Reaction Mechanisms of Histidine and Carnosine with Hypochlorous Acid Along with Chlorination Reactivity of N-Chlorinated Intermediates: A Computational Study

Abstract

Hypochlorous acid (HOCl) released from activated leukocytes not only plays a significant role in the human immune system but is also implicated in numerous diseases including atherosclerosis and some cancers due to its inappropriate production. Histidine (His) and carnosine (Car), as a respective mediator and protective agent of HOCl damage, have attracted considerable attention; however, their detailed reaction mechanisms are still unclear. In this study, using a His residue with two peptide bond groups (HisRes) as a model, the reaction mechanisms of HisRes and Car including NεH and NδH tautomers with HOCl along with the chlorination reactivity of N-chlorinated intermediates were investigated by quantum chemical methods. The obtained results indicate that in the imidazole side chain, the pyridine-like N is the most reactive site rather than the pyrrole-like N, and the kinetic order of all of the possible reaction sites in HisRes follows pyridine-like N > imidazole Cδ ≫ imidazole Cε > pyrrole-like N, while that in Car is pyridine-like N ≫ imidazole Cδ ≫ amide N. As for N-chlorinated intermediates at imidazole, although the unprotonated form has a low chlorination reactivity as expected, it can still chlorinate tyrosine. Especially, the protonated form exhibits similar ability to HOCl, causing secondary damage in vivo. N-Chlorinated Car features higher internal chlorine migration ability than its intermolecular transchlorination, preventing further HOCl-induced damage. Additionally, a generally overlooked nucleophilic Cl– shift is also found in N-chlorinated Car/HisRes, indicating that nucleophilic sites in biomolecules also need to be considered. The outcomes of this study are expected to expand our understanding of secondary damage and protective mechanisms involved in HOCl in humans.

Insights into C–C Bond Cleavage Mechanisms in Dichloroacetonitrile Formation during Chlorination of Long-Chain Primary Amines, Amino Acids, and Dipeptides

“…The results indicate that OCl – is dramatically less reactive than HOCl in the N -chlorination with the Δ G ⧧ value remarkably larger than that of HOCl (60 vs 4 kcal/mol). This implies that no contribution is from the OCl – species, which is inconsistent with our previous results about the N -chlorination of imidazole . In addition to HOCl, chlorinating agents Cl 2 and Cl 2 O were identified to play important roles in various systems; ,− therefore, HOCl, Cl 2 , and Cl 2 O species were all considered in this study.…”

“…This implies that no contribution is from the OCl − species, which is inconsistent with our previous results about the Nchlorination of imidazole. 65 In addition to HOCl, chlorinating agents Cl 2 and Cl 2 O were identified to play important roles in various systems; 47,51−56 52 In addition, in view of some existing forms of substrates accounting for a small fraction but featuring high reactivity, i.e., the deprotonated amino group of all the precursors investigated here in the N-chlorination reaction and the phenolate form of the phenolic compounds in the chlorination, addition, and C−C cleavage reactions, thus, their contributions to the reactions should be considered. Therefore, two existing forms of these substrates in the above reactions were considered in the estimation of apparent rate constants (k obs-est ) as presented in eq 3…”

Identification of chlorinated products from tyrosine and tyrosyl dipeptides during chlorination: a computational study

“…This infers the possibility of the chlorine transfer from the products chlorinated at the amino site to the phenol C site, similar to the chlorine transfer from the imidazole N site to the amino site for carnosine. 57,58…”

“…This infers the possibility of the chlorine transfer from the products chlorinated at the amino site to the phenol C site, similar to the chlorine transfer from the imidazole N site to the amino site for carnosine. 57,58 For the dichlorination, only the chlorination of N-Cl-Tyr, 3-Cl-Tyr, and 5-Cl-Tyr was studied because they are the main products in the monochlorination. As shown in Scheme 4, the amino N site of N-Cl-Tyr, as the dominant product from the monochlorination of Tyr, can be attacked by HOCl with DG sobsest and k obs-est values of 12.4 kcal mol −1 and $10 to that in Tyr.…”

Antibacterial and mildew‐proof aramid fiber III: The chlorination mechanism through experimental and computational investigation

“…The HClO will attack the two Nitrogen atoms with equal probability, and finally a mixture of two substitution products can be obtained. However, recent studies have shown that imidazole ring can also undergo chlorination through another pathway in neutral environments, in which the hypochlorous acid molecule binds with NH bond via electrostatic and synergic effect of water molecules, and replaces the hydrogen atom directly 39 . Therefore, in order to clarify the mechanism of chlorination on the imidazole ring in this chemical environment, the possible reaction paths are listed as unimolecular route and the bimolecular route (Figure 7e,f), respectively, and the Gibbs free energy of the reaction was calculated and compared to find the optimal reaction pathway, with relevant thermodynamic data listed in Table S2.…”