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Mammalian porphobilinogen synthase (PBGS) is a metalloenzyme, which requires Zn2+ and reduced thiol groups for maximal catalytic activity, and is an important molecular target for the widespread environmental toxic metals. The mechanism underlying the PBGS inhibition by elements of Group 13 metals (Al3+, Ga3+, In3+, and Tl3+) has not yet been determined. The main objective of the present study was to characterize, in a comparative way, the molecular mechanism of PBGS inhibition caused by salts of elements of Group 13. Al3+, Ga3+, and In3+i inhibited purified hepatic bovine PBGS, and the IC50 for PBGS inhibition by Ga3+ (IC50 = 442 ± 63 μmol l−1) was higher than that for Al3+ (IC50 = 319 ± 41 μmol l−1) and In3+ (IC50 = 298 ± 44 μmol l−1). Zn2+ restored completely aluminum-induced inhibitory effect on PBGS activity. Tl3+ inhibited liver bovine PBGS (IC50 = 8.5 ± 0.9 μmol l−1) and glutathione reduced markedly this inhibitory effect (IC50 = 87 ± 8 μmol l−1). GSH had no protective effects on the inhibitory actions of Al3+ and Ga3+ against PBGS; in contrast, GSH reduced the inhibitory effect of In3+ on PBGS. dl-Dithiothreitol (DTT) restored completely the enzyme activity inhibited by Tl3+ and had only a modest effect on the inhibitory effect of In3+. Zn2+ was unable to change the inhibitory effect of Tl3+ on liver bovine PBGS; in contrast, Zn2+ recovered almost completely the enzyme inhibition caused by In3+ and Ga3+. Thus, our results indicated that Al3+, Ga3+, and In3+ inhibit PBGS by competing with Zn2+, whereas Tl3+ and In3+ inhibit bovine PBGS by directly oxidizing essential sulfhydryl groups.