Sialic acid synthase catalyzes the third step in the biosynthesis of the sialic acids and condenses phosphoenolpyruvate (PEP) with ManNAc 6-phosphate (ManNAc6P) to give neuraminic acid 9-phosphate (Neu5Ac9P) (Figure 7). Sialic acids play key roles in mediating cellular interactions in humans, and controlling their biosynthesis could have profound implications in a variety of disease states. Two general mechanistic strategies can be invoked for this reaction. The first involves the generation of an enolate by the dephosphorylation of PEP, followed by an attack of the enolate on the open chain form of the sugar (Figure 7, Path 1). A second mechanism involves the attack of the C-3 carbon of PEP onto the aldehyde of ManNAc6P (Figure 7, Path 2). The addition of water at C-2 followed by the loss of phosphate and subsequent ring closure could then generate the product. The first two steps of this reaction would likely proceed in a stepwise manner, involving an oxocarbenium ion intermediate. Isotopic labeling studies are currently underway that will discern between these mechanisms and will uncover the stereospecificity of the PEP addition.
Figure 7. Two Potential Mechanisms for the Reaction Catalyzed by Sialic Acid Synthase
Dave Simard, B.Sc. Dalhousie, Ph.D. Candidate, e-mail: