Structural Basis of Outstanding Multivalent Effects in Jack Bean α‐Mannosidase Inhibition

Howard, Eduardo; Cousido-Siah, A.; Lepage, Mathieu L.; Schneider, Jérémy P.; Bodlenner, Anne; Mitschler, A.; Meli, Alessandra; Izzo, Irene; Alvarez, H. Ariel; Podjarny, A.; Compain, Philippe

doi:10.1002/ange.201801202

Cited by 7 publications

(5 citation statements)

References 36 publications

(27 reference statements)

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“…Binding affinities were significantly increased with sialidase lectin domains, but strong inhibition of the enzymatic activity was observed on the catalytic domain. The design of multivalent glycosidase modulators is a promising emerging field, as illustrated by the continuous reports of potent glycosidase activators and inhibitors based on clusterized iminosugars or sugar substrates . This concept is now extended to the inhibition of bacterial and pathogenic sialidases, for which transition‐state inhibitors fail to reach the sub‐micromolar level.…”

Section: Discussionmentioning

confidence: 99%

Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases

Brissonnet

assailly

Saumonneau

et al. 2019

Chemistry A European J

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Sialidases (SAs) hydrolyze sialyl residues from glycoconjugates of the eukaryotic cell surface and are virulence factors expressed by pathogenic bacteria, viruses, and parasites. The catalytic domains of SAs are often flanked with carbohydrate‐binding module(s) previously shown to bind sialosides and to enhance enzymatic catalytic efficiency. Herein, non‐hydrolyzable multivalent thiosialosides were designed as probes and inhibitors of V. cholerae, T. cruzi, and S. pneumoniae (NanA) sialidases. NanA was truncated from the catalytic and lectinic domains (NanA‐L and NanA‐C) to probe their respective roles upon interacting with sialylated surfaces and the synthetically designed di‐ and polymeric thiosialosides. The NanA‐L domain was shown to fully drive NanA binding, improving affinity for the thiosialylated surface and compounds by more than two orders of magnitude. Importantly, each thiosialoside grafted onto the polymer was also shown to reduce NanA and NanA‐C catalytic activity with efficiency that was 3000‐fold higher than that of the monovalent thiosialoside reference. These results extend the concept of multivalency for designing potent bacterial and parasitic sialidase inhibitors.

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Section: Discussionmentioning

confidence: 99%

Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases

Brissonnet

assailly

Saumonneau

et al. 2019

Chemistry A European J

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“…The crystal structure confirmed the sandwich-type complex arrangement in which four inhitopes are buried in the active sites of the H-chain of two JBα-man molecules (Figure 4 ). 58 Beyond our expectations, the iminosugar head and its linker – a flexible nonyl chain – could be seen due to hydrophobic contacts with the mannosidase surface, as could be observed at the end of the linker, the triazole located just before the branching point of the trivalent dendron of the 36-valent cluster 2 . The existence of nonspecific binding sites could not be revealed by the crystal structure since the DNJ inhitopes could only be seen in the JBα-man active sites in the electron-density map at 2.0 Å resolution.…”

Section: Sweet Giantsmentioning

confidence: 56%

“…The structure of the JBα-man complexed with the 36-valent cluster was very similar to that of the apo form showing that multimeric inhibitor binding did not perturb the mannosidase. 58…”

Section: Sweet Giantsmentioning

confidence: 99%

From Sweet Molecular Giants to Square Sugars and Vice Versa

Compain¹

2023

Synlett

Self Cite

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This account describes our recent studies in the field of glycomimetics. Our efforts in understanding the structural basis of multivalent effects in glycosidase inhibition have led to decisive mechanistic insights supported by X-ray diffraction analyses and to the discovery of multimeric iminosugars displaying one of the largest binding enhancements reported so far for a non-polymeric enzyme inhibitor. Pushing the limits of the inhibitory multivalent effect has also driven progress in synthetic methodology. The unexpected observation of side products en route to the synthesis of our targets has been the starting point of several new synthetic methodologies, including metal-free deoxygenation of alcohols and one-pot double thioglycosylation. In parallel to our work on ‘giant’ neoglycoclusters, we have developed access to original constrained glycomimetics based on a 4-membered ring (‘square sugars’). Carbohydrates with a quaternary (pseudo)anomeric position were also synthesized from exo-glycals through catalytic hydrogen atom transfer and a novel oxidative radical-polar crossover process.1 Introduction2 Sweet Giants3 Multivalency Spin-Offs4 Sweet Curiosities4.1 Square Sugars4.2 From C,C-Glycosides to Formal Glycosylation of Quinones5 Conclusion

