PubMed · 15590563
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G A Nevinsky, V N Buneva. 2004. Is there an answer?. https://doi.org/10.1080/15216540400014729
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H11 is the first antibody reported to have dual activity as a non-concerted, Diels-Alderase and hydrolytic catalyst. It was previously shown to catalyse the cycloaddition of acetoxybutadiene 1a to N-alkyl maleimides 2 to afford hydroxy-substituted bicyclic adducts 3 with a 30% ee of a major isomer. To better understand this mechanism and the partial stereospecificity, a homology model of H11 was constructed and used in docking studies to evaluate potential antibody-ligand complexes. The model suggested the hydrolytic nature of H11 was due to Glu 95H acting as a catalytic base, and evaluation of the shape complementarity of the proposed antibody-ligand complexes confirmed at a semi-quantitative level the observation that the major enantiomer is produced in a 30% ee.
It was shown for the first time that a small fraction of milk secretory IgA (sIgA) is tightly bound to oligosaccharides (oligoSACs) and polysaccharides (polySACs). The ability of sIgA to phosphorylate oligo- and polysaccharides was shown to be an intrinsic property of this antibody. In contrast to known kinases, sIgAs with polysaccharide kinase activity can transfer phosphoryl group to oligo- and polysaccharides not only from [gamma-(32)P]ATP but can also use [(32)P]orthophosphate as a substrate of phosphorylation reaction. An extremely unusual property of polysaccharide kinase Abs is their high affinity for orthophosphate (K(m) = 15-77 microM), and orthophosphate is a better substrate than ATP. Two first examples of natural abzymes (Abzs) with synthetic activity were milk sIgA with protein and lipid kinase activities. Polysaccharide kinase sIgA of human milk is the third example of natural antibodies (Abs) with synthetic activity.
We have performed a series of first-principles electronic structure calculations to examine the reaction pathways and the corresponding free energy barriers for the ester hydrolysis of protonated cocaine in its chair and boat conformations. The calculated free energy barriers for the benzoyl ester hydrolysis of protonated chair cocaine are close to the corresponding barriers calculated for the benzoyl ester hydrolysis of neutral cocaine. However, the free energy barrier calculated for the methyl ester hydrolysis of protonated cocaine in its chair conformation is significantly lower than for the methyl ester hydrolysis of neutral cocaine and for the dominant pathway of the benzoyl ester hydrolysis of protonated cocaine. The significant decrease of the free energy barrier, approximately 4 kcal/mol, is attributed to the intramolecular acid catalysis of the methyl ester hydrolysis of protonated cocaine, because the transition state structure is stabilized by the strong hydrogen bond between the carbonyl oxygen of the methyl ester moiety and the protonated tropane N. The relative magnitudes of the free energy barriers calculated for different pathways of the ester hydrolysis of protonated chair cocaine are consistent with the experimental kinetic data for cocaine hydrolysis under physiologic conditions. Similar intramolecular acid catalysis also occurs for the benzoyl ester hydrolysis of (protonated) boat cocaine in the physiologic condition, although the contribution of the intramolecular hydrogen bonding to transition state stabilization is negligible. Nonetheless, the predictability of the intramolecular hydrogen bonding could be useful in generating antibody-based catalysts that recruit cocaine to the boat conformation and an analog that elicited antibodies to approximate the protonated tropane N and the benzoyl O more closely than the natural boat conformer might increase the contribution from hydrogen bonding. Such a stable analog of the transition state for intramolecular catalysis of cocaine benzoyl-ester hydrolysis was synthesized and used to successfully elicit a number of anticocaine catalytic antibodies.