Inhibition of several enzymes by gold compounds. II. beta-Glucuronidase, acid phosphatase and L-malate dehydrogenase by sodium thiomalatoraurate (I), sodium thiosulfatoaurate (I) and thioglucosoaurate (I).
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.
Lee
M T
MT
Department of Chemistry, Auburn University, AL 36849-5312.
Ahmed
T
T
Haddad
R
R
Friedman
M E
ME
D000135:Acid Phosphatase / Q000037:antagonists & inhibitors*; D000818:Animals; D006051:Aurothioglucose / Q000494:pharmacology*; D002417:Cattle; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D012971:Gold Sodium Thiosulfate / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors*
D006052:Gold Sodium Thiomalate; D006051:Aurothioglucose; D012971:Gold Sodium Thiosulfate; D008291:Malate Dehydrogenase; D000135:Acid Phosphatase; D005966:Glucuronidase