Protons, water-mediated transfer

Fig. 6.9 Water mediation in catalysis (I). In the action of this DNA polymerase, the initial proton transfer to the a-phosphate of the substrate via a bridging crystal water molecule is the rate-limiting step. Subsequently, departure of the pyrophosphate is facilitated by a proton relay mechanism through mediation of water, which neutralizes the evolving negative charge. (Reprinted with permission from Ref. [67], 2007 American Chemical Society.)...

Tyrosine Yz is also an important mediator in the catalysis of water oxidation by the Mn4Ca cluster in the OEC. This proceeds via a series of proton-coupled electron transfer events, each of which reduces one radical Yz and increases the oxidation state of the cluster. The different oxidation states of the OEC are known as S-states. Once state S4 is attained, corresponding to the accumulation of four electron holes, two water molecules are oxidised, and a molecule of oxygen is formed. Kok proposed a S-state cycle describing the successive... 

Brousmiche, D. W. Wan, P. Excited state (formal) intramolecular proton transfer (ESIPT) in p-hydroxyphenyl ketones mediated hy water. J. Photochem. Photobiol. A Chem. 2000, 130, 113-118. 

Fischer, M. Wan, P. m-Quinone methides from m-hydroxy-1,1-diaryl alkenes via excited-state (formal) intramolecular proton transfer mediated by a water trimer. J. Am. Chem. Soc. 1998, 120, 2680-2681. 

As an illustration, we briefly discuss the SCC-DFTB/MM simulations of carbonic anhydrase II (CAII), which is a zinc-enzyme that catalyzes the interconversion of CO2 and HCO [86], The rate-limiting step of the catalytic cycle is a proton transfer between a zinc-bound water/hydroxide and the neutral/protonated His64 residue close to the protein/solvent interface. Since this proton transfer spans at least 8-10 A depending on the orientation of the His 64 sidechain ( in vs. out , both observed in the X-ray study [87]), the transfer is believed to be mediated by the water molecules in the active site (see Figure 7-1). To carry out meaningful simulations for the proton transfer in CAII, therefore, it is crucial to be able to describe the water structure in the active site and the sidechain flexibility of His 64 in a satisfactory manner. 

Proton exchange rates in aqueous solutions are enhanced by small amounts (0.5% V/V) of hydrophobic substances (e.g., methanol, dioxane) because of a consequent increase in H-bonded water structure in the hydration shells through which the proton transfer is mediated (9). 

The mechanism of long-range proton transfer processes in solutions is complex becanse seqnential proton hops from initial proton donors to proton acceptors are mediated by water (or solvent) molecules or other groups capable of ionization. 

The collapse of the proteolytic tetrahedral intermediate of the promoted-water pathway requires a proton donor in order to facilitate the departure of the leaving amino group. Rees and Lipscomb (1982) considered Glu-270, but favored Tyr-248 for this role, but Monzingo and Matthews (1984) fully elaborated on a role for Glu-270 of carboxypeptidase A and Glu-143 of thermolysin as intermediate proton donors. This proposal for carboxypeptidase A is corroborated by the near-normal activity observed for the Tyr-248- Phe mutant of rat carboxypeptidase A (Garden et al, 1985 Hilvert et al, 1986) and is reflected in the mechanistic scheme of Fig. 31 (Christianson and Lipscomb, 1989). Mock (1975) considered Glu-270 a proton donor in the carboxypeptidase A mechanism, but his mechanism does not favor a Glu-270/zinc-promoted water molecule as the hydrolytic nucleophile. Schepartz and Breslow (1987) observed that Glu-270 may mediate an additional proton transfer in the generation of the Pi product carboxylate. 

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