Chemoenzymatic Assembly of Mammalian O‐Mannose Glycans

Meng, Caicai; Sasmal, Aniruddha; Zhang, Yan; Gao, Tian; Liu, Changcheng; Khan, Naazneen; Varki, Ajit; Wang, Fengshan; Cao, Hongzhi

doi:10.1002/ange.201804373

Cited by 16 publications

(14 citation statements)

References 36 publications

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“…A total of 49 glycans were the more common, mucin-type GalNAc core glycans, and 21 were assigned as mannose-core structures based on previous knowledge of mammalian mannose-core glycans in the brain. 24 , 37 In addition, there were two confirmed peeling products (Gal and NeuNAcα2-3Gal) and two more possible peeling products containing a HexNAc reducing end [Fucα1-2Galβ1-3(Fucα1-4)HexNAc and NeuNAcα2-6Galβ1-3HexNAc], which do not typify common GalNAc core structures and may instead contain GlcNAc at their core. A disialic structure (NeuNAc–NeuNAc) was also detected, which may have peeled from larger unconfirmed structures.…”

Section: Resultsmentioning

confidence: 99%

“… 23 Up to 30% of O -glycans from associated tissue contain a core mannose residue, derived from glycoproteins including α-dystroglycan, which extend often by the addition of N -acetylglucosamine, galactose, fucose, sialic acid, and the uncommon 3- O -sulfated glucuronic acid residue, generating potential 50–60 structures. 24 , 25 The glycosylation of α-dystroglycan is known to play a vital role in the correct muscle function, with hypoglycosylation causing congenital muscular dystrophy (CMD) and being associated with cancer metastasis. 26 Core 1 mucin-type structures were found to be differentially regulated in the PD mice model, in midbrain, stratum, and hippocampus regions with an accumulation of core 1 glycans on microtubule-associated protein 6 in the disease state, 27 hypothesized to damage neurons within the dopaminergic pathway.…”

Section: Introductionmentioning

confidence: 99%

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The O-Glycome of Human Nigrostriatal Tissue and Its Alteration in Parkinson’s Disease

et al. 2021

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O -Glycosylation changes in misfolded proteins are of particular interest in understanding neurodegenerative conditions such as Parkinson’s disease (PD) and incidental Lewy body disease (ILBD). This work outlines optimizations of a microwave-assisted nonreductive release to limit glycan degradation and employs this methodology to analyze O -glycosylation on the human striatum and substantia nigra tissue in PD, ILBD, and healthy controls, working alongside well-established reductive release approaches. A total of 70 O -glycans were identified, with ILBD presenting significantly decreased levels of mannose-core ( p = 0.017) and glucuronylated structures ( p = 0.039) in the striatum and PD presenting an increase in sialylation ( p < 0.001) and a decrease in sulfation ( p = 0.001). Significant increases in sialylation ( p = 0.038) in PD were also observed in the substantia nigra. This is the first study to profile the whole nigrostriatal O -glycome in healthy, PD, and ILBD tissues, outlining disease biomarkers alongside benefits of employing orthogonal techniques for O -glycan analysis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The O-Glycome of Human Nigrostriatal Tissue and Its Alteration in Parkinson’s Disease

et al. 2021

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“…To probe the corresponding epitopes of human anti-Kdn antibodies, we used an extensive array of diverse glycans displaying Sia as the terminal residue (Fig. 2) (56,57). These chemoenzymatically synthesized glycans represent oligosaccharide sequences commonly found terminating natural glycoconjugates.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae

