Inhibition of myo-inositol monophosphatase isoforms by aromatic phosphonates.
alpha-Hydroxyphosphonates are moderately potent (Ki = 6-600 microM) inhibitors of the enzyme myo-inositol monophosphatase (McLeod et al., Med. Chem. Res. 1992, 2, 96). Hydroxy-[4-(5,6,7,8-tetrahydronaphtyl-1-oxy)phenyl]methyl phosphonate (3) was resynthesized and its inhibitory potency towards the recombinant bovine brain enzyme confirmed (Ki = 20 microM). Similar aromatic difluoro-, keto-, and ketodifluorophosphonates (5, 7, 9) were inactive. Compound 3 was 15-fold less active on the human as compared to the bovine enzyme. Molecular modeling suggested that the hydrophobic part of the inhibitor interacts with amino acid side chains that are located at the interface between the enzyme subunits in an area (amino acids 175-185) with low similarity between the two isozymes. Phe-183 in the human enzyme was replaced with leucine, the corresponding residue in the bovine isoform. The three isozymes (human wild-type, bovine wild-type and human F183L) had similar kinetic properties, except that the bovine enzyme was less effectively inhibited by high concentrations of the activator Mg2+. The F183L mutant enzyme had a twofold increased affinity for compound 3 as compared to the human wild-type form. We conclude that residue 183 contributes to the binding of aromatic hydroxyphosphonates to IMPase, but it is not the only determining factor for inhibitor specificity with respect to different isozymes.
Ganzhorn
A J
AJ
Marion Merrell Research Institute, Strasbourg, France.
Hoflack
J
J
Pelton
P D
PD
Strasser
F
F
Chanal
M C
MC
Piettre
S R
SR
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009596:Nitrophenols / Q000378:metabolism; D063065:Organophosphonates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
C116525:1-(4-(5,6,7,8-tetrahydronaphthyloxy)phenyl)-1-hydroxymethylphosphonic acid; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009596:Nitrophenols; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D013764:Tetrahydronaphthalenes; C008644:nitrophenylphosphate; D015720:5'-Nucleotidase