The amino acid histidine exhibits aromatic chemical properties
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Peer-reviewed literature and reference texts establish that histidine contains an imidazole ring and exhibits aromatic characteristics or participates in aromatic interactions.
Imidazole is, from a structural point of view, a heterocycle consisting of three C atoms and two N atoms, belonging to the class of diazoles, having two N atoms at the first and third positions in the aromatic ring. Being a polar and ionizable aromatic compound, it has the role of improving the pharmacological properties of lead molecules, thus being used to optimize their solubility and bioavailability. Imidazole is a constituent of many important biological compounds, like histidine, histamine, and purine compounds, the most widespread heterocyclic compound in nature. In current practice, substituted imidazole derivatives play a major role in antifungal, antibacterial, anti-inflammatory, CNS active compounds, antiprotozoal, as well as anticancer therapy. Thus, imidazole derivatives have demonstrated significant anticancer activities by inhibiting the key metabolic pathways essential for tumor cell growth and survival. Nitroimidazoles, for instance, have been employed as hypoxia-directed therapeutic agents, targeting oxygen-deprived tumor tissues, while mercaptopurine derivatives are well-established in oncological treatments. Structural modifications of the imidazole nucleus have led to the novel compounds exhibiting increased selective cytotoxicity against cancer cells, while sparing normal healthy cells. In accordance with what has been stated, this review highlights recent research on the medicinal and pharmaceutical interest of novel imidazole derivatives, emphasizing their potential in the development of new drugs.
Superactivation of thermolysin by acylation with amino acid N-hydroxysuccinimide esters. Synthesis of a series of active N-hydroxysuccinimide esters of aliphatic and aromatic amino acids has yielded a new class of reagents for the covalent modification of proteolytic enzymes such as thermolysin. The activities of aliphatic acyl amino acid thermolysins are from 1.7 to 3.6 times greater than that of the native enzyme when hydrolyzing durylacryloyl-Gly-Leu-NH2, the substrate employed most widely. By comparison, the aromatic acylamino acid derivatives are "superactive," their activities being as much as 70-fold greater. Apparently, the aromatic character of the amino acid introduced is a critical variable in the determination of the functional response. The increased activity is completely restored to that of the native enzyme by deacylation with nucleophiles, such as hydroxylamine, and the rate of restoration of native activity is a function of the particular acyl group incorporated. Preliminary evidence regarding the chemical properties of the modified enzyme suggests that tyrosine, rather than lysine, histidine, or arginine, may be the residue modified.
Interaction of aromatic amino acids with neutral polyadenylic acid.
The aromatic amino acids tryptophan, phenylalanine, and histidine interact with singlestranded polyadenylic acid [poly(A)] as observed by proton magnetic resonance spectroscopy. The chemical shift of the C(2) and C(8) protons of the adenine moiety of poly(A) is consistent with a destacking of the initially partly-stacked polynucleotide chain by the intercalation of the planar ring structure. The relative magnitude of this interaction is tryptophan>phenylalanine>histidine.
Published in Proceedings of the National Academy of Sciences of the United States of America (1971)
from the past grouping of molecules based on odor, before their general chemical properties were understood. The current definition of aromatic compounds
Aromatic compounds or arenes are organic compounds "with a chemistry typified by benzene" and "cyclically conjugated."
The word "aromatic" originates from the past grouping of molecules based on odor, before their general chemical properties were understood. The current definition of aromatic compounds does not have any relation to their odor. Aromatic compounds are now defined as cyclic compounds
The benzene dimer is the prototypical system for the study of pi stacking, and is experimentally bound by 8–12 kJ/mol (2–3 kcal/mol) in the gas phase with a separation of 4.96 Å between the centers of mass for the T-shaped dimer. X-ray crystallography reveals perpendicular and offset parallel configurations for many simple aromatic compounds. Similar offset parallel or perpendicular geometries were observed in a survey of high-resolution x-ray protein crystal structures in the Protein Data Bank. Analysis of the aromatic amino acids phenylalanine, tyrosine, histidine, and tryptophan indicates that dimers of these side chains have many stabilizing interactions at distances larger than the average van der Waals radii.
Histidine (His) stands out as the most versatile natural amino acid due to its side chain's facile propensity to protonate at physiological pH, leading to a transition from aromatic to cationic characteristics and thereby enabling diverse biomolecular interactions. In this study, our objective was to quantify the energetics and geometries of pairwise interactions involving His at varying pH levels. Through quantum chemical calculations, we discovered that His exhibits robust participation in both π-π and cation-π interactions, underscoring its ability to adopt a π or cationic nature, akin to other common residues. Of particular note, we found that the affinity of protonated His for aromatic residues (via cation-π interactions) is greater than the affinity of neutral His for either cationic residues (also via cation-π interactions) or aromatic residues (via π-π interactions). Furthermore, His frequently engages in CH-π interactions, and notably, depending on its protonation state, we found that some instances of hydrogen bonding by His exhibit greater stability than is typical for interamino acid hydrogen bonds. The strength of the pH-dependent pairwise energies of His with aromatic residues is supported by the abundance of pairwise interactions with His of low and high predicted pKa values. Overall, our findings illustrate the contribution of His interactions to protein stability and its potential involvement in conformational changes despite its relatively low abundance in p
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