Isozyme-specific enzyme inhibitors. 10. Adenosine 5'-triphosphate derivatives as substrates or inhibitors of methionine adenosyltransferases of rat normal and hepatoma tissues

Abstract

Monosubstituted adenosine 5'-triphosphate (ATP) derivatives with a substituent of up to four atoms at any of eight positions in the adenosine moiety, or with an isosteric group replacement at O5' or in the triphosphate moiety, have been evaluated kinetically as substrates and inhibitors of liver (I), kidney (II), and Novikoff hepatoma (T) variants of rat methionine adenosyltransferase. Inhibitory potencies were expressed as KM(ATP)/Ki (for competitive inhibition vs. ATP) or as KM(ATP)/KM when no Ki value was available. Variant I was inhibited more powerfully than II or T by all of four ATP derivatives for which comparative data were obtained. Among 15 ATP derivatives, four were substrates of II or T and the remainder inhibited II and T competitively with respect to ATP; most derivatives exhibited at least moderate (greater than 0.5) inhibitory potency. Differential inhibition of II and T was shown by 11 of 14 ATP derivatives; relative inhibitory potencies (T:II) ranged from 5.5 with 2-SCH3-ATP [KM(ATP)/Ki = 1.3 with T] to 0.24 with the ATP isostere with a C5'-CH2-P alpha system [KM(ATP)/Ki = 1.9 with II]. The most effective inhibitor was the P beta, P gamma imido isostere of ATP with inhibitory potencies of 25 and 35 for II and T, respectively. The findings provide further evidence that substrate derivatives with single short groups attached at various positions, or with single isosteric group replacements, are frequently useful probes in the design of isozyme-selective inhibitors.

Anti‐HIV‐1 activity of 3‐deaza‐adenosine analogs

“…However, there has been no evaluation of the effect of the phosphate analogs of DZA‐nucleotides as substrate or inhibitors of ATP: l ‐methionine‐ S ‐adenosyltransferase (AdoMet synthetase). It can not be predicted whether deaza‐nucleotides would alter AdoMet synthetase activity based on the potency of ATP and ADP derivatives to act as substrates or inhibitors of AdoMet synthetase [47], and that adenine and ribose moieties have minor contacts compared to the phosphate groups with the enzyme active site [48,49]. As DZAri has been shown to inhibit AdoMet decarboxylase in HeLa cell extracts [50], it is likely that other DZA analogs also affect the AdoMet decarboxylase.…”

Multisubstrate adduct inhibitors: Drug design and biological tools

“…Methionine S-adenosyltransferase (MAT; EC: 2.5.1.6) is an enzyme which catalyzes the attack of the sulfur atom of l-methionine on C5′ of ATP [116][117][118] . Hampton et al…”

“…reported the synthesis of new potential inhibitors for two isozymes of MAT: M-2 and M-T [116][117][118] . A preliminary study looked at the effect of the distance between S and C5′ in the covalent adduct 45 of l-methionine and ,-imido-ATP [116][117][118] .…”

“…A preliminary study looked at the effect of the distance between S and C5′ in the covalent adduct 45 of l-methionine and ,-imido-ATP [116][117][118] . Compounds were tested as inhibitors of M-2 and M-T forms of methionine S-adenosyltransferase (Table 7).…”

“…It was also found that replacement of the 6-amino group of the ATP-moiety by S-nBu gave a compound three-fold more selective for the target isozyme. Hampton reported a new series of potential inhibitors which were evaluated and compared for potency with 45 [116][117][118]120 .These compounds showed an inhibitory activity comparable to 45 but were found to have great selectivity between M-2 and M-T when methionine was used as substrate.…”