Differential effects of flavonoids on bovine kidney low molecular mass protein tyrosine phosphatase

Abstract

Among the structurally related flavonoids tested on the bovine kidney low molecular weight protein tyrosine phosphatase (LMrPTP) activity, quercetin activated by about 2.6-fold the p-nitrophenyl-phosphate (p-NPP)-directed reaction, in contrast to morin that acted as a competitive inhibitor, with Ki values of 87, 73 and 50 microM for p-NPP, FMN, and tyrosine-phosphate, respectively. Other related flavonoids, such as rutin, kaempferol, catechin, narigin, phloretin and taxifolin did not significantly affect the LMrPTP activity. The positions of the hydroxyl groups in the structures of the flavonoids were important for their distinct effects on LMrPTP activity. The hydroxyl groups at C3' and C4' and the presence of a double bond at C2 and C3 were essential for the activating effect of quercetin. The absence of the 3'-OH (kaempferol), absence of the double bond (taxifolin) and the presence of the sugar rutinose at the 3-OH (rutin) suppressed the effect of quercetin. The C2'- and C4'-hydroxyl groups, the presence of the double bond, and a C4-ketone group were important requirements for the inhibitory effects of morin.

Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery

“…Two natural products morin and ferruginol are reported to weakly inhibit LMW-PTP [147, 148]. In an effort to optimize flavonoid-based LMW-PTP inhibitors, Forghieri et al identified several compounds having sub-micromolar to low micromolar IC 50 to LMW-PTP, although these compounds display similar inhibitory activity to PTP1B [149].…”

Low Molecular Weight Phosphotyrosine Protein Phosphatases as Emerging Targets for the Design of Novel Therapeutic Agents

“…Morin reached an IC 50 of 10 μM in the presence of phosphotyrosine as substrate. Other tested molecules (catechin, myricetin, phloretin, and rutin) produced lower inhibition levels (from 14% to 25% inhibition at 400 μM with p -NPP as substrate), whereas narigin, kaempferol, and taxifolin did not exert any significant effect …”

“…Other tested molecules (catechin, myricetin, phloretin, and rutin) produced lower inhibition levels (from 14% to 25% inhibition at 400 μM with p-NPP as substrate), whereas narigin, kaempferol, and taxifolin did not exert any significant effect. 157 It is still unclear whether the activation mechanism of quercetin is similar to the one proposed by Wang et al for the activation of the yeast LMW-PTP by adenine. 83 Miranda et al 157 suggested that, like adenine, the hydroxy groups at positions 3′ and 4′ of quercetin might form hydrogen bonds with a water molecule and keep it in a suitable orientation for the hydrolysis of the phosphoenzyme intermediate, thus promoting the catalytic reaction.…”

“…It was proposed that the displacement of one hydroxy group from the position 3′ of quercetin to position 2′ of morin could prevent the interaction with the water molecule responsible for the hydrolysis of the phosphoenzyme intermediate. Thus, morin could inhibit LMW-PTP by establishing interactions between the hydroxy groups in positions 2′ and 4′ and residues of the catalytic site . The double bond between C2 and C3 and the ketone group in position 4 were also hypothesized to be important for the inhibitory effect of morin, but the interaction mode of the molecule with LMW-PTP was not definitely clarified. , …”

From immune response to cancer: a spot on the low molecular weight protein tyrosine phosphatase

“…However, these compounds did not present low inhibition constants [81]. We have shown that the flavonoid morin acts as a competitor inhibitor of LMWPTP, displaying an inhibitory constant at microM range [82]. Another natural compound, ferruginol, was able to inhibit the human recombinant LMWPTP and also inhibited this enzyme in prostate cancer treated with ferruginol [83].…”