INHIBITION OF MYOINOSITOL MONOPHOSPHATASE ISOFORMS BY AROMATIC PHOSPHONATES

alpha-Hydroxyphosphonates are moderately potent (K-i = 6-600 mu M) inh ibitors of the enzyme myo-inositol monophosphatase (McLeod et al., Med . Chem. Res. 1992, 2, 96). -[4-(5,6,7,8-tetrahydronaphtyl-1-oxy)phenyl ]methyl phosphonate (3) was resynthesized and its inhibitory potency t owards the recombinant bovine brain enzyme confirmed (K-i = 20 mu M). 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 h ydrophobic part of the inhibitor interacts with amino acid side chains that are located at the interface between the enzyme subunits in an a rea (amino acids 175-185) with low similarity between the two isozymes . Phe-183 in the human enzyme was replaced with leucine, the correspon ding residue in the bovine isoform. The three isozymes (human wildtype , bovine wild-type and human F183L) had similar kinetic properties, ex cept that the bovine enzyme was less effectively inhibited by high con centrations of the activator Mg2+. The F183L mutant enzyme had a twofo ld increased affinity for compound 3 as compared to the human wild-typ e form. We conclude that residue 183 contributes to the binding of aro matic hydroxyphosphonates to IMPase, but it is not the only determinin g factor for inhibitor specificity with respect to different isozymes. (C) 1998 Elsevier Science Ltd. All rights reserved.