FIGURE 7.

Proposed mechanism for the conjugation of LTA₄ with GSH and release of product from LTC4S. A, the thiol of bound GSH (PDB code 2UUH) gets activated by Arg-104. B, LTA₄ enters the active site with its ω-end shielded from the membrane by Trp-116, as indicated by the position of the aliphatic side chain of DDM (PDB code 2UUH). In the conjugation reaction, the thiolate attacks at C6 of the epoxide ring, presumably according to an SN2 mechanism. C, As LTA₄ and GSH get coupled together the evolving product moves toward Trp-116, which rotates outwards exposing the product to the lipid bilayer and facilitating product release, as indicated by our structure of W116F in complex with analog I. Carbons of analog I extending from the sulfur are shown in as a black ball-and-stick diagram.