The Chemistry and Biology of Trypanosomal <i>trans</i>‐Sialidases: Virulence Factors in Chagas Disease and Sleeping Sickness

Schauer, Roland; Kamerling, Johannis P.

doi:10.1002/cbic.201100421

Cited by 38 publications

(28 citation statements)

References 192 publications

(24 reference statements)

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“…Several inhibitors of TS have been described (Table S1), most of them based on the TS crystal structure using the SA binding site (Schauer and Kamerling, 2011). TS acts as an enzyme and as a binding protein, recognizing their substrates (lactose and SA) and cellular receptors (nerve growth factor) through different domains.…”

Section: Discussionmentioning

confidence: 99%

Trypanosoma cruzi trans-sialidase as a multifunctional enzyme in Chagas’ disease

Rubin

Schenkman²

2012

Cell Microbiol

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Summary Trypanosoma cruzi trans‐sialidase (TS) was identified three decades ago. TS catalyses a trans‐glycosylation reaction, transferring SA from sialylated donors to the terminal galactose mucin‐glycoconjugates, or non‐mucin galactyosyl‐glycoconjugates. It is an external surface protein that is also released from the parasite, displaying several binding properties in addition to its enzymatic function. TS structure has been solved and its catalytic properties are well known, providing tools for development of new inhibitors, as potential chemotherapeutic agents against Chagas’ disease. However, there are still several unsolved questions regarding TS role in the biology of T. cruzi and in the pathology of Chagas’ disease. In this review, we will describe the multifunctional roles of TS regarding the development of Chagas’ disease and propose that these multiple functions have to be considered in future investigations aiming to use TS as a drug target.

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Section: Discussionmentioning

confidence: 99%

Trypanosoma cruzi trans-sialidase as a multifunctional enzyme in Chagas’ disease

Rubin

Schenkman²

2012

Cell Microbiol

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“…36 Therefore, the trans -sialidase activity in TcTS can, in part, be favored by the exclusion of water molecules and the establishment of nonpolar interactions between the active site residues and the lactose group. 24,37 Moreover, we have recently found that when lactose is not present in the active site, the catalytic couple Tyr342-Glu230 is dissociated when TcTS is found in its covalent intermediate (CI) form. However, that behavior was not observed in TrSA.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Differences of the Hydrolytic Activity of Trypanosoma cruzi trans-Sialidase and Trypanosoma rangeli Sialidase: A Quantum Mechanics–Molecular Mechanics Modeling Study

2014

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Chagas’ disease, also known as American trypanosomiasis, is a lethal, chronic disease that currently affects more than 10 million people in Central and South America. The trans-sialidase from Trypanosoma cruzi (T. cruzi, TcTS) is a crucial enzyme for the survival of this parasite: sialic acids from the host are transferred to the cell surface glycoproteins of the trypanosome, thereby evading the host’s immune system. On the other hand, the sialidase of T. rangeli (TrSA), which shares 70% sequence identity with TcTS, is a strict hydrolase and shows no trans-sialidase activity. Therefore, TcTS and TrSA represent an excellent framework to understand how different catalytic activities can be achieved with extremely similar structures. By means of combined quantum mechanics–molecular mechanics (QM/MM, SCC-DFTB/Amberff99SB) calculations and umbrella sampling simulations, we investigated the hydrolysis mechanisms of TcTS and TrSA and computed the free energy profiles of these reactions. The results, together with our previous computational investigations, are able to explain the catalytic mechanism of sialidases and describe how subtle differences in the active site make TrSA a strict hydrolase and TcTS a more efficient trans-sialidase.

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“…We also detected sialidase activity in the washed solution (data not shown). These observations suggest that sialidase solubilized with NP40 is associated with the membrane structure of the thymus but not anchored in the membrane by a signal peptide or GPI‐anchor, for example, trans ‐sialidase .…”

Section: Resultsmentioning

confidence: 96%

Possible association of Neu2 with plasma membrane fraction from mouse thymus exhibited sialidase activity with fetuin at pH 7.0 but not at pH 4.5

Kijimoto-Ochiai

Doi

Fujii

et al. 2013

Microbiology and Immunology

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Compared to other organs, the mouse thymus exhibits a high level of sialidase activity in both the soluble and crude membrane fractions, as measured at neutral pH using 4MU-Neu5Ac as a substrate. The main purpose of the present study was to identify the sialidase with a high level of the activity at neutral pH in the crude membrane. Several parameters were analyzed using the soluble (S) fraction, N and D fractions that were obtained by NP-40 or DOC/NP-40 solubilization from the thymus crude membrane. The main sialidase activity in the N fraction exhibited almost the same pI as that of soluble Neu2 and 60% of the activity was removed from the membrane by three washes with 10 mM Trisbuffer, at pH 7.0. The N fraction preferentially hydrolyzed the sialic acid bond of glycoprotein and exhibited sialidase activity with fetuin at pH 7.0 but not at pH 4.5. The same activity was observed in a plasma membrane-rich fraction. To date, the removal of sialic acid from fetuin at pH 7.0 was reported only with soluble Neu2 and the membrane fraction from Neu2-transfected COS cells. We analyzed the gene that controls the sialidase activity in the crude membrane fraction at pH 7.0 using SMXA recombinant mice and found that compared with other three genes, Neu2 presented the best correlation with the activity level. We suggest that Neu2 is most likely responsible for the main activity in the N fraction, due to its association with the membrane by an unknown mechanism.Key words membrane-associated, Neu2, plasma membrane, thymus.Cell-to-cell interactions are important for the exchange of information among cells, especially in the immune system. The removal of sialic acid from the cell surface strongly affects this interaction. We have previously reported that sialidase treatment of Epstein-Barr virus (EBV)-transformed B cells resulted in large cell aggregation (1, 2). We speculated that a natural sialidase might exist on the surfaces of immune cells and searched for a membrane-associated sialidase that acts at a neutral pH in immune organs. We found a high level of sialidase activity

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The Chemistry and Biology of Trypanosomal trans‐Sialidases: Virulence Factors in Chagas Disease and Sleeping Sickness

Cited by 38 publications

References 192 publications

Trypanosoma cruzi trans-sialidase as a multifunctional enzyme in Chagas’ disease

Trypanosoma cruzi trans-sialidase as a multifunctional enzyme in Chagas’ disease

Unraveling the Differences of the Hydrolytic Activity of Trypanosoma cruzi trans-Sialidase and Trypanosoma rangeli Sialidase: A Quantum Mechanics–Molecular Mechanics Modeling Study

Possible association of Neu2 with plasma membrane fraction from mouse thymus exhibited sialidase activity with fetuin at pH 7.0 but not at pH 4.5

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