Structural Insights into the Substrate Specificity of a 6-Phospho-β-glucosidase BglA-2 from Streptococcus pneumoniae TIGR4

Yu, Wancheng; Jiang, Yong-Liang; Pikis, Andreas; Wang, Cheng; Bai, Xiaohui; Ren, Yan-Min; Thompson, John F.; Zhou, Cong‐Zhao; Chen, Yuxing

doi:10.1074/jbc.m113.454751

Cited by 21 publications

(44 citation statements)

References 43 publications

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“…Surprisingly, > 30% of the proteins involved in dietary glycan processing have been identified as putative virulence factors in STM studies ( Table 1). Sucrose and cellobiose are imported via PTS transporters [189,191,192] and subsequently degraded by a GH32 (ScrH) [191] or a GH1 (BglA-1/BglA-2) [193], respectively. 5).…”

Section: Degradation Of O-linked and Related Glycansmentioning

confidence: 99%

Glycan‐metabolizing enzymes in microbe–host interactions: the Streptococcus pneumoniae paradigm

2018

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Streptococcus pneumoniae is a frequent colonizer of the upper airways; however, it is also an accomplished pathogen capable of causing life-threatening diseases. To colonize and cause invasive disease, this bacterium relies on a complex array of factors to mediate the host-bacterium interaction. The respiratory tract is rich in functionally important glycoconjugates that display a vast range of glycans, and, thus, a key component of the pneumococcus-host interaction involves an arsenal of bacterial carbohydrate-active enzymes to depolymerize these glycans and carbohydrate transporters to import the products. Through the destruction of host glycans, the glycan-specific metabolic machinery deployed by S. pneumoniae plays a variety of roles in the host-pathogen interaction. Here, we review the processing and metabolism of the major host-derived glycans, including N- and O-linked glycans, Lewis and blood group antigens, proteoglycans, and glycogen, as well as some dietary glycans. We discuss the role of these metabolic pathways in the S. pneumoniae-host interaction, speculate on the potential of key enzymes within these pathways as therapeutic targets, and relate S. pneumoniae as a model system to glycan processing in other microbial pathogens.

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Section: Degradation Of O-linked and Related Glycansmentioning

confidence: 99%

Glycan‐metabolizing enzymes in microbe–host interactions: the Streptococcus pneumoniae paradigm

2018

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“…Although most of these stabilizing interactions are not conserved among related enzymes (Fig. ), a similar homo‐dimeric structure has been observed in other homologous 6‐phospho‐β‐glycosidases structures , suggesting that such monomer‐monomer assembly may have a significance beyond the general stabilization provided by a dimer formation. Interestingly, mapping the calculated electrostatic potential onto the surface of the current structure of the Gan1D dimer reveals a significant negative potential patch in the groove formed at the interface between the two monomers.…”

Section: Discussionmentioning

confidence: 71%

“…These loops include the loop that was modeled in two alternate conformations in the Gan1D‐E170Q structure (residues 347–352), and the large loop (residues 311–329) that displayed relatively high B‐factors in the Gan1D‐WT structure, and which could not be modeled in the Gan1D‐E170Q structure due to a lack of electron density (Figs C and ). The difficulty in modeling the loops in these locations has been reported also in homologous enzyme structures . Also, in cases where it was possible to model these loops, they assumed different sizes, shapes and/or orientations, as compared with the corresponding loops in the current Gan1D structures (Fig.…”

Section: Discussionmentioning

confidence: 87%

Structural basis for enzyme bifunctionality – the case of Gan1D from Geobacillus stearothermophilus

et al. 2017

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“…In the D39 strain there are five BglA3 paralogs displaying 31 to 47% similarity, namely, SPD_0277, SPD_0427, SPD_ 0503, SPD_1046, and SPD_1830 (15). Recently an enzyme with 6-phospho-␤-glucosidase activity (BglA2; SPD_0503) in S. pneumoniae was characterized structurally (16). Interestingly, this protein has only 31% identity, while BglJ (sgo_1759) of Streptococcus gordonii has 88% amino acid sequence identity to BglA3.…”

