A computational study of 1-formyl 1,2-ethanediol aminolysis predicts a stepwise mechanism involving syn-2-OH-assisted proton transfer. The syn-oriented 2-OH takes over the catalytic role of the external water or amine molecule previously observed in 2-deoxy ester aminolysis. It provides more favorable, that is, more linear, proton transfer geometry for the rate-limiting transition state resulting in an almost billion-fold rate acceleration of the overall reaction. These findings provide structural basis for explanation of the efficiency of the proton shuttling mechanism and imply double proton transfer catalysis by peptidyl tRNA A76 2'-OH as a possible catalytic strategy used by ribosome.
The pathological DNA-specific B lymphocytes in lupus are logical targets for a selected therapeutic intervention. We have hypothesized that it should be possible to suppress selectively the activity of these B cells in lupus mice by administering to them an artificial molecule that cross-links their surface immunoglobulins with the inhibitory FccIIb surface receptors. A hybrid molecule was constructed by coupling the DNAmimicking DWEYSVWLSN peptide to a monoclonal anti-mouse FccRIIb antibody. This chimeric antibody was added to cultured spleen cells from sick MRL/lpr mice, immunized with diphtheria toxoid, resulting in reduction of the numbers of anti-DNA but not of anti-diphtheria IgG antibody-producing cells. Intravenous infusions with the DNA-peptide antibody chimera to 7-wk-old animals prevented the appearance of IgG anti-DNA antibodies and of albuminuria in the next 2 months. The administration of the DNA-peptide chimeric antibody to 18 wk-old mice with full-blown disease resulted in the maintenance of a flat level of IgG anti-DNA antibodies and in delay of the aggravation of the lupus glomerulonephritis. The use of chimeric antibodies targeting inhibitory B lymphocyte receptors represents a novel approach for the selective suppression of autoreactive disease-associated B cells in autoimmune diseases.
This computational study provoked by the process of peptide bond formation in the ribosome investigates the influence of the vicinal OH group in monoacylated diols on the elementary acts of ester aminolysis. Two alternative approaches for this influence on ester ammonolysis were considered: stabilization of the transition states by hydrogen bonds and participation of the vicinal hydroxyl in proton transfer (proton shuttle). The activation due to hydrogen bonds of the vicinal hydroxyl via tetragonal transition states was rather modest; the free energy of activation was reduced by only 5.2 kcal/mol compared to the noncatalyzed reaction. The catalytic activation via the proton shuttle mechanism with participation of the vicinal OH in the proton transfer via hexagonal transition states resulted in considerable reduction of the free energy of activation to 33.5 kcal/mol, i.e., 16.0 kcal/mol lower than in the referent process. Accounting for the influence of the environment on the reaction center by a continuum model (for ε from 5 to 80) resulted in further stabilization of the rate-determining transition state by 4-5 kcal/mol. The overall reduction of the reaction barrier by about 16 kcal/mol as compared to the noncatalyzed process corresponds to about 10(9)-fold acceleration of the reaction, in agreement with the experimental estimate for acceleration of this process in the ribosome.
The possible catalytic effect of the vicinal hydroxyl group during the ammonolysis of acetylcatechol has been studied by first principle calculations. A very efficient intramolecular catalysis was found to occur when the catechol ester o-OH group is deprotonated: the activation energy of the ammonolysis decreases by 24 kcal mol(-1) as compared to that of acetylphenol ammonolysis. Using this value, the o-oxyanion-catalysed intramolecular ammonolysis was estimated to be orders of magnitude faster than the ammonolysis of acetylphenol or nonionised acetylcatechol. The analogy with the aminolysis of peptidyl-tRNA that occurs during protein biosynthesis implies several orders of magnitude acceleration due to complete or partial deprotonation of its 3'-terminal adenosine 2'-OH providing a mechanistic possibility for general acid-base catalysis by the ribosome.
A physical organic study reveals general base catalysis by the 2′‐oxyanion of the peptidyl adenosine ethanolysis; this implies a proton‐shuttle role for the 2′‐OH of peptidyl tRNA A76 in the ribosome substrate‐assisted catalytic mechanism.
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