Inhibition of Several Enzymes by Gold Compounds II. β-Glucuronidase, Acid Phosphatase and L-Malate Dehydrogenase by Sodium Thiomalatoraurate (I), Sodium Thiosulfatoaurate (I) and Thioglucosoaurate (I)

Abstract

Bovine liver beta-D-glucuronide glucuronohydrolase, EC 3.2.1.32), wheat germ acid phosphatase (orthophosphoric monoesterphosphohydrolase, EC 3.1.3.2) and bovine liver L-malate dehydrogenase (L-malate: NAD oxidoreductase, EC 1.1.1.37) were inhibited by a series of gold (I) complexes that have been used as anti-inflammatory drugs. Both sodium thiosulfatoaurate (I) (Na AuTs) and sodium thiomalatoraurate (NaAuTM) effectively inhibited all three enzymes, while thioglucosoaurate (I) (AuTG) only inhibited L-malate dehydrogenase. The equilibrium constants (K1) ranged from nearly 4000 microM for the NaAuTM-beta-glucuronidase interaction to 24 microM for the NaAuTS-beta-glucuronidase interaction. The rate of covalent bond formation (kp) ranged from 0.00032 min-1 for NaAuTM-beta-glucuronidase formation to 1.7 min-1 for AuTG-L-malate dehydrogenase formation. The equilibrium data shows that the gold (I) drugs bind by several orders lower than the gold (III) compounds, suggesting a significantly stronger interaction between the more highly charged gold ion and the enzyme. Yet the rate of covalent bond formation depends as much on the structure of the active site as upon the lability of the gold-ligand bond. It was also observed that the more effective the gold inhibition the more toxic the compound.

Anticancer Activity of Metal Complexes: Involvement of Redox Processes

“…), Au I complexes effect the GR and Gpx system only at higher concentrations. Explanations for this are either the structure of the active site or the lability of the gold–ligand bonds (122, 209). Further, it has been shown that the generation of H 2 O 2 by Au I complexes did not cause significant lipid peroxidation.…”

Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase

“…In vitro studies on the interaction with TrxR, GR and GPx showed that all phosphine gold complexes, as already stated for a variety of gold compounds, mostly inhibit cytosolic and mitochondrial TrxR enzyme isoforms while GR and GPx required higher concentrations to be inhibited. In this context, previous studies established that the rate of enzyme inhibition may depend either on the structure of the active site or on the lability of the gold-ligand bond [53].…”

Effect of 2-Chloro-Substitution of Adenine Moiety in Mixed-Ligand Gold(I) Triphenylphosphine Complexes on Anti-Inflammatory Activity: The Discrepancy between the In Vivo and In Vitro Models

“…The ability of gold(I) species to interact with the active site of thioredoxin reductase can be clarified sufficiently by the application of the Pearson’s principle of hard and soft acids and bases, while the gold(I) species as a soft acid tend to bind with the soft base ligands [ 19 ]. Therefore it prefers the binding to selenolate groups of TrxR, subsequently leading to the inhibition of its activity both in cytosol and mitochondria, leaving the similar system of glutahione reductase, containing the thiolate groups in the active site, unaffected [ 19 , 22 ] up to high concentrations. The sum of all the above mentioned effects, the TrxR inhibition, disturbance of mitochondrial respiration, increased production of reactive oxygen species by redox cycling, mitochondrial swelling, and decreasing in the mitochondrial membrane potential, subsequently lead to apoptosis [ 4 ].…”