The Cyclopentenone Product of Lipid Peroxidation, 15-A2t-Isoprostane (8-Isoprostaglandin A2), Is Efficiently Conjugated with Glutathione by Human and Rat Glutathione Transferase A4-4

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Abstract
Glutathione transferases (GSTs) are a large family of enzymes that can be divided into different classes based on structure. There has been considerable interest in the ability of GSTs to conjugate and inactivate endogenously derived reactive lipid peroxidation products that contain α,β-unsaturated carbonyl moieties such as 4-hydroxyalkenals. One enzyme with prominent activity toward these substrates is human GST A4-4. Recently, we described a novel series of compounds termed A2/J2-isoprostanes (IsoPs) that are formed endogenously in humans from the free radical-initiated peroxidation of arachidonic acid. These compounds contain α,β-unsaturated carbonyl groups and have structures similar to cyclooxygenase-derived PGA2 and PGJ2. Because of their chemical reactivity, these compounds may mediate tissue injury associated with oxidant stress. Herein, we report that the A-ring IsoP 15-A2t-IsoP (8-iso-PGA2) is efficiently conjugated to glutathione (GSH) by human GST A4-4 with a kcat/Km value of >200 s-1 mM-1. The kcat/Km value for conjugation of 15-A2t-IsoP by the homologous rat GST A4-4 is >2000 s-1 mM-1. Similar high enzyme activities were observed when PGA2 was used as a substrate. In contrast, the human GSTs A1-1, M1-1, M2-2, P1-1, and T1-1 and rat GST T2-2 did not significantly metabolize 15-A2t-IsoP. These studies have therefore defined a potentially important route by which cyclopentenone IsoPs are metabolized that may serve as a mechanism for the inactivation of these highly reactive compounds.

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