Prostaglandins PGA1 and PGB1. Crystallographic Studies of the Conformational Requirements for 15-Hydroxyprostaglandin Dehydrogenase Activity

Prostaglandins PGA1 and PGB, are double-bond isomers with radically differing conformations and biological activity profiles. Single-crystal X-ray diffraction studies of the two prostaglandins reveal that PGA1 assumes a “hairpin” conformation, i.e., one in which the carboxylic acid (a) and pentyl (ω) side chains are approximately parallel and in close proximity at their ends, while PGB, assumes an atypical “L-shape” conformation, i.e., one in which the α and ω side chains are approximately perpendicular. The unusual L shape of PGB1 is a consequence of the all-trans dienone system 0(9)=C(9)-C(8)=C(12)-C(13)=C(14)-C(15) and cis orientation of the O(15) hydroxyl with respect to the exocyclic unsaturation. The L shape of PGB, has been shown to persist in solution, indicating that prostaglandin-specific enzymes very likely interact with an L-shaped PGB,. (15S)-15-Hydroxyprostaglandin dehydrogenase, the primary metabolizing enzyme for the prostaglandins, oxidizes the C(15)-O(15) bond of PGA1 to form 15-keto-PGA1, but PGB1 is resistant to metabolism. Two possible explanations for the inability of the dehydrogenase to metabolize PGB1 are suggested by the observed prostaglandin conformations: either the more open L-shape prevents PGB, from attaining the prostaglandin site on the enzyme or, attaining the site, the disposition of the C(15) hydrogen with respect to the nicotinamide ring of NAD+, an obligatory coenzyme for prostaglandin dehydrogenase, prevents hydrogen abstraction. The conformational studies, in conjunction with binding and activity data, suggest that prostaglandin dehydrogenase metabolizes hairpin-shaped prostaglandins. Crystals of PGA, are monoclinic, space group [formula ommited] crystals of PGB, are orthorhombic, space group [formula ommited].