Theoretical calculations and reaction analysis on the interaction of pentavalent thioarsenicals with biorelevant thiol compounds.
To obtain a rational understanding of the extraordinary interaction of pentavalent thioarsenicals with biorelevant thiol compounds, we carried out ab initio calculations on related arsenic compounds and discussed the correlation between the distribution of observed arsenic species in actual reaction systems and the corresponding calculated reaction enthalpies. Previously, it was considered that pentavalent arsenicals do not form thiol conjugates. However, the dimethylmonothioarsinic acid-glutathione conjugate (DMMTAV-GSH) was recently reported as the first stable conjugate of a pentavalent arsenical with a thiol compound. We carried out detailed analysis of the DMMTAV-GSH formation reaction and demonstrated that this conjugate could be formed nonenzymatically under weakly acidic conditions. On the basis of the ab initio calculations, this conjugation was an exothermic reaction (delta H = -4.85 kcal/mol) and gave the minimum energy point during the reaction sequence of DMMTAV with a thiol compound. However, in the case of dimethylarsinic acid (DMAV), a corresponding oxo acid to DMMTAV, conjugation with a thiol compound is an endothermic reaction (delta H = +0.06 kcal/mol). The minimum energy point of the reaction sequence of DMAV with a thiol compound was the formation of a trivalent dimethylarsinous acid (DMAIII)-GSH conjugate. Because the formation of arsenic-sulfur bonds is one of the major mechanisms for arsenic toxicity, these energetic results could account for the extraordinary behaviors and toxicities of thioarsenicals in vivo and in vitro in comparison with those of the corresponding oxo acids.
Suzuki
Noriyuki
N
Graduate School of Pharmaceutical Sciences, Chiba University, Chuo, Chiba 260-8675, Japan.
Naranmandura
Hua
H
Hirano
Seishiro
S
Suzuki
Kazuo T
KT
D020261:Arsenic Poisoning; D002101:Cacodylic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004785:Environmental Pollutants / Q000009:adverse effects / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry*; D008956:Models, Chemical; D021241:Spectrometry, Mass, Electrospray Ionization; D013816:Thermodynamics; D001149:Arsenates
D002101:Cacodylic Acid; D004785:Environmental Pollutants; D005978:Glutathione; C518667:dimethylmonothioarsinic acid; D001149:Arsenates