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“…Structures have been determined for several a-mannosidases in the GH38 family, including Drosophila Golgi a-mannosidase II (dGMII), bovine lysosomal amannosidase (bLAM), Jack bean a-mannosidase (JBaman), bacterial Streptococcus pyogenes a-mannosidase (SpGH38), and ScAms1 [18,19,28,[30][31][32] (Fig. 6A,B).…”

Section: Comparison With Other Gh38 Protein Structuresmentioning

confidence: 99%

“…Particles were extracted with a box size of 240 pixels, downsized by fourfold and subjected to 2D and 3D classification with a mask of 200 A diameter. The cryo-EM density map of ScAms1 (EMD-8166) was low-pass filtered to 30 A and used as the initial model for 3D classification [28]. After one round of 2D classification and two rounds of 3D classification, 75 460 particles from high-resolution classes were selected for 3D autorefinement with imposed D2 symmetry.…”

Section: Image Processingmentioning

confidence: 99%

Cryo‐EM structure of fission yeast tetrameric α‐mannosidase Ams1

Zhang

Wang

et al. 2020

FEBS Open Bio

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Fungal a-mannosidase Ams1 and its mammalian homolog MAN2C1 hydrolyze terminal a-linked mannoses in free oligosaccharides released from misfolded glycoproteins or lipid-linked oligosaccharide donors. Ams1 is transported by selective autophagy into vacuoles. Here, we determine the tetrameric structure of Ams1 from the fission yeast Schizosaccharomyces pombe at 3.2 A resolution by cryo-electron microscopy. Distinct from a low resolution structure of S. cerevisiae Ams1, S. pombe Ams1 has a prominent N-terminal tail that mediates tetramerization and an extra bsheet domain. Ams1 shares a conserved active site with other enzymes in glycoside hydrolase family 38, to which Ams1 belongs, but contains extra N-terminal domains involved in tetramerization. The atomic structure of Ams1 reported here will aid understanding of its enzymatic activity and transport mechanism. Asparagine-linked glycans (N-glycans) are one of the most important modifications in eukaryotic proteins and plays a crucial role in protein folding and quality control and molecular recognition [1,2]. Biosynthesis of N-glycans starts with the assembly of a donor substrate dolicholpyrophosphate-linked Glc 3 Man 9 GlcNAc 2 (Glc: glucose; Man: mannose; GlcNAc: N-acetylglucosamine) on the membrane of the endoplasmic reticulum (ER). The lipid-linked oligosaccharide is transferred to selected asparagine residues in nascent polypeptides by the oligosaccharyltransferase. N-glycans are then trimmed by glycosidases and extended by glycosyltransferases in the ER and Golgi, giving rise to their myriad structures. Catabolism of glycoproteins is important for maintaining cellular homeostasis. Most N-glycoproteins are degraded in the lysosome/vacuole [3], where N-glycans are digested by exoglycosidases at the nonreducing end and released from peptides with cleavage of the glycan-peptide bond at the reducing end. In addition, nascent glycoproteins that do not correctly fold in the ER are targeted for ER-associated degradation, a process in which misfolded glycoproteins are recognized

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Structural Basis of Outstanding Multivalent Effects in Jack Bean α‐Mannosidase Inhibition

Cited by 7 publications

References 36 publications

Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases

Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases

From Sweet Molecular Giants to Square Sugars and Vice Versa

Cryo‐EM structure of fission yeast tetrameric α‐mannosidase Ams1

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