Proton in vivo

Paroxetine. In the structure of paroxetine (Paxih.J amino group, protonated in vivo could H-bond with IK -CHj-O- unshared elcxtruns. A /S-arylamine-like strucKii with an extra aryl group results. The compound is a itr-highly. selective SERT. As expected, it is an effectiveanliil pres.sant and anxiolytic. 

Differences in the availability of the P lone pair for a series of phosphines are likely to have profound effects on their biological chemistry. For instance, the question arises as to whether a particular phosphine is likely to become protonated in vivo. The pKa s of hydrophobic phosphines can not be measured in H2O. Consequently most of the experimental data have been obtained by titration in non-aqueous media (usually nitro-methane). Conversion to aqueous pKj values is usually carried out using a relationship between half neutralisation potentials in CH3NO2 and pKa(H20) that exists for amines. For monodentate tertiary phosphines, introduction of phenyl-substituents lowers the pKa (Table 2). There appear to have been no similar determinations of the pKa s of diphosphines. It seems likely that phenyldiphosphines (e.g. dppe) are weakly basic (pKa < 3) and therefore will not be significantly protonated at pH 7. Preliminary experimental data measured by R. Norman in our laboratory suggest that this is the case . ... 

Infrared (IR) spectroscopy, which is highly sensitive to even minute alterations in bond lengths and energies, thus constitutes an attractive method for probing the structural changes in the RC at the level of individual bonds of both the cofactors and the protein. The vibrational spectrum of the quinones in their different states of ionization and/or protonation in vivo is expected to provide information on the geometrical and energetic... 

Protonated and diprotonated carbonic acid and carbon dioxide may also have implications in biological carboxylation processes. Although behavior in highly acidic solvent systems cannot be extrapolated to in vivo conditions, related multidentate interactions at enzymatic sites are possible. 

Shin JM, S achs G (2004) Differences in binding properties of two proton pump inhibitors on the gastric H+,K+-ATPase in vivo. Biochem Pharmacol 68 2117-2127... 

The importance of protonated N-hydroxy arylamines as ultimate carcinogens has been suggested for some time (28,40,139). From studies on their reactivity with nucleic acids at different pH s (2,15,16,63,130,131), the pK for protonation of the N-hydroxy group appears to be between pH 5a and 6 thus, a significant proportion (1-10%) of the N-hydroxy derivative exists as the protonated form even under neutral conditions. This would account for the significant levels of covalent modification of DNA observed in vitro by reaction with N-hydroxy arylamines at neutral pH. Consequently, it has been proposed that in vivo formation of non-acetylated aryl... 

The electrodes used in the above studies were double-barreled glass pH sensitive microelectrodes, and the spatial retinal pH profile was recorded by withdrawing the microelectrode tip at a rate of 1 //m/s or lOOpm/step across the retina in vivo or in vitro. In a typical retina pH profile (Fig. 10.9), measured in cat retina by the microelectrode, started from the choroids (Ph = 7.41, at distance Ojum). The pH steadily decreased to a minimum value (a maximum [H+] concentration) in the proximal portion of the outer nuclear layer (pH = 7.14 at —140 jum), then increased to —7.28 (at —310 pm) at the vitreous retinal border. The peak [H+] concentration in this layer indicated that a net production of proton occurred across the avascular outer retina [76],... 

D.R. McMillin, Purdue University In addition to the charge effects discussed by Professor Sykes, I would like to add that structural effects may help determine electron transfer reactions between biological partners. A case in point is the reaction between cytochrome C551 and azurin where, in order to explain the observed kinetics, reactive and unreactive forms of azurin have been proposed to exist in solution (JL). The two forms differ with respect to the state of protonation of histidine-35 and, it is supposed, with respect to conformation as well. In fact, the lH nmr spectra shown in the Figure provide direct evidence that the nickel(II) derivative of azurin does exist in two different conformations, which interconvert slowly on the nmr time-scale, depending on the state of protonation of the His35 residue (.2) As pointed out by Silvestrini et al., such effects could play a role in coordinating the flow of electrons and protons to the terminal acceptor in vivo. 

Carbon nanotubes have been also used as a macromolecular scaffold for Gdm complexes. An amphiphilic gadolinium(III) chelate bearing a C16 chain was adsorbed on multiwalled carbon nanotubes (264). The resulting suspensions were stable for several days. Longitudinal water proton relaxivities, r] showed a strong dependence on the GdL concentration, particularly at low field. The relaxivities decreased with increasing field as predicted by the SBM theory. Transverse water proton relaxation times, T2, were practically independent of both the frequency and the GdL concentration. An in vivo feasibility MRI study has been... 

Herminghaus, S., Frolich, L., Gorriz, C. et al. Brain metabolism in Alzheimer disease and vascular dementia assessed by in vivo proton magnetic resonance spectroscopy. Psychiat. Res. 123 183-190, 2003. 

Tendency for epoxide protonation. When the epoxide is formed in vivo it is believed that protonation of the oxygen occurs. This idea is supported by the fact that there are subcellular regions with high proton activity [49-52]. Protonation of an epoxide oxygen weakens the C-0 bonds and promotes ring opening [53-57]. 

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