Browsing by Author "Smythe, George A."
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Item Inhibition of Indoleamine 2,3 Dioxygenase Activity by H2O2(2006-06-01) Smythe, George A.; Sachdev, Perminder; Walker, Mark J.; Truscott, Roger J.; Littlejohn, Tamantha K.; Takikawa, Osamu; Willows, Robert D.; Jamie, Joanne F.; Austin, Chris J.; Grant, Ross; Poljak, AnneIndoleamine 2,3-dioxygenase is the first and rate limiting enzyme of the kynurenine pathway of tryptophan metabolism, has potent effects on cell proliferation and mediates antimicrobial, antitumorogenic, and immunosuppressive effects. As a potent cytotoxic effector, the mechanisms of indoleamine 2,3-dioxygenase inhibition deserve greater attention. The work presented here represents the first systematic study exploring the mechanisms by which low levels of hydrogen peroxide (10–100 μM) inhibit indoleamine 2,3-dioxygenase in vitro. Following brief peroxide exposure both enzyme inhibition and structural changes were observed. Loss of catalysis was accompanied by oxidation of several cysteine residues to sulfinic and sulfonic acids, observed by electrospray and MALDI mass spectrometry. Enzyme activity could in part be preserved in the presence of sulfhydryl containing compounds, particularly DTT and methionine. However, these structural alterations did not prevent substrate (l-tryptophan) binding. Some enzyme activity could be recovered in the presence of thioredoxin, indicating that the inhibitory effect of H2O2 is at least partially reversible in vitro. We present evidence that cysteine oxidation represents one mechanism of indoleamine 2,3-dioxygenase inhibition.
Item The Physiological Action of Picolinic Acid in the Human Brain(2009-01-01) Smythe, George A.; Coggan, S E.; Grant, RossPicolinic Acid is an endogenous metabolite of L-tryptophan (TRP) that has been reported to possess a wide range of neuroprotective, immunological, and anti-proliferative affects within the body. However the salient physiological function of this molecule is yet to be established. The synthesis of picolinic acid as a product of the kynurenine pathway (KP) suggests that, similar to other KP metabolites, picolinic acid may play a role in the pathogenesis of inflammatory disorders within the CNS and possibly other organs. In this paper we review the limited body of literature dealing with the physiological actions of picolinic acid in the CNS and its associated synthesis via the kynurenine pathway in health and disease. Discrepancies and gaps in our current knowledge of picolinic acid are identified highlighting areas of research to promote a more complete understanding of its endogenous function in the brain.[from article]