Tautomerism histidine

Annular tautomerism of azoles and benzazoles [the nonaromatic tautomers of imidazole 17, 2H and 4(5)H have been calculated at the MP2/6-31G level to be about 15 kcal mol less stable than the IH tautomer (95JOC2865)]. We present here the case of 4(5)-substituted imidazoles, different from the histamine, histidine, and derivatives already discussed. By analogy with these histamines, 4-methylimidazole 17a is often named distal [N(t)H] and 5-methylimidazole 17b, proximal [N(7t)H] (Scheme 9). 

Special attention has been given to the study of tautomeric equilibria in solutions of histidine 22 because the key functional role of such equilibria in proteins is recognized. In aqueous solutions the tautomers of histidine rapidly interconvert and only a single averaged signal is observed for each ring nitrogen (Scheme 10). 

Pelton JG, Torchia DA, Meadow ND, Roseman S. Tautomeric states of the active-site histidines of phosphorylated and unphosphorylated IIIGlc, a signal-transuding protein from Escherichia coli, using two-dimensional heteronuclearNMR techniques. Prot Sci 1993 2 543-558. 

Tanokura M (1983) 1 II-NMstudy R on the tautomerism of the imidazole ring of histidine residues I. Microscopic pK values and molar ratios of tautomers in histidine-containing peptides. Biochim Biophys Acta 742 576-585. 

Classical simulations of MbCO using the CHARMM force field were performed for different tautomerization states of the distal histidine residue (His64) [33], These simulations showed that when His64 is protonated at N,5 (denoted the tautomer) it often rotates such that it exposes either the N,>—H bond or the un-protonated N atom to the CO, as depicted in Scheme 3.4. We... 

Therefore, when we meet structures for the imidazole-containing amino acid histidine, we may encounter either of the tautomeric forms shown. Though there... 

The process continues, in that the now uncharged histidine is suitably placed to remove a proton from the second of the two hydroxyls, and tautomerization is achieved by abstraction of a proton from the now non-ionized... 

However, the environment of individual histidine residues within a protein structure may affect this tautomeric equilibrium. 

The conformational ambiguity of the histidine side chain is resolved when histidine coordinates to a metal ion. Logically, only N , and not C-H, may coordinate to a metal. The tautomeric ambiguity of the neutral histidine side chain is similarly resolved when histidine coordinates to a metal ion. Interestingly, the complexation of histidine with zinc may affect the tautomeric equilibrium, since the majority of histidine ligands found in zinc protein structures are in the N8-H form (Chakrabarti, 1990c). 

The tautomeric ratio of B to A for histidine in water (Eq. 2-6) has been estimated, using 15N- and 13C-NMR, as 5.0 when the a-amino group is proto-nated and as 2.5 when at high pH it is unprotonated.17 This tautomerism of the imidazole group is probably important to the function of many enzymes and other proteins for example, if Ne of structure A (Eq. 2-6) is embedded in a protein, a proton approaching from the outside can induce the tautomerism shown with the release of a proton in the interior of the protein, perhaps at the active site of an enzyme. The form protonated on Ns (B of Eq. 2-6), which is the minor form in solution, predominates in some positions within proteins.18... 

For example, cells of E. coli can be grown on a minimal medium containing [15N] NH4C1. Since 13C can also be introduced in a similar way it is possible to incorporate both isomers simultaneously. Production of uniformly labeled protein containing 15N and / or 13C provides the basis for multidimensional isotope-edited spectra necessary for protein structure determination (next section) and for study of tautomerization of histidine rings (Eq. 2-6) 460/462-464 15N chemical shifts of groups in proteins are spread over a broad range (Table 3-3).465... 

The phenolic group of the GFP chromophore is apparently dissociated in the form absorbing at 395 nm and is in a tautomeric equilibrium with the other species. However, some histidine-containing replacement mutants have pH-dependent spectral changes in which the dipolar ionic form shown above, and absorbing at a longer wavelength, loses... 

Some peculiar aspects of the kinetic behavior of histidine are ascribed to the formation of a tautomeric form of the anion (11). favored by the ammonium group in the side chain. 

AMI semiempirical calculations have shown that, as far as tautomerism is concerned, there is a structural relationship between jS-dicarbonyl compounds and NH-pyrazoles, and in a wide variety of NH-pyrazoles studied " the most stable tautomer was found to be that having the largest single-bond character between the C(3)—C(4) bond. The problem of proton transfer in NH-pyrazole crystals has been subjected to a detailed theoretical study, while a study of the tautomerism of 2-aryl and 2-heteroaryl derivatives of benzimidazole has indicated that tautomerism takes place by the intermolecular relay of protons between stacked molecules. The first report of the stable co-existence of two different histidine tautomers in one peptide crystal structure has appeared. Ab initio calculations have been used to study the tautomerism of both histamine and pyrazolo[3,4-i/]pyridazine in the gas phase and in aqueous solution, and a theoretical study of the NH tautomerism in free-base porphyrin has been undertaken. ... 

In the MAS NMR spectra of histidine-dipeptides, the C chemical shifts for and C span a large range (up to 13 ppm) and are highly influenced by the tautomer effect and intermolecular interactions <2005JA12544>. The imidazole ring chemical shifts of 50 (158.6, 123.8 (Vcf = 36.0), 131.0 ppm, Scheme 14) resemble more closely those of l-methyl-5-(/i-tolyl)-4-trifluoromethyl-l//-imidazole (137.6, 128.8 ( cF = 37.4Hz), 133.0ppm). Based on this observation, it was proposed that in the solid state 50 most likely assumes the tautomeric form 50a rather than 50b <2001JHC773>. 

Comparison of C-NMR chemical shifts and pH profiles for histidine and its 1- and 3-methyl derivatives shows that in basic solution the preferred structure is 106. This tautomeric form is maintained in a number of histidine... 

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