Leukotrienes are synthesized from arachidonic acid,
a normal constituent of the phospholipid bilayer, which
is liberated by the action of phospholipases in responses
to various stimuli. Leukotrienes are formed by the
activation of 5-lipoxygenase (5-LO) enzyme on arachidonic
acid to form an unstable intermediate, 5-hydroperoxyeicosatetraenoic
acid (5-HPETE) which is converted
to epoxide leukotriene (LT)A4 [9]. 5-LO is a member
of a family of lipoxygenases, and is an iron-containing
enzyme consisting of 673 amino acids, which is dependent
on Ca++, adenosine triphosphate and several cofactors
for maximal activity [10]. 5-LO translocates from
the cytosol to the nuclear cell membrane to initiate
leukotriene biosynthesis. 5-HPETE is formed through
the action of 5-LO and the 5-lipoxygenase-activating
protein (FLAP), a nuclear membrane protein to which
5-LO binds to make a stable complex [11].
LTA4 is the pivotal intermediate from which all other
leukotrienes are synthesized. LTA4 hydrolase is a zinccontaining
cytosolic metalloproteinase possessing intrisic
aminopeptidase activity [12], with considerable homology
to the aminopeptidase N family of enzymes. LTA4
enzymatic activity can be inhibited by metallohydrolase
inhibitors, such as bestatin. LTA4 is unstable and may
be hydrolysed to the dihydroxyacid LTB4 by LTA4