INFLUENZA-B VIRUS NEURAMINIDASE CAN SYNTHESIZE ITS OWN INHIBITOR

Background: Neuraminidase, one of the mio surface glycoproteins of inf luenza virus, cleaves terminal sialic acid residues from glycolipids o r glycoproteins. Its crystal structure is known at high resolution, bu t the mechanism of glycosyl hydrolysis remains unclear. Results: We ha ve determined the crystal structure at 1.8 Angstrom resolution of two complexes of influenza B/Beijing neuraminidase containing either the r eaction product, sialic acid, or the transition state analogue inhibit or, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA). The sialic aci d is bound in a distorted 'boat' conformation closely resembling that of bound DANA, stabilized by a conserved tyrosine residue (Tyr408). Th is distortion also gives rise to a suicidal side reaction that convert s sialic acid to DANA at a low rate. Conclusions: The mechanism of neu raminidase action is distinct from that of other known glycosyl hydrol ases. Substrate distortion appears to be the driving force in glycosyl bond hydrolysis and the proton required for catalysis can probably be donated by water, rather than by residues in the active site, thus al lowing the enzyme to operate at high pH. The side reaction converting sialic acid to DANA appears reasonably favourable, and it is unclear h ow this is minimized by the enzyme.