How does hexachlorobenzene treatment affect liver uroporphyrinogen decarboxylase?

The role of type I and type II 5′ deiodinases on hexachlorobenzene-induced alteration of the hormonal thyroid status

“…As kidney mRNA from HCB and control rats are not different, two mechanisms for this effect are possible: HCB may directly inhibit 5 D-I activity, or the enzyme synthesis in a post-transcriptional mechanism. In this respect, it has been reported that HCB modifies the physicochemical properties of liver uroporphyrinogen decarboxylase leading to a sharp decrease of its activity (Chaufan et al, 2001). Another pesticide, methoxychlor, interferes with thyroid hormone metabolism binding to cysteine 372 or 375 or to lysine 376 of hepatic 5 D-I (Zhou et al, 1995).…”

Absolute requirement for iron in the development of chemically induced uroporphyria in mice treated with 3-methylcholanthrene and 5-aminolevulinate

“…4). The formation of an inhibitor of UROD in livers of mice treated with iron and hexachlorobenzene has been demonstrated (Chaufan et al 2001). Inhibition of the UROD pathway naturally increases the substrate available for the UROX pathway, and therefore, results in the accumulation of the oxidation product, URO.…”

The Importance of the MM Environment and the Selection of the QM Method in QM/MM Calculations

“…URO-III serving to bind and recognize the substrate (Chaufan, de Molina, & de Viale, 2001;Phillips et al, 2003). Notably, of the polarpositive residues within the active site, one or more arginyl residues (hUROD: Arg37, Arg41, and Arg50) have been found to be catalytically important.…”

“…Indeed, for several variants of UROD, the rate-limiting step appears to be decarboxylation of the 7-carboxylate intermediate. For UROD from various species, the experimentally determined barriers for the first decarboxylation lie in the range of 8.4-51.5 kJ mol À1 (Chaufan et al, 2001;Juaréz et al, 2007). Thus, the QM/MM calculated barrier is in fact in better agreement with related experimentally reported values for the first decarboxylation of ring D. Moreover, the explicit treatment of the protein environment provided details that were not observed in the DFT/cluster-based calculations.…”