The Aspergillus fumigatus Sialidase Is a 3-Deoxy-d-glycero-d-galacto-2-nonulosonic Acid Hydrolase (KDNase)
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Aspergillus fumigatus is a filamentous fungus that can cause severe respiratory disease in immunocompromised individuals. A putative sialidase from A. fumigatus was recently cloned and shown to be relatively poor in cleaving N-acetylneuraminic acid (Neu5Ac) in comparison with bacterial sialidases. Here we present the first crystal structure of a fungal sialidase. When the apo structure was compared with bacterial sialidase structures, the active site of the Aspergillus enzyme suggested that Neu5Ac would be a poor substrate because of a smaller pocket that normally accommodates the acetamido group of Neu5Ac in sialidases. A sialic acid with a hydroxyl in place of an acetamido group is 2-keto-3-deoxynononic acid (KDN). We show that KDN is the preferred substrate for the A. fumigatus sialidase and that A. fumigatus can utilize KDN as a sole carbon source. A 1.45-Å resolution crystal structure of the enzyme in complex with KDN reveals KDN in the active site in a boat conformation and nearby a second binding site occupied by KDN in a chair conformation, suggesting that polyKDN may be a natural substrate. The enzyme is not inhibited by the sialidase transition state analog 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) but is inhibited by the related 2,3-didehydro-2,3-dideoxy-D-glycero-D-galacto-nonulosonic acid that we show bound to the enzyme in a 1.84-Å resolution crystal structure. Using a fluorinated KDN substrate, we present a 1.5-Å resolution structure of a covalently bound catalytic intermediate. The A. fumigatus sialidase is therefore a KDNase with a similar catalytic mechanism to Neu5Ac exosialidases, and this study represents the first structure of a KDNase.
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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 [67]
The Discussion (page unavailable) says the Aspergillus sialidase active site is very rigid, and Figure 3 compares its substrate-free structure with a ligand-bound sialidase. This supports a preorganized active site, but the paper does not establish that the specific corresponding catalytic loop is productively positioned without substrate. The NEU2 clause is attached to a different citation and is not assessed here. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe murine NEU1 crystal structure is most similar to that of human NEU2 and, to a lesser extent, to the Aspergillus fumigatus sialidase.
“the murine NEU1 crystal structure is most similar to that of human NEU2 (fig. S1A) (11) and, to a lesser extent, to the Aspergillus fumigatus sialidase (67).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [67]
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Research works printed but not linked: 5
- Varki, A., and Schauer, R. (2009) in Essentials of Glycobiology (Varki, A., Cummings, R., Esko, J., Freeze, H., Stanley, P., Bertozzi, C., Hart, G., and Etzler, M., eds) Cold Spring Harbor Laboratory Press 2. Inoue, S., and Kitajima, K. (2006) Glycoconj. J. 23, 277-290
- Ziak, M., Qu, B., Zuo, X., Zuber, C., Kanamori, A., Kitajima, K., Inoue, S., Inoue, Y., and Roth, J. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 2759 -2763
- Qu, B., Ziak, M., Zuber, C., and Roth, J. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 8995-8998
- Crennell, S. J., Garman, E. F., Laver, W. G., Vimr, E. R., and Taylor, G. L. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 9852-9856
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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
- Telford, J. C., Yeung, J. H. F., Xu, G., Kiefel, M. J., Watts, A. G., Hader, S., Chan, J., Bennet, A. J., Moore, M. M., & Taylor, G. L.
- Affiliations
- University of St Andrews (GB)
- Department of Biological Sciences (RU)
- Griffith University (AU)
- University of Bath (GB)
- Simon Fraser University (CA)
- Corresponding author
- Taylor, Garry L.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 286
- Issue
- 12
- Pages
- 10783-10792
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3060529
- OpenAlex
- W2088134563
- Cited by
- 43
- References
- 0
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 3 · 2021: 7 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 1 · 2015: 2 · 2014: 2 · 2013: 5 · 2012: 1
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Griffith Research Online (submittedVersion)
- Funders
- Wellcome Trust
- Scottish Funding Council
- Directorate for Biological Sciences
- Natural Sciences and Engineering Research Council of Canada
- Biotechnology and Biological Sciences Research Council
- 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
- Aspergillus fumigatus, neuraminidase, sialic acid, N-acetylneuraminic acid, substrate specificity, enzyme inhibition, catalytic intermediates, fluorinated substrates, fungal pathogens
- MeSH terms
- Aspergillus fumigatus, Binding Sites, Fungal Proteins, Glycoside Hydrolases, Neuraminidase, Structure-Activity Relationship, Protein Structure, Tertiary, Crystallography, X-Ray, N-Acetylneuraminic Acid
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