Section: Resultsmentioning

confidence: 99%

“…The presence of multiple copies of phosphoglycosyl hydrolases indicates that the pneumococcus encounters ␤-glucosides in the host. Among these, BglA2 (SPD_0503) has been structurally characterized (16), and all except SPD_0247 are associated with sugar transporters implicated in the transport of various sugars, including ␤-glucosides and lactose. While most of the phosphoglycosyl hydrolases have been linked to the utilization of sugars, the function of the putative orphan protein encoded by SPD_0247 is not known.…”

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confidence: 99%

Pneumococcal 6-Phospho-β-Glucosidase (BglA3) Is Involved in Virulence and Nutrient Metabolism

et al. 2016

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For the generation of energy, the important human pathogen Streptococcus pneumoniae relies on host-derived sugars, including ␤-glucoside analogs. The catabolism of these nutrients involves the action of 6-phospho-␤-glucosidase to convert them into usable monosaccharaides. In this study, we characterized a 6-phospho-␤-glucosidase (BglA3) encoded by SPD_0247. We found that this enzyme has a cell membrane localization and is active only against a phosphorylated substrate. A mutated pneumococcal ⌬SPD0247 strain had reduced 6-phospho-glucosidase activity and was attenuated in growth on cellobiose and hyaluronic acid compared to the growth of wild-type D39. ⌬SPD0247-infected mice survived significantly longer than the wild-type-infected cohort, and the colony counts of the mutant were lower than those of the wild type in the lungs. The expression of SPD_0247 in S. pneumoniae harvested from infected tissues was significantly increased relative to its expression in vitro on glucose. Additionally, ⌬SPD0247 is severely impaired in its attachment to an abiotic surface. These results indicate the importance of ␤-glucoside metabolism in pneumococcal survival and virulence. Streptococcus pneumoniae is a frequent occupant of the human nasopharynx, where it resides without causing symptoms (1). Conversely, the bacterium also is a major human pathogen, being a leading cause of bacterial pneumonia, otitis media, meningitis, and septicemia (1). The increasing trend of antibiotic resistance and the shortcomings of existing vaccines mean that a better understanding of the pathogenesis of pneumococcal diseases is required.Almost one-third of the transporters in the pneumococcal genome are dedicated to sugars (2), stressing the important role that these carbon sources play in the ability of pneumococci to survive in the host. The pneumococcus has been shown to ferment 32 different sugars in vitro, including various hexoses, ␣-and ␤-galactosides, and glucosides, as well as polysaccharides (3, 4). However, the concentrations of readily available simple carbohydrates in the respiratory tract are low (5); thus, the pneumococcus relies on complex host glycans for growth in vivo (4). Central to this is the ability to sequentially deglycosylate host glycoproteins (6).Mammalian extracellular matrix is rich in glycosaminoglycans (GAGs; e.g., hyaluronic acid), which contain ␤-linked disaccharide repeating units (7,8). The degradation of GAGs leads to the generation of structural analogues of cellobiose or N,N=-diacetylchitobiose [(GlcNAc) 2 ] and other ␤-linked disaccharides (9). Disaccharides such as these can be transported into the bacterial cell through phosphoenolpyruvate-dependent phosphotransferase systems (PTS), which transport and phosphorylate sugars simultaneously (10). The phosphorylated disaccharides then are hydrolyzed by cytoplasmic phospho-␤-glucosidases (EC 3.2.1.86) or phospho-␤-galactosidases (EC 3.2.1.85) that usually do not have hydrolytic activity toward nonphosphorylated substrates. The resulting glucose and glucose 6-pho...

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Structural Insights into the Substrate Specificity of a 6-Phospho-β-glucosidase BglA-2 from Streptococcus pneumoniae TIGR4

Cited by 21 publications

References 43 publications

Glycan‐metabolizing enzymes in microbe–host interactions: the Streptococcus pneumoniae paradigm

Glycan‐metabolizing enzymes in microbe–host interactions: the Streptococcus pneumoniae paradigm

Structural basis for enzyme bifunctionality – the case of Gan1D from Geobacillus stearothermophilus

Pneumococcal 6-Phospho-β-Glucosidase (BglA3) Is Involved in Virulence and Nutrient Metabolism

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