown by NMR spectroscopy and quantitative kinetic analyses to undergo quantitative conversion to their pharmacologically active lactones via a non-enzymatic mechanism that at pH 7.4 is favored over direct hydrolysis. The alternate pathway involves the reversible intramolecular nucleophilic amine attack at the camptothecin E-ring carbonyl to generate a lactam (I) followed by a second intramolecular reaction to produce a bicyclic hemiorthoester (I′). The intermediates were isolated and shown to exist in an apparent equilibrium dominated by the hemiorthoester in DMSO using NMR spectroscopy. The conversion of prodrugs of camptothecin or DB-67 containing either α-NH 2 or α-NHCH 3 and their corresponding hemiorthoesters were monitored versus time in aqueous buffer (pH 3.0 and 7.4) at 37°C and the kinetic data were fit to a model based on the proposed mechanism. The results indicated that while the prodrugs are relatively stable at pH 3, facile lactone release occurs from both the prodrugs and their corresponding hemiorthoester intermediates under physiological conditions (pH 7.4). The glycinate esters and their hemiorthoesters were found to be more cytotoxic than the N-methylglycinates or their corresponding hemiorthoester intermediates in vitro using a human breast cancer cell line (MDA-MB-435S), consistent with their more rapid conversion to active lactone. The pH dependence of the nonenzymatic pathway for conversion of these α-amino acid ester prodrugs suggests that they may be useful for tumor-targeting via liposomes, as they can be stabilized in an acidic environment in the core of liposomes and readily convert to the active lactone following their intratumoral release.

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“…The oxyanion could be stabilised by hydrogen bonds with the peptide NH of residue 76 and possibly of residue 77, in a manner analogous to that proposed for serine proteinases [22], with minor contributions from the dipole of the helix formed by residues 304-310, whose S+ end is directed towards the active site. Hydrogen bonds from the flap to the charged oxygen may serve to orientate the orbitals so that there is a lone pair antiperiplanar to the C-N bond but not to the hydroxyl C-O bond, thereby ensuring that on collapse of the tetrahedral intermediate, the leaving group is the free amine rather than the original nucleophile [23]. Pyrimidalisation of the peptide nitrogen may be favoured by the binding-induced peptide rotation, which would direct the free lone pair generally towards the catalytic groups, and consequently no inversion of the lone pair and proton directions would be required for protonation of the NH leaving group, in contrast to that suggested for the serine proteinases [24].…”

Section: Catalytic Mechanismmentioning

confidence: 99%

The catalytic mechanism of aspartic proteinases

Pearl

1987

FEBS Letters

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The highly symmetric active site of an aspartic proteinase, endothiapepsin, binds a water molecule ideally situated for nucleophilic attack on a substrate peptide bond whose distortion from planarity is stabilised by interactions of the substrate with the extended binding cleft. The apparent electrophilicity of the catalysis results from this distortion. The scissile peptide bond is orientated with the carbonyl oxygen hydrogen bonding to the tip of the p-hairpin 'flap' which lies over the cleft. Nucleophilic attack by the bound water leads to a tetrahedral intermediate similar to observed complexes with hydroxyl inhibitors and stabilised by hydrogen bonds with the flap.

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Stereoelectronic control in the cleavage of tetrahedral intermediates in the hydrolysis of esters and amides

Cited by 257 publications

References 60 publications

The crystal and molecular structure of the third domain of silver pheasant ovomucoid (OMSVP3)

The crystal and molecular structure of the third domain of silver pheasant ovomucoid (OMSVP3)

Kinetics and Mechanisms of Activation of α-Amino Acid Ester Prodrugs of Camptothecins

The catalytic mechanism of aspartic proteinases

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