• Marjolein Thunnissen

Inflammation is a major pathological characteristic of a wide array of severe endemic illnesses potentially affecting almost all tissues and organ systems of the human body. These acute and chronic inflammatory diseases represent a severe burden to Western health care systems and a major challenge to medical research. The development and maintenance of inflammation are governed by a complex network of cellular and soluble factors, to which belong the eicosanoids, an array of structurally related paracrine hormones derived from the metabolism of arachidonic acid. The leukotrienes (LT) are one central family of eicosanoids specifically implicated in the pathophysiology of inflammatory and allergic disorders, in particular bronchial asthma.

Of the two main groups of leukotrienes, leukotriene (LT) B4, a potent chemotactic stimulus for leukocytes, is regarded as an important agent of inflammation and has been detected in diseases like arthritis and psoriasis. LTB4 is formed from arachidonic acid via the sequential action of two enzymes: 5-lipoxygenase catalyses the formation of the epoxide intermediate LTA4 which is in turn converted into LTB4 by the enzyme LTA4 hydrolase, the rate limiting enzyme in the formation of LTB4.

LTA4 hydrolase is a 69 kDa monomer with one Zn2+ ion in the active site. In addition to its epoxide hydrolase activity, LTA4 hydrolase also has peptidase/amidase activity towards synthetic substrates. Both activities are dependent on Zn2+ and can be inhibited by bestatin, a aminopeptidase inhibitor. Not much is known about the epoxide hydrolase activity, although the mutations at position 296 and 383 showed that the active sites are not identical but rather overlapping. The structure of LTA4 hydrolase has recently been determined. Based on the structure it was possible to propose a mechanism for the epoxide hydrolysis in which the Zn2+ ion is involved in the ring-opening of the epoxide moeity. In accordance with an SN1 mechanism, this would generate a carbocation whose charge will be delocalised over the conjugated triene system from C6 to C12. The conserved Asp375 is positioned such that it could control the proper positional and stereospecific insertion of the 12R hydroxyl group in the product LTB.