Structure and function of sedoheptulose-7-phosphate isomerase, a critical enzyme for lipopolysaccharide biosynthesis and a target for antibiotic adjuvants

The barrier imposed by lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria presents a significant challenge in treatment of these organisms with otherwise effective hydrophobic antibiotics. The absence of L-glycero-D-manno-heptose in the LPS molecule is associated with a dramatically increased bacterial susceptibility to hydrophobic antibiotics and thus enzymes in the ADP-heptose biosynthesis pathway are of significant interest. GmhA catalyzes the isomerization of D-sedoheptulose 7-phosphate into D-glycero-D-manno-heptose 7-phosphate, the first committed step in the formation of ADP-heptose. Here we report structures of GmhA from Escherichia coli and Pseudomonas aeruginosa in apo, substrate, and product-bound forms, which together suggest that GmhA adopts two distinct conformations during isomerization through reorganization of quaternary structure. Biochemical characterization of GmhA mutants, combined with in vivo analysis of LPS biosynthesis and novobiocin susceptibility, identifies key catalytic residues. We postulate GmhA acts through an enediol-intermediate isomerase mechanism.

John P. Mackintosh, Devolution and the Union

This article provides a discussion of the political thinking of John P. Mackintosh (1929–1978) around the debate over Scottish devolution, and the constitutional reform of the UK, during the 1960s and 1970s. The article explores Mackintosh's ‘Union State’ vision of the UK and connects this to his interest in, and study of, the Northern Ireland experience of devolution from 1921 to 1972. It also considers the significance of Mackintosh's confrontations with Scottish nationalism and suggests that his unionism was representative of a more authentic and rooted tradition than is usually acknowledged. The article offers an evaluation of Mackintosh's legacy and considers the extent to which the questions he posed, and the lines of argument he advanced, have retained their relevance and interest in the new context of partial devolution in the UK, and in the current period of renewed constitutional speculation and debate over the future of the Union and the UK.