Host glycan utilization within the Bacteroidetes Sus-like paradigm

Abstract

The Bacteroidetes are numerically abundant Gram-negative organisms of the distal human gut with a greatly expanded capacity to degrade complex glycans. A subset of these are adept at scavenging host glycans within this environment, including mucin O-linked glycans, N-linked glycoproteins and highly sulfated glycosaminoglycans (GAGs) such as heparin (Hep) and chondroitin sulfate (CS). Several recent biochemical studies have revealed the specific polysaccharide utilization loci (PULs) within the model symbiont Bacteroides thetaiotaomicron for the deconstruction of these host glycans. Here we discuss the Sus-like paradigm that defines glycan uptake by the Bacteroidetes and the salient details of the PULs that target heparin/heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (DS)/hyaluronic acid (HA), respectively, in B. thetaiotaomicron. The ability of the Bacteroidetes to target highly sulfated host glycans is key to their success in the gut environment but can lead to inflammation in susceptible hosts. Therefore, our continued understanding of the molecular strategies employed by these bacteria to scavenge carbohydrate nutrition is likely to lead to novel ways to alter their metabolism to promote host health.

Keywords: Bacteroides; N-linked glycans; gut microbiota; heparin; mucin.

Fig. 1

Architecture and activities within B. theta PUL_HEP, as described by Cartmell et al. 2017. (A) Cartoon representation of the extracellular and periplasmic components of PUL_Hep. Heparin/heparan sulfate is captured at the cell surface, minimally processed by BT4662-PL12, and the oligosaccharides are imported by the SusCD-like complex with assistance from the SGBP BT4661. Once imported, an elaborate network of enzymes reduces the glycan to desulfated monosaccharides. The SusC-like protein is not the Hep SusC-like protein but is the recently determined homolog BT2264 (Glenwright et al. 2017) (PDB 4FQ8). The SusD-like protein is the Hep SusD-like protein (PDB 3IHV). The SGBP structure is a combination of the ligand (Δ4,5UA2S-GlcNS6S-IdoA2S-GlcN6S-IdoA2S-GlcNS6S) from PDB 4AK2 and the full-length protein from PDB 4AK1 (Cartmell et al. 2017). SGBP ligand and all subsequent ligands are colored in dark gray. Unliganded 4662-PL12 is PDB 4FNV (Dong et al. 2012). Unliganded 4657-PL12 is PDB 5JMF (Ulaganathan et al. 2017). 4675-PL13 is shown complexed with a heparin-derived dodecasaccharide and PDB 3INA (Han et al. 2009). The 2O-sulfatase BT1596-S1_9 is complexed with Δ4,5UA2S-GlcNS6S (PDB 5G2T (Cartmell et al. 2017)). The 6O-sulfatase BT4656-S1_11 is complexed with GlcNS6S (PDB 5G2V (Cartmell et al. 2017)). The dimeric periplasmic domain of the HTCS BT4663 is complexed with Δ4,5UA-GlcNAc6S (PDB 4A2M (Lowe et al. 2012)). (B) Architecture of the genetic loci. The gene representations are to scale and colored the same as their protein products.

Fig. 2

Architecture and activities within B. theta PUL_CS/DS/HA, as described by Ndeh et al. 2020. (A) Cartoon representation of extracellular and periplasmic components of PUL_CS/DS/HA. Carbohydrate at the cell surface undergoes some processing by BT3328-PL29, and the oligosaccharides are imported by the SusCD-like complex with help from two SGBP proteins, BT3329 and BT3330. Once imported, a suite of PL enzymes, a GH88, and three sulfatases depolymerize and desulfate all four carbohydrates shown. As in Figure 1A, the SusC-like protein is not the CS/DS/HA SusC-like protein but is the recently determined homolog BT2264 (Glenwright et al. 2017) (PDB 4FQ8). The SusD-like protein is that from PUL_HEP (PDB 3IHV). Unliganded BT3324-PL8 is PDB 2Q1F (Shaya et al. 2008). The 2O-sulfatase BT1596-S1_9 is complexed with Δ4,5UA2S-GlcNS6S (PDB 5G2T (Cartmell et al. 2017)). The 4O-sulfatase BT3349-S1_27 (PDB 6S21) is complexed with Δ4,5UA-GalNAc4S-GlcA, colored in gray (Ndeh et al. 2020). The 6O-sulfatase BT3333-S1_15 (PDB 6S20) is complexed with GalNAc6S, colored in gray (Ndeh et al. 2020). Instead of the cognate HTCS regulator, BT3334, the dimeric periplasmic domain of the PUL_HEP BT4663-HTCS is shown complexed with Δ4,5UA-GlcNAc6S (PDB 4A2M (Lowe et al. 2012)). (B) Architecture of the genetic loci. The gene representations are to scale and colored the same as their protein products.