Engineering the Sialome

Edgar, Landon J.

doi:10.1021/acschembio.1c00273

Cited by 13 publications

(11 citation statements)

References 114 publications

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“…In vivo targeting of Neu5Ac is a promising avenue for cancer therapies (98, 99). Cancer cells often hypersialate the cell surface to evade the immune system via Siglec-binding.…”

Section: Discussionmentioning

confidence: 99%

Human gut metagenomes encode diverse GH156 sialidases

Mann

Shekarriz

Surette

2022

Preprint

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The intestinal lining is protected by a mucous barrier composed predominantly of complex carbohydrates. Gut microbes employ an array of glycoside hydrolases (GHs) to liberate mucosal sugars as a nutrient source to facilitate host colonization. Intensive catabolism of mucosal glycans, however, may contribute to barrier erosion, pathogen encroachment and inflammation.Sialic acid is an acidic sugar featured at terminal positions of host glycans. Characterized sialidases from the microbiome belong to the GH33 family, according to CAZy (Carbohydrate Active enZyme) database classification. A 2018 functional metagenomics screen using thermal spring DNA uncovered the founding member of the GH156 sialidase family, which lacks homology to GH33 sialidases and could not be taxonomically assigned. Subsequent structural analysis revealed critical active site residues. We sought to determine if GH156 sialidases are present in the human gut microbiome where they might contribute to mucous erosion.A subset of GH156 sequences from the CAZy database containing key sialidase residues was used to build a Hidden Markov Model. HMMsearch against public databases revealed ∼10X more putative GH156 sialidases than currently recognized by CAZy. Represented phyla include Bacteroidota, Verrucomicrobiota and Firmicutes_A from human microbiomes, all of which play notable roles in carbohydrate fermentation. Genomic analyses suggested that taxa containing GH156-encoding genes may utilize host-glycans. Analyses of metagenomic datasets revealed that GH156s are frequently encoded in metagenomes, with a greater variety and abundance of GH156 genes observed in traditional hunter-gatherer or agriculturalist societies than in industrialized societies, particularly relative to individuals with IBD. A GH156 gene frequently detected in traditional populations was cloned from stool sample DNA and the recombinant protein exhibited sialidase activity with a fluorogenic substrate.ImportanceSialic acids occupy terminal positions of human glycans where they act as receptors for microbes, toxins and immune signaling molecules. Microbial enzymes that remove sialic acids, sialidases, are abundant in the human microbiome where they may contribute to shaping the microbiota community structure or contribute to pathology. Furthermore, sialidases have proven to hold therapeutic potential for cancer therapy. Here we examined the sequence space of a sialidase family of enzymes, GH156, previously unknown to the human gut environment. Our analyses suggest that human populations with disparate dietary practices harbour distinct varieties and abundances of GH156-encoding genes. Furthermore, we demonstrate the sialidase activity of a gut derived GH156. These results expand the diversity of sialidases that may contribute to host glycan degradation and these sequences may have biotechnological or clinical utility.

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“…In vivo targeting of Neu5Ac is a promising avenue for cancer therapies (98, 99). Cancer cells often hypersialate the cell surface to evade the immune system via Siglec-binding.…”

Section: Discussionmentioning

confidence: 99%

Human gut metagenomes encode diverse GH156 sialidases

Mann

Shekarriz

Surette

2022

Preprint

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“…We briefly summarized the general principle, the advantages/disadvantages of these methods, the recommended in‐depth reviews and/or frontier progresses for these foundational chemical biological approaches (Figure 1, bottom). Some classical reviews that systematically introduced and summarized the above‐mentioned methods are also listed in the reference [18–21] …”

Section: Glycan Hierarchy and Current Glycan Manipulation Methodsmentioning

confidence: 99%

Recent Advances in Protein‐Specific Glycan Imaging and Editing

Zheng

Meng

et al. 2023

ChemBioChem

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“…In vertebrates, STs are classified into four groups (ST6Gal, ST6GalNAc, ST3Gal, and ST8Sia) according to the glycosidic linkage formed and the sugar acceptor specificity (94,95). It is important to mention that synthetic derivatives of ManNAc (ManNR) or Sia (SiaNR) can be used to metabolically label sialic acid; examples include ManNAz and SiaNAz where Nacetyl is replaced with N-azidoacetyl (9).…”

Section: Biosynthesis Of Polysia In Mammalsmentioning

confidence: 99%

“…The type of Sia, the chemical modifications it can be subject to including acetyl, sulfonyl, lactyl, methyl, and lactone groups, and the configuration of the glycosidic linkage constitute stereospecific biophysical information that cells can dynamically modify and also be sensed by specific endogenous glycan-binding proteins such as selectins, sialic acid-binding immunoglobulin-type lectins (Siglecs), or CD28, thus establishing key functional pathways in the immune response (8,9).…”

Section: Introductionmentioning

confidence: 99%

Polysialic Acid in the Immune System

et al. 2022

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Polysialic acid (polySia) is a highly regulated polymer of sialic acid (Sia) with such potent biophysical characteristics that when expressed drastically influences the interaction properties of cells. Although much of what is known of polySia in mammals has been elucidated from the study of its role in the central nervous system (CNS), polySia is also expressed in other tissues, including the immune system where it presents dynamic changes during differentiation, maturation, and activation of different types of immune cells of the innate and adaptive response, being involved in key regulatory mechanisms. At least six polySia protein carriers (CCR7, ESL-1, NCAM, NRP2, ST8Sia 2, and ST8Sia 4) are expressed in different types of immune cells, but there is still much to be explored in regard not only to the regulatory mechanisms that determine their expression and the structure of polySia chains but also to the identification of the cis- and trans- ligands of polySia that establish signaling networks. This review summarizes the current knowledge on polySia in the immune system, addressing its biosynthesis, its tools for identification and structural characterization, and its functional roles and therapeutic implications.

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Engineering the Sialome

Cited by 13 publications

References 114 publications

Human gut metagenomes encode diverse GH156 sialidases

Human gut metagenomes encode diverse GH156 sialidases

Recent Advances in Protein‐Specific Glycan Imaging and Editing

Polysialic Acid in the Immune System

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