Cataloging natural sialic acids and other nonulosonic acids (NulOs), and their representation using the Symbol Nomenclature for Glycans

Abstract

Nonulosonic acids or non-2-ulosonic acids (NulOs) are an ancient family of 2-ketoaldonic acids (α-ketoaldonic acids) with a 9-carbon backbone. In nature, these monosaccharides occur either in a 3-deoxy form (referred to as "sialic acids") or in a 3,9-dideoxy "sialic-acid-like" form. The former sialic acids are most common in the deuterostome lineage, including vertebrates, and mimicked by some of their pathogens. The latter sialic-acid-like molecules are found in bacteria and archaea. NulOs are often prominently positioned at the outermost tips of cell surface glycans, and have many key roles in evolution, biology and disease. The diversity of stereochemistry and structural modifications among the NulOs contributes to more than 90 sialic acid forms and 50 sialic-acid-like variants described thus far in nature. This paper reports the curation of these diverse naturally occurring NulOs at the NCBI sialic acid page (https://www.ncbi.nlm.nih.gov/glycans/sialic.html) as part of the NCBI-Glycans initiative. This includes external links to relevant Carbohydrate Structure Databases. As the amino and hydroxyl groups of these monosaccharides are extensively derivatized by various substituents in nature, the Symbol Nomenclature For Glycans (SNFG) rules have been expanded to represent this natural diversity. These developments help illustrate the natural diversity of sialic acids and related NulOs, and enable their systematic representation in publications and online resources.

Keywords: NulO; glycans; nonulosonic acid; sialic acid; symbol nomenclature.

Fig. 1

The non-2-ulosonic acids (NulOs). a–d) The 3-deoxy-non-2-ulosonic acids (sialic acids): The parent compound in this class is a) neuraminic acid (Neu, 5-amino-3,5-dideoxy-d-glycero-d-galacto-non-2-ulosonic acid). The presence of acetamido and hydroxyacetamido substituents at C5 results in b) N-acetylneuraminic acid (Neu5Ac, 5-acetamido-3,5-dideoxy-d-glycero-d-galacto-non-2-ulosonic acid), and c) N-glycolylneuraminic acid (Neu5Gc, 3,5-dideoxy-5-hydroxyacetamido-d-glycero-d-galacto-non-2-ulosonic acid), respectively. Replacement of the C5 amine with hydroxyl results in d) ketodeoxynononic acid (Kdn, 3-deoxy-d-glycero-d-galacto-non-2-ulosonic acid). e–j) The 3,9-dideoxy-non-2-ulosonic acids (sialic-acid-like subclass compounds). This family includes six subclasses of compounds: e) pseudaminic acid (Pse, 5,7-diamino-3,5,7,9-tetradeoxy-l-glycero-l-manno-non-2-ulosonic acid), f) legionaminic acid (Leg, 5,7-diamino-3,5,7,9-tetradeoxy-d-glycero-d-galacto-non-2-ulosonic acid), G) 4-epi-legionaminic acid (4eLeg, 5,7-diamino-3,5,7,9-tetradeoxy-d-glycero-d-talo-non-2-ulosonic acid), h) 8-epi-legionaminic acid (8eLeg, 5,7-diamino-3,5,7,9-tetradeoxy-l-glycero-d-galacto-non-2-ulosonic acid), i) acinetaminic acid (Aci, 5,7-diamino-3,5,7,9-tetradeoxy-l-glycero-l-altro-non-2-ulosonic acid), and j) 8-epi-acinetaminic acid (8eAci, 5,7-diamino-3,5,7,9-tetradeoxy-d-glycero-l-altro-non-2-ulosonic acid). The ²C₅ chair conformations of Neu, Neu5Ac, Neu5Gc, Kdn, Leg, 4eLeg, and 8eLeg are presented in the α-anomeric configuration and the ²C₅ chair conformations of Pse, Aci, and 8eAci are in the β-anomeric configuration. Note that in all structures shown here, the COOH group at C2 has an axial orientation. All SNFG figures in this report were rendered using DrawGlycan-SNFG (Cheng et al. 2017).

Fig. 2

Modifications to the monosaccharide base structure. The complete chemical structures and associated SNFG representations of a) lactam (Neu1,5lactam), b) lactone (Neu1,7lactone5Ac), c) anhydro (Neu2,7an5Ac), and d) didehydro (Neu2en5Ac) sialic acids.

Fig. 3

Selected examples of new SNFG rules. a) 7-N-acetyl-5-N-(2,3-di-O-methyl-glyceryl)-pseudaminic acid [Pse7Ac5(Gr2,3Me₂)], b) O-glycan from Tannerella forsythia (Tomek et al. 2018), with the terminal acids: 5-N-acetimidoyl-7-N-glyceryl-pseudaminic acid (Pse5Am7Gr) and 4-O-methyl-N-acetylmannosaminuronamide (ManA4Me6N2NAc). Note the use of “2NAc” to indicate C2 location of N-acetyl group, as this is not implicit in the base ManA symbol. c) Correct (top) and incorrect (bottom) representation of 4,7-di-O-acetyl-2-keto-3-deoxy-nononic acid [Kdn4,7Ac₂].