Schematic depiction of the sequential degradation of histo-blood group antigens by pneumococcal GHs. GHs are indicated in bold next to the arrow for the reaction they catalyze. A, degradation of LewisY can be initiated either by SpGH29C, which yields the type II H-trisaccharide (H-Tri), or by SpGH95C, which yields LewisX. The complementary α-fucosidase then acts to produce N-acetyllactosamine (LacNAc), which is cleaved into its constituent monosaccharides by BgaA. Sialyl-LewisX must be desialylated by NanA prior to SpGH29C activity. B, degradation of LewisB can be initiated either by SpGH29C, which yields the type I H-trisaccharide, or by SpGH95C, which yields LewisA. The complementary α-fucosidase then acts to produce lacto-N-biose, which is cleaved into its constituent monosaccharides by BgaC. Sialyl-LewisA must be desialylated by NanA prior to SpGH29C activity. See Fig. S3 for experimental validation for the sequential depolymerization of each of the boxed species in this figure.