9-O-Acetylation of sialic acids is catalysed by CASD1 via a covalent acetyl-enzyme intermediate

Baumann, Anna-Maria; Bakkers, Mark J. G.; Buettner, Falk F. R.; Hartmann, M.D.; Grove, Melanie; Langereis, Martijn A.; Groot, Raoul J. de; Mühlenhoff, Martina

doi:10.1038/ncomms8673

Cited by 109 publications

(77 citation statements)

References 70 publications

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“…We generated HEK293 cells that do not express 9-O-acetylated sialosides and counterpart cells that express 9-O-acetylated sialosides, via knocking-out (KO) and overexpressing (OE) the Cas1 domain containing 1 (CASD1) gene, respectively. CASD1 is responsible for the addition of the O-acetyl group to Neu5Ac [30]. 9-O-acetylated sialosides are indeed absent in the CASD1 KO cells, while present in the cell surface of the CASD1 OE cells ( Fig 7A).…”

Section: The Role Of 9-o-acetyl Modification In Typhoid Toxin-mediatementioning

confidence: 92%

The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication

et al. 2020

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Typhoid toxin is an A 2 B 5 toxin secreted from Salmonella Typhi-infected cells during human infection and is suggested to contribute to typhoid disease progression and the establishment of chronic infection. To deliver the enzymatic 'A' subunits of the toxin to the site of action in host cells, the receptor-binding 'B' subunit PltB binds to the trisaccharide glycan receptor moieties terminated in N-acetylneuraminic acid (Neu5Ac) that is α2-3 or α2-6 linked to the underlying disaccharide, galactose (Gal) and N-acetylglucosamine (GlcNAc). Neu5Ac is present in both unmodified and modified forms, with 9-O-acetylated Neu5Ac being the most common modification in humans. Here we show that host cells associated with typhoid toxin-mediated clinical signs express both unmodified and 9-O-acetylated glycan receptor moieties. We found that PltB binds to 9-O-acetylated α2-3 glycan receptor moieties with a markedly increased affinity, while the binding affinity to 9-O-acetylated α2-6 glycans is only slightly higher, as compared to the affinities of PltB to the unmodified counterparts, respectively. We also present X-ray co-crystal structures of PltB bound to related glycan moieties, which supports the different effects of 9-O-acetylated α2-3 and α2-6 glycan receptor moieties on the toxin binding. Lastly, we demonstrate that the cells exclusively expressing unmodified glycan receptor moieties are less susceptible to typhoid toxin than the cells expressing 9-O-acetylated counterparts, although typhoid toxin intoxicates both cells. These results reveal a fine-tuning mechanism of a bacterial toxin that exploits specific chemical modifications of its glycan receptor moieties for virulence and provide useful insights into the development of therapeutics against typhoid fever.The Gram-negative rod-shaped bacteria Salmonella enterica serovar Typhi (S. enterica serovar Typhi or S. Typhi) is the cause of the life-threatening disease typhoid fever. Many millions of people including children under the age of five are affected by this infectious disease. Molecular mechanisms underlying typhoid disease progression and the establishment of chronic infection important for the transmission of this human-adapted pathogen are incompletely understood, but typhoid toxin, one of the virulence factors of S. Typhi, is suggested to contribute to these processes. Typhoid toxin consists of three functionally distinct subunits: two enzymatic 'A' subunits important for intoxicating host cells after the delivery into host cells and one homopentamer of receptor-binding 'B' subunit important for the delivery of the toxin into host cells. Typhoid toxin 'B' subunit recognizes specific three-sugar structures decorating the host cell surface, whose terminal sugar called N-acetylneuraminic acid (Neu5Ac) can be present in unmodified or modified forms. The modified Neu5Ac possesses additional chemical groups, with 9-O-acetylation being the most frequently found modification in humans. This study analyzes glycan expression profiles of primary tissues and cells assoc...

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Section: The Role Of 9-o-acetyl Modification In Typhoid Toxin-mediatementioning

confidence: 92%

The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication

et al. 2020

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“…The degree of Sia diversity (including modified inhibitors or decoys) in alternative hosts or tissues may influence potential viral emergence. containing 1) encodes a 9-O-acetyltransferase enzyme that mediates the formation of 9-Oacetyl Sia (9-O-Ac) from a CMP-Neu5Ac precursor [13,19,20]. However, while enzymatic activity for a 4-O-acetyltransferase has been demonstrated, a candidate gene has not yet been identified [21].…”

Section: Sias: Modifications and Variationmentioning

confidence: 99%

Effects of Sialic Acid Modifications on Virus Binding and Infection

Wasik

Barnard

Parrish

2016

Trends in Microbiology

118

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Sialic acids (Sias) are abundantly displayed on the surfaces of vertebrate cells, and particularly on all mucosal surfaces. Sias interact with microbes of many types, and are the targets of specific recognition by many different viruses. They may mediate virus binding and infection of cells, or alternatively can act as decoy receptors that bind virions and block virus infection. These nine-carbon backbone monosaccharides naturally occur in many different modified forms, and are attached to underlying glycans through varied linkages, creating significant diversity in the pathogen receptor forms. Here we review the current knowledge regarding the distribution of modified Sias in different vertebrate hosts, tissues, and cells, their effects on viral pathogens where those have been examined, and outline unresolved questions.

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“…Expression of this protein and characterization as O-acetyltransferase were achieved more recently. 847 CMP-Neu5Ac as substrate of the enzyme was confirmed.…”

Section: O-acetylated Sialic Acidsmentioning

confidence: 72%

Exploration of the Sialic Acid World

Schauer

Kamerling

2018

Advances in Carbohydrate Chemistry and Biochemistry

261

225

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The Sialic Acid World Table 1 Survey of Reported Structures of Naturally Occurring Members of the Sialic Acid Family-cont'd Name Abbreviation References5-N-Acetyl-8-O-acetyl-9-Olactyl-neuraminic acid Neu5,8Ac 2 9Lt 45 5-N-Acetyl-8-O-methylneuraminic acid Neu5Ac8Me 6,19,25,33,46 5-N-Acetyl-4-O-acetyl-8-Omethyl-neuraminic acid Neu4,5Ac 2 8Me 19 5-N-Acetyl-9-O-acetyl-8-Omethyl-neuraminic acid Neu5,9Ac 2 8Me 6,19,33,46 5-N-Acetyl-9-O-methylneuraminic acid Neu5Ac9Me 47 5-N-Acetyl-4-O-sulfoneuraminic acid Neu5Ac4S 48 5-N-Acetyl-8-O-sulfoneuraminic acid Neu5Ac8S 19,32,49,50 5-N-Acetyl-4-O-acetyl-8-Osulfo-neuraminic acid Neu4,5Ac 2 8S 19 5-N-Acetyl-9-O-phosphoneuraminic acid f,g Neu5Ac9P 51 5-N-Acetyl-2-deoxy-2,3didehydro-neuraminic acid g,h Neu2en5Ac 6,30,33,43,52-54 5-N-Acetyl-9-O-acetyl-2deoxy-2,3-didehydroneuraminic acid g Neu2en5,9Ac 2 55,56 5-N-Acetyl-2-deoxy-2,3didehydro-9-O-lactylneuraminic acid g Neu2en5Ac9Lt 55,565-N-Acetyl-2,7-anhydroneuraminic acid g,i

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9-O-Acetylation of sialic acids is catalysed by CASD1 via a covalent acetyl-enzyme intermediate

Cited by 109 publications

References 70 publications

The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication

The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication

Effects of Sialic Acid Modifications on Virus Binding and Infection

Exploration of the Sialic Acid World

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