Inhibition of human seminal fluid and Leishmania donovani phosphatases by molybdate heteropolyanions.
Inhibition of a tartrate-resistant acid phosphatase (ACP) from Leishmania donovani and the tartrate-sensitive ACP from human seminal fluid (prostatic ACP) was examined using a series of 13 molybdate-containing heteropolyanions. The heteropolyanions were divided into four groups based on the number of molybdenum atoms they contain: Group I, Mo4; Group II, Mo6-8; Group III, Mo12; Group IV, Mo18. Two of the four groups, those consisting of compounds that contain either an Mo4 unit or an Mo18 unit with a heteroatom in the central cavity, were potent inhibitors and exhibited the highest degree of selectivity against the leishmanial and seminal fluid ACPs. The inhibition of prostatic ACP by complex E2 could be completely reversed by dialysis. Little inhibition of the acid phosphatase, beta-glucuronidase, or alpha-mannosidase from human spleen was observed with complexes B' and E2. For the seminal fluid phosphatase, the Ki values obtained with arsenate and vanadate depended markedly on pH, suggesting that, unlike most other phosphatases, the conformation of the inhibitor binding site on human seminal fluid ACP is pH-dependent. Results of competition experiments performed with various inhibitor pairs indicated that complex D2 binds to the active site of prostatic ACP while complex M binds at some site on the enzyme that affects the active site. Binding of complex M also modifies the affinity of the enzyme for other inhibitors such as vanadate. The potency of several heteropolyanion complexes and their selective inhibition of pathophysiologically significant acid phosphatases indicate that these compounds may have value as tools for study of the structure and function of this class of enzyme and perhaps in the therapy of human disease.
Saha
A K
AK
Department of Biochemistry, School of Medicine, University of New Mexico, Albuquerque 87131.
Crans
D C
DC
Pope
M T
MT
Simone
C M
CM
Glew
R H
RH
D000135:Acid Phosphatase / Q000037:antagonists & inhibitors*; D000818:Animals; D000838:Anions; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D007893:Leishmania donovani / Q000201:enzymology*; D008297:Male; D008982:Molybdenum / Q000494:pharmacology*; D012661:Semen / Q000201:enzymology*; D013644:Tartrates
D000838:Anions; D013644:Tartrates; C044659:molybdate; D008982:Molybdenum; D000135:Acid Phosphatase; C029768:tartaric acid