Proton shuttle

Lill MA, Helms V (2002) Proton shuttle in green fluorescent protein studied by dynamic simulations. Proc Natl Acad Sci USA 99 2778-2781... 

As the proton shuttles from the 04 to N5, there is a barrier of about 8.8 kcal/mol at which point the 04-H04 distance is 1.4 A. Once this barrier is crossed, the system becomes more stabilized. Following proton transfer the energy is reduced by -6.9 kcal/mol. This series of findings support the possibility that an energetically feasible mechanism can be proposed for proton transfer from 04 to N5 via an intermediate water molecule. But as has been discussed earlier, there was no solvent molecule in direct contact with either 04 or N5 of the substrate during these simulations. 

Catalytic asymmetric protonation of a prochiral amide enolate by a chiral diamine (10mol%) has been achieved through careful optimization of the proton-shuttle conditions which must apply. ... 

Any residue that facilitates entry or departure of a proton from an enzyme active site or to another region within an active site. Occasionally, proton shuttle groups can be removed by site-directed mutagenesis, and chemical rescue can be demonstrated by providing buffer salts to replace the shuttle group. See Chemical Rescue... 

An example is the hydration of CO2, as catalyzed by carbonic anhydrasek The catalytic reaction requires proton transfer from the zinc-bound water at the active site to solution to regenerate Zn-OH in each catalytic cycle. The most efficient isozyme forms use His-64 as a nearby proton shuttle group other forms contain residues that are less effective in proton transfer and limit overall catalytic efficiency. 

X-ray crystallographic work suggests that the role of His-64 as a proton shuttle may involve rapid conformational changes about the C -Cy and C -C bonds of the side chain (Krebs et al., 1991 Nair and Christianson, 1991). 

In that report, electron-rich olefins were found to react with Rh(I) vinylidenes differently from the manner in which electron-neutral olefins do (Scheme 9.5). A nucleophilic addition reaction, rather than a pericyclic ring closure, was evident. Because the reaction is strongly promoted by organic base, proton-shuttling is believed to account for the conversion of zvfitterionic intermediate 26 to the observed... 

These ideas have been illustrated in a recent study of the co-crystalline complex of 1-meCyt 5-FUra [19]. Using model calculations, it was shown how the hydrogen-bonding network of the crystal is able to sustain a proton shuttle which leads to the selective formation of certain radicals. Calculations predict that the site of reduction would be the cytosine base, yielding the N3 protonated cytosine anion, Cyt(N3-I-H), while the uracil base would be the site of oxidation, yielding the N1 deprotonated uracil cation, Ura(Nl—H) ... 

C-P-Q is converted to the charge separated diradical state C h-P -Q-. Then an electron is transferred from Q to the lipid-soluble 2,5-diphenylbenzoquinone Qs 133b yielding Qs. In the third step uncharged semiquinone QsH is formed when the latter accepts a proton from the external aqueous solution. The basic function of a proton shuttle is carried out when the semiquinone radical diffuses through the membrane in the fourth step. It is then oxidized to Qs + by the carotenoid radical cation... 

Compounds which enhance the catalytic activities of the CAs are known as activators. Activators of carbonic anhydrases are less studied because CA is one of the most efficient enzymes known. Carbonic anhydrase II activation by phosphorylation in the presence of protein kinase and cAMP has been reported (195,196). Also some anions are activators for CA III (197,198) the catalytic effect is due to the proton shuttling capacities of such activators. Histamine, a well known activator, for native and Co(II)-substituted isoenzymes I and II CA is reported by Briganti et al. (199). Amines [Ar-CH(R3)CH(R2)NH(R1) Ar =Aromatic/heterocyclic group R1 =R2 = H, Me R3 = H, OH, COOH] and amino acids are efficient activators for CA I—III (200-207). These amines possess a bulky aromatic/heterocyclic moiety in their molecular structure and act as proton acceptor (204-207). 

A possible structural basis for the ordered kinetic mechanism of coenzyme binding before alcohol is the need for the 2 -hydroxyl of the ribose in the proton shuttle of equation 16.4.14,30 Comparison of the structures of apo- and holoen-zymes reveals extensive conformational changes on coenzyme binding.12 The induced conformational changes are probably related to the kinetically detected isomerization, and may be another factor that contributes to ordered binding. 

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