Invited Speaker

Analysis of the Mechanism by which Tryptophan Analogs Inhibit Human Myeloperoxidase
Husam M. Abu-Soud, Inga Sliskovic,Manju Sharma, Ibrahim Abdulhamid
USA

Myeloperoxidase (MPO) catalyzes the formation of oxidants that have been implicated in the pathogenesis of various diseases including cardiovascular, pulmonary, and cancer. Inhibition of MPO- oxidant generating activity represents an attractive target for preventing the progression of inflammatory conditions. Recently, we have shown that melatonin and tryptophan serve as potent inhibitors of MPO. In this work, peroxidation and chlorination catalytic activity were utilized to screen for the most effective tryptophan analog that inhibits MPO. Rapid kinetic measurements were performed to determine the mechanisms through which these compounds inhibit the catalytic activity of the enzyme. Substituent on the amino and carboxy terminus of tryptophan enhances its affinity towards MPO as compared to the substituent on the indole ring. Hydrogen bond donor capabilities and positive charge of the amino group is not required for MPO inhibition. Hydroxyl-containing indoles did not inhibit MPO H2O2-consumption activity. Elimination of the negative charge from carboxy terminus by introducing the hydrophobic character significantly enhanced tryptophan analog affinity for MPO and improved its inhibitory properties. Further mechanistic studies indicated that indole compounds inhibited MPO activity through the accumulation of Compound II, an inactive MPO intermediate. Our results show that specific structural features of tryptophan analogs are involved in increasing affinity for MPO, and providing a significantly greater inhibition of MPO's catalytic activities. Indole-dependent inhibition of MPO occurred with a wide range of concentrations that span various physiological and supplemental ranges. Thus, the interplay between MPO and these inhibitors may have a broader implication in the function of several biological systems. This dual regulation by indole inhibitors is unique and represents a new means through which these compounds can control MPO and its downstream inflammatory pathways.