Human Leukotriene C4 Synthase at 4.5 Å Resolution in Projection

Leukotriene (LT) C4 synthase, an 18 kDa integral membrane enzyme, conjugates LTA4 with reduced glutathione to form LTC4, the parent compound of all cysteinyl leukotrienes that play a crucial role in the pathobiology of bronchial asthma. We have calculated a projection map of recombinant human LTC4 synthase at a resolution of 4.5 Å by electron crystallography, which shows that the enzyme is a trimer. A map truncated at 7.5 Å visualizes four transmembrane α helices per protein monomer. The densities in projection indicate that most of the α helices run nearly perpendicular to the plane of the membrane. At this resolution, LTC4 synthase is strikingly similar to microsomal glutathione S-transferase 1, which belongs to the same gene family but bears little sequence identity and no resemblance in substrate specificity to the LTC4 synthase. These results provide new insight into the structure and function of membrane proteins involved in eicosanoid and glutathione metabolism.