Saha

Coady

Sasmal

et al. 2021

mBio

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Surface expression of the common vertebrate sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) by commensal and pathogenic microbes appears structurally to represent “molecular mimicry” of host sialoglycans, facilitating multiple mechanisms of host immune evasion. In contrast, ketodeoxynonulosonic acid (Kdn) is a more ancestral Sia also present in prokaryotic glycoconjugates that are structurally quite distinct from vertebrate sialoglycans. We detected human antibodies against Kdn-terminated glycans, and sialoglycan microarray studies found these anti-Kdn antibodies to be directed against Kdn-sialoglycans structurally similar to those on human cell surface Neu5Ac-sialoglycans. Anti-Kdn-glycan antibodies appear during infancy in a pattern similar to those generated following incorporation of the nonhuman Sia N-glycolylneuraminic acid (Neu5Gc) onto the surface of nontypeable Haemophilus influenzae (NTHi), a human commensal and opportunistic pathogen. NTHi grown in the presence of free Kdn took up and incorporated the Sia into its lipooligosaccharide (LOS). Surface display of the Kdn within NTHi LOS blunted several virulence attributes of the pathogen, including Neu5Ac-mediated resistance to complement and whole blood killing, complement C3 deposition, IgM binding, and engagement of Siglec-9. Upper airway administration of Kdn reduced NTHi infection in human-like Cmah null (Neu5Gc-deficient) mice that express a Neu5Ac-rich sialome. We propose a mechanism for the induction of anti-Kdn antibodies in humans, suggesting that Kdn could be a natural and/or therapeutic “Trojan horse” that impairs colonization and virulence phenotypes of free Neu5Ac-assimilating human pathogens. IMPORTANCE All cells in vertebrates are coated with a dense array of glycans often capped with sugars called sialic acids. Sialic acids have many functions, including serving as a signal for recognition of “self” cells by the immune system, thereby guiding an appropriate immune response against foreign “nonself” and/or damaged cells. Several pathogenic bacteria have evolved mechanisms to cloak themselves with sialic acids and evade immune responses. Here we explore a type of sialic acid called “Kdn” (ketodeoxynonulosonic acid) that has not received much attention in the past and compare and contrast how it interacts with the immune system. Our results show potential for the use of Kdn as a natural intervention against pathogenic bacteria that take up and coat themselves with external sialic acid from the environment.

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“…Sialoglycan Microarray. The sialoglycan microarray method was adapted and modified from the literature reported earlier (45,46). Defined sialosides with amine linker were chemoenzymatically synthesized and then quantitated utilizing an improved DMB-HPLC method.…”

Section: Purification Of Ypeb the Y Pestis Ypeb Open Reading Frame (Orf) Was Chemically Synthesizedmentioning

confidence: 99%

Rapid evolution of bacterial AB5 toxin B subunits independent of A subunits: sialic acid binding preferences correlate with host range and toxicity

Khan

Sasmal

Khedri

et al. 2021

Preprint

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Cytotoxic A subunits of bacterial AB5 toxins enter the cytosol following B subunit binding to host cell glycans. We report that A subunit phylogeny evolves independently of B subunits and suggest a future B subunit nomenclature based on species name. Phylogenetic analysis of B subunits that bind sialic acids (Sias) with homologous molecules in databases also show poor correlation with phylogeny. These data indicate ongoing lateral gene transfers between species, with mixing of A and B subunits. Some B subunits are not even associated with A subunits e.g., YpeB of Yersinia pestis, the etiologic agent of plague epidemics. Plague cannot be eradicated because of Y. pestis adaptability to numerous hosts. YpeB shares 58% identity/79% similarity with the homo-pentameric B subunit of E. coli Subtilase cytotoxin, and 48% identity/68% similarity with the B subunit of S. Typhi typhoid toxin. We previously showed selective binding of B5 pentamers to a sialoglycan microarray, with Sia preferences corresponding to hosts e.g., N-acetylneuraminic acid (Neu5Ac; prominent in humans) or N-glycolylneuraminic acid (Neu5Gc; prominent in ruminant mammals and rodents). Consistent with much broader host range of Y. pestis, YpeB binds all mammalian sialic acid types, except for 4-O-acetylated ones. Notably, YpeB alone causes dose-dependent cytotoxicity, abolished by a mutation (Y77F) eliminating Sia recognition, suggesting cell proliferation and death via lectin-like cross-linking of cell surface sialoglycoconjugates. These findings help explain the host range of Y. pestis and could be important for pathogenesis. Overall, our data indicate ongoing rapid evolution of both host Sias and pathogen toxin-binding properties.

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Chemoenzymatic Assembly of Mammalian O‐Mannose Glycans

Abstract: Scheme 4. a) The three enzyme modules for enzymatic diversification. b) Enzymatic assemblyo fcore M1 O-mannose glycans 16-21 from 1. c) Enzymatic assembly of C6-branched core M1 O-mannose glycan isomers 22-27 from 2.d)Enzymatic assemblyo fsymmetricalc ore M2 O-mannose glycans 28-33 from 3.

Cited by 16 publications

References 36 publications

The O-Glycome of Human Nigrostriatal Tissue and Its Alteration in Parkinson’s Disease

The O-Glycome of Human Nigrostriatal Tissue and Its Alteration in Parkinson’s Disease

Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae

Rapid evolution of bacterial AB5 toxin B subunits independent of A subunits: sialic acid binding preferences correlate with host range and toxicity

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