ArticleBiochemistry2011
Free energy study of the catalytic mechanism of Trypanosoma cruzi trans-sialidase. From the Michaelis complex to the covalent intermediate.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- Crystal structure of the Propionibacterium acnes surface sialidase, a drug target for P. acnes-associated diseases.Glycobiology · 2022Article
- Comparative studies of catalytic pathways for Streptococcus pneumoniae sialidases NanA, NanB and NanC.Scientific reports · 2019Article
- Catalytic mechanism of type C sialidase from Streptococcus pneumoniae: from covalent intermediate to final product.Journal of molecular modeling · 2018Article
- Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase.Biochemistry · 2018Article
- Unraveling the differences of the hydrolytic activity of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase: a quantum mechanics-molecular mechanics modeling study.The journal of physical chemistry. B · 2014Article
- Article
- Design of e-pharmacophore models using compound fragments for the trans-sialidase of Trypanosoma cruzi: screening for novel inhibitor scaffolds.Journal of molecular graphics & modelling · 2013Article
- Catalytic mechanism of aromatic prenylation by NphB.Biochemistry · 2012Article
- Insights into the mechanistic dichotomy of the protein farnesyltransferase peptide substrates CVIM and CVLS.Journal of the American Chemical Society · 2012Article
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3 authors.
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Abstract
Trypanosoma cruzi trans-sialidase (TcTS) is a crucial enzyme for the infection of Trypanosoma cruzi, the protozoa responsible for Chagas' disease in humans. It catalyzes the transfer of sialic acids from the host's glycoconjugates to the parasite's glycoconjugates. Based on kinetic isotope effect (KIE) studies, a strong nucleophilic participation at the transition state could be determined, and recently, elaborate experiments used 2-deoxy-2,3-difluorosialic acid as substrate and were able to trap a long-lived covalent intermediate (CI) during the catalytic mechanism. In this paper, we compute the KIE and address the entire mechanistic pathway of the CI formation step in TcTS using computational tools. Particularly, the free energy results indicate that in the transition state there is a strong nucleophilic participation of Tyr342, and after this, the system collapsed into a stable CI. We find that there is no carbocation intermediate for this reaction. By means of the energy decomposition method, we identify the residues that have the biggest influence on catalysis. This study facilitates the understanding of the catalytic mechanism of TcTS and can serve as a guide for future inhibitor design studies.
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