Kinetic and Structural Characterization of Sialidases (Kdnases) from Ascomycete Fungal Pathogens
Abstract
Sialidases catalyze the release of sialic acid from the terminus of glycan chains. We previously characterized the sialidase from the opportunistic fungal pathogen, Aspergillus fumigatus, and showed that it is a Kdnase. That is, this enzyme prefers 3-deoxy-d-glycero-d-galacto-non-2-ulosonates (Kdn glycosides) as the substrate compared to N -acetylneuraminides (Neu5Ac). Here, we report characterization and crystal structures of putative sialidases from two other ascomycete fungal pathogens, Aspergillus terreus ( At S) and Trichophyton rubrum ( Tr S). Unlike A. fumigatus Kdnase ( Af S), hydrolysis with the Neu5Ac substrates was negligible for Tr S and At S; thus, Tr S and At S are selective Kdnases. The second-order rate constant for hydrolysis of aryl Kdn glycosides by At S is similar to that by Af S but 30-fold higher by Tr S. The structures of these glycoside hydrolase family 33 (GH33) enzymes in complex with a range of ligands for both At S and Tr S show subtle changes in ring conformation that mimic the Michaelis complex, transition state, and covalent intermediate formed during catalysis. In addition, they can aid identification of important residues for distinguishing between Kdn and Neu5Ac substrates. When A. fumigatus , A. terreus, and T. rubrum were grown in chemically defined media, Kdn was detected in mycelial extracts, but Neu5Ac was only observed in A. terreus or T. rubrum extracts. The C8 monosaccharide 3-deoxy-d- manno -oct-2-ulosonic acid (Kdo) was also identif…
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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 [68]
Cites
Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision
Bongomin, F., Gago, S., Oladele, R., & Denning, D. (2017) · Journal of Fungi · doi:10.3390/jof3040057 · Cited by 2,953 · see citing works
Possible Environmental Origin of Resistance of <i>Aspergillus fumigatus</i> to Medical Triazoles
Snelders, E., Huis in 't Veld, R. A. G., Rijs, A. J. M. M., Kema, G. H. J., Melchers, W. J. G., & Verweij, P. E. (2009) · Applied and Environmental Microbiology · doi:10.1128/aem.00231-09 · Cited by 423 · see citing works
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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
- Nejatie, A., Steves, E., Gauthier, N., Baker, J., Nesbitt, J., McMahon, S. A., Oehler, V., Thornton, N. J., Noyovitz, B., Khazaei, K., Byers, B. W., Zandberg, W. F., Gloster, T. M., Moore, M. M., & Bennet, A. J.
- Affiliations
- Simon Fraser University (CA)
- University of St Andrews (GB)
- University of British Columbia (CA)
- Corresponding author
- Bennet, Andrew J.
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-11-01
- Volume
- 16
- Issue
- 11
- Pages
- 2632-2640
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W3210246605
- Cited by
- 11
- References
- 2
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 2 · 2023: 2
- FWCI
- 0.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canada Foundation for Innovation (35246)
- Natural Sciences and Engineering Research Council of Canada (03929, 105704, 201704910)
- Biotechnology and Biological Sciences Research Council (BB/R008035/1)
- British Columbia Knowledge Development Fund
- Canadian Networks of Centres of Excellence - Glyconet (AM6)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- neuraminidase, sialic acid, Aspergillus fumigatus, Aspergillus terreus, Trichophyton rubrum, enzyme kinetics, crystal structure, substrate specificity, N-acetylneuraminic acid, KDO, fungal pathogens, cell surface localization, fluorescent probes
- MeSH terms
- Ascomycota, Catalysis, Culture Media, Enzyme Stability, Fluorescent Dyes, Hydrogen-Ion Concentration, Kinetics, Neuraminidase, Protein Conformation, Substrate Specificity, Temperature, Catalytic Domain
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