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A sialidase mutant displaying trans-sialidase activity.

Paris G, Ratier L, Amaya MF, Nguyen T, Alzari PM, Frasch AC
J Mol Biol 345 923-34 (2005)
Cited: 45 times
EuropePMC logo PMID: 15588836

Abstract

Trypanosoma cruzi, the agent of Chagas disease, expresses a modified sialidase, the trans-sialidase, which transfers sialic acid from host glycoconjugates to beta-galactose present in parasite mucins. Another American trypanosome, Trypanosoma rangeli, expresses a homologous protein that has sialidase activity but is devoid of transglycosidase activity. Based on the recently determined structures of T.rangeli sialidase (TrSA) and T.cruzi trans-sialidase (TcTS), we have now constructed mutants of TrSA with the aim of studying the relevant residues in transfer activity. Five mutations, Met96-Val, Ala98-Pro, Ser120-Tyr, Gly249-Tyr and Gln284-Pro, were enough to obtain a sialidase mutant (TrSA(5mut)) with trans-sialidase activity; and a sixth mutation increased the activity to about 10% that of wild-type TcTS. The crystal structure of TrSA(5mut) revealed the formation of a trans-sialidase-like binding site for the acceptor galactose, primarily defined by the phenol group of Tyr120 and the indole ring of Trp313, which adopts a new conformation, similar to that in TcTS, induced by the Gln284-Pro mutation. The transition state analogue 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA), which inhibits sialidases but is a poor inhibitor of trans-sialidase, was used to probe the active site conformation of mutant enzymes. The results show that the presence of a sugar acceptor binding-site, the fine-tuning of protein-substrate interactions and the flexibility of crucial active site residues are all important to achieve transglycosidase activity from the TrSA sialidase scaffold.

Articles - 1wcs mentioned but not cited (3)

  1. Rational design of a new Trypanosoma rangeli trans-sialidase for efficient sialylation of glycans. Jers C, Michalak M, Larsen DM, Kepp KP, Li H, Guo Y, Kirpekar F, Meyer AS, Mikkelsen JD. PLoS One 9 e83902 (2014)
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Reviews citing this publication (11)

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  12. A Pasteurella multocida sialyltransferase displaying dual trans-sialidase activities for production of 3'-sialyl and 6'-sialyl glycans. Guo Y, Jers C, Meyer AS, Arnous A, Li H, Kirpekar F, Mikkelsen JD. J Biotechnol 170 60-67 (2014)
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  19. Enzymatic Synthesis of 6'-Sialyllactose, a Dominant Sialylated Human Milk Oligosaccharide, by a Novel exo-α-Sialidase from Bacteroides fragilis NCTC9343. Guo L, Chen X, Xu L, Xiao M, Lu L. Appl Environ Microbiol 84 e00071-18 (2018)
  20. Galactosyl-lactose sialylation using Trypanosoma cruzi trans-sialidase as the biocatalyst and bovine κ-casein-derived glycomacropeptide as the donor substrate. Wilbrink MH, ten Kate GA, van Leeuwen SS, Sanders P, Sallomons E, Hage JA, Dijkhuizen L, Kamerling JP. Appl Environ Microbiol 80 5984-5991 (2014)
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