Catalytic Mechanism of 3-Deoxy-D-manno-2-octulosonate-8-phosphate Synthase

Catalytic mechanism of 3-deoxy-D-manno-2-octulosonate-8-phosphate (KDO8P) synthase (EC 4.1.2.16), an enzyme involved in the biosynthesis of lipopolysaccharides of Gram-negative bacteria, remains a fascinating subject for both bioorganic and medicinal researches. The enzyme catalyzes an aldol-type condensation of D-arabinose 5-phosphate with phosphoenolpyruvate to produce the unusual eight-carbon saccharide KDO8P and inorganic phosphate. The structure and mechanism of KDO8P synthase have actively studied during last decade as this enzyme represents an important target for antibiotic therapy. This review summarizes the most mechanistically relevant information reported to date, with special emphases on the synthesis and evaluation of a number of analogues of substrates, product and proposed intermediates of the KDO8P-synthase- catalyzed reaction. The results introduced here illustrate the value of organic synthesis to characterize enzymatic reaction. Mechanistic postulates have pointed the way to the design of potent inhibitors, and these in turn have provided insight into details of the reaction, as well as useful structural models for elusive intermediates.