Simulating the enzymes of ganglioside biosynthesis with Glycologue

Abstract

Gangliosides are an important class of sialylated glycosphingolipids linked to ceramide that are a component of the mammalian cell surface, especially those of the central nervous system, where they function in intercellular recognition and communication. We describe an in silico method for determining the metabolic pathways leading to the most common gangliosides, based on the known enzymes of their biosynthesis. A network of 41 glycolipids is produced by the actions of the 10 enzymes included in the model. The different ganglioside nomenclature systems in common use are compared and a systematic variant of the widely used Svennerholm nomenclature is described. Knockouts of specific enzyme activities are used to simulate congenital defects in ganglioside biosynthesis, and altered ganglioside status in cancer, and the effects on network structure are predicted. The simulator is available at the Glycologue website, https://glycologue.org/.

Keywords: Glycologue; Svennerholm nomenclature; gangliosides; glycosyltransferases; neuropathy.

Figure 1

Chemical structure of ganglioside GM1a (a β-ᴅ-galactosyl-(1→3)-N-acetyl-β-ᴅ-galactosaminyl-(1→4)-[α-N-acetylneuraminyl-(2→3)]-β-ᴅ-galactosyl-(1→4)-β-ᴅ-glucosyl-(1↔1)-ceramide). Substituents of the core are labelled with Roman numerals I–IV (I, Glc; II, Gal; III, GalNAc; IV, Gal). IUPAC name: II³Neu5Ac-Gg₄Cer.

Figure 2

Construction of the Svennerholm name GP1cα from its Glycologue structure identifier. At each step of the procedure, the parts of the structure identifier that determine the corresponding part of the systematic Svennerholm name (SSN) are shown in bold face.

Figure 3

Ganglioside carbohydrates predicted by the model. All structures are linked to ceramide at the base glucose or galactose residue.

Figure 4

Ganglioside biosynthetic reaction network predicted by the Glycologue enzyme simulator. Starting from ceramide, which is the root (leftmost) node, 41 carbohydrate structures are predicted using 10 enzymes. The edges of the graph represent enzyme reactions, colored according to the type of sugar transferred: yellow (galactosyltransferases); blue (glucosyltransferases); brown (N-acetylgalactosaminyltransferases); magenta (sialyltransferases).

Figure 5

Predicted effects on the pathways of ganglioside biosynthesis when individual enzyme activities are completely inhibited or knocked-out. Panels 1–10 correspond to the enzymes of Table 2. Enzyme reactions are shown as lines colored according to the type of sugar transferred: yellow (galactosyltransferases); blue (glucosyltransferases); brown (N-acetylgalactosaminyltransferases).