The crystal structure of an intramolecular trans-sialidase with a NeuAcα2→3Gal specificity
Open accessAbstract
Background Intramolecular trans-sialidase from leech (Macrobdella decora) is a unique enzyme which cleaves the terminal neuraminic acid (NeuAc) residue from sialoglycoconjugates, releasing 2, 7-anhydro-neuraminic acid (2,7-anhydro-NeuAc). It is the first enzyme found to exhibit strictly specific cleavage of NeuAc alpha2-->3Gal linkages in sialoglycoconjugates. The release of 2,7-anhydro-NeuAc instead of NeuAc implies a unique mechanism, in which the sialosyl linkage is transferred within the sialoglycoconjugate rather than hydrolyzed. The aims of the structural study were to gain structural insight into the strict specificity and unique mechanism of this unusual enzyme. Results . The 2.0 A crystal structure of recombinant leech intramolecular trans-sialidase has been solved by multiple isomorphous replacement. The 1.8 A structure of the enzyme in complex with 2-deoxy-2, 3-didehydro-NeuAc was also solved. The refined model comprising residues 81-769 has a catalytic beta-propeller domain (C), a N-terminal lectin-like domain (II) and an irregular beta-stranded domain (III) inserted into the catalytic domain. The structure reveals several possible carbohydrate-binding features: domain II has a concave face, like that of other sialidases, and there is a suitable surface charge distribution at the domain III-C interface. Conclusions Structural comparisons showed closer evolutionary relationships to bacterial sialidases than to viral neuraminidases. Mainchain and sidechain atoms around Thr593 make the glycerol-binding pocket incapable of accommodating an extended equatorial 6-glycerol group, implying that the 6-glycerol group of the reaction intermediate may occupy an axial position, which is also required by the catalytic mechanism. The steric hindrance introduced by the bulky sidechain of Trp734 above the 2-carboxylate group may explain the lack of water involvement in the cleavage reaction and the substrate specificity.
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The catalytic loop transitions from disordered to ordered upon substrate binding to NEU2, but in other eukaryotic sialidases of the GH33 family, this loop is productively positioned even without substrate.
“The corresponding loop transitions from disordered to ordered upon substrate binding to NEU2 (11), but in other eukaryotic sialidases of the GH33 family, this loop is productively positioned even without substrate (65–68).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [65]
The Results and discussion (Overall structure; page not provided) report a substrate-free structure of leech IT-sialidase in which residues 81–759 are resolved, and describe a loop in its catalytic domain. This supports the presence of an ordered loop without bound substrate, but the passages do not establish that it is the corresponding catalytic loop or that it is productively positioned. The NEU2 clause is attached to a different citation and is not judged here. (LLM, conf=0.70)
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Research works printed but not linked: 3
- [1]1. Schauer, R. Origin and biological role of the great chemical diversity of natural sialic acids Trends Glycosci. Glycotech. 1997; 9:315-330 Crossref Scopus (22) Google Scholar
- [2]2. Roth, J. Cellular sialoglycoconjugates: a histochemical perspective Histochem. J. 1993; 25:687-710 94110087 PubMed Google Scholar
- [3]3. Schauer, R. Sialic acids and their role as biological masks Trends Biochem. Sci. 1985; 10:357-360
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Tailford, L. E., Owen, C. D., Walshaw, J., Crost, E. H., Hardy-Goddard, J., Le Gall, G., de Vos, W. M., Taylor, G. L., & Juge, N. (2015) · Nature Communications · doi:10.1038/ncomms8624 · Cited by 183 · see citing works
Sialic acid recognition by Vibrio cholerae neuraminidase
Moustafa, I., Connaris, H., Taylor, M., Zaitsev, V., Wilson, J. C., Kiefel, M. J., von Itzstein, M., & Taylor, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404965200 · Cited by 165 · see citing works
Structure of the immunoregulatory sialidase NEU1
Gorelik, A., Illes, K., Mazhab-Jafari, M. T., & Nagar, B. (2023) · Science Advances · doi:10.1126/sciadv.adf8169 · Cited by 36 · see citing works
- Authors
- Luo, Y., Li, S.-C., Chou, M.-Y., Li, Y.-T., & Luo, M.
- Affiliations
- University of Alabama at Birmingham (US)
- Tulane University (US)
- Corresponding author
- Luo, Ming
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 1998-04
- Volume
- 6
- Issue
- 4
- Pages
- 521-530
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2072473330
- Cited by
- 59
- References
- 0
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 3 · 2021: 1 · 2020: 3 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 1 · 2012: 4
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Keywords
- Macrobdella decora, sialoglycoconjugates, sialic acid cleavage, catalytic mechanism, carbohydrate-binding site, lectin-like domain, beta-propeller domain, bacterial sialidases, enzyme-substrate complex
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Carbohydrate Conformation, Glycoconjugates, Leeches, Micromonospora, Models, Molecular, Molecular Sequence Data, Neuraminidase, Sialic Acids, Substrate Specificity, Sequence Alignment, Protein Structure, Secondary, Crystallography, X-Ray, Evolution, Molecular, N-Acetylneuraminic Acid
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