ArticleBiochemistry2011
Proton transfer facilitated by ligand binding. An energetic analysis of the catalytic mechanism of Trypanosoma cruzi trans-sialidase.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 33 citations in OpenAlex.
- Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach.International journal of molecular sciences · 2021Article
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- Chloroquine and hydroxychloroquine inhibitors for COVID-19 sialic acid cellular receptor: Structure, hirshfeld atomic charge analysis and solvent effect.Journal of molecular structure · 2021Article
- Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase.Biochemistry · 2018Article
- Mechanism by which water and protein electrostatic interactions control proton transfer at the active site of channelrhodopsin.PloS one · 2018Article
- Galactosyl-lactose sialylation using Trypanosoma cruzi trans-sialidase as the biocatalyst and bovine κ-casein-derived glycomacropeptide as the donor substrate.Applied and environmental microbiology · 2014Article
- 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
- Evidence of ternary complex formation in Trypanosoma cruzi trans-sialidase catalysis.The Journal of biological chemistry · 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
- Thermodynamic framework for identifying free energy inventories of enzyme catalytic cycles.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Sialic acid: a sweet swing between mammalian host and Trypanosoma cruzi.Frontiers in immunology · 2012Article
- Free energy study of the catalytic mechanism of Trypanosoma cruzi trans-sialidase. From the Michaelis complex to the covalent intermediate.Biochemistry · 2011Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Trans-sialidase is a crucial enzyme for the infection of Trypanosoma cruzi, the protozoa responsible for Chagas' disease in humans. This enzyme catalyzes the transfer of sialic acids from mammalian host cells to parasitic cell surfaces in order to mask the infection from the host's immune system. It represents a promising target for the development of therapeutics to treat the disease and has been subject of extensive structural studies. Elaborate experiments suggested formation of a long-lived covalent intermediate in the catalytic mechanism and identified a Tyr/Glu pair as an unusual catalytic couple. This requires that the tyrosine hydroxyl proton is transferred to the carboxylate group of glutamate before the nucleophilic attack. Since the solution pK(a)s of tyrosine and glutamate are very different, this transfer can only be accomplished if the reaction environment selectively stabilizes the product state. We compute the free energy profile for the proton transfer in different environments, and our results indicate that it can take place in the active site of trans-sialidase, but only after substrate binding. By means of the energy decomposition method, we explain the influence that the active site residues exert on the reaction and how the pattern is changed when the substrate is present. This study represents an initial step that can shed light on our understanding of the catalytic mechanism of this reaction.
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