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Research Themes Novel Proteins

Microbiome: Fiber Degraders Revealed

SBKB [doi:10.1038/sbkb.2014.231]
Technical Highlight - November 2014
Short description: A combination of phylogenetic, genomic and structural analyses identifies two new glycoside hydrolase families.

Cartoon representation of the BT2193 structure. The N-terminal domain is depicted in shades of grey, the C-terminal domain in a variety of colours. 2

Humans lack the enzymes necessary for the breakdown of many plant-derived polysaccharides contained in our diet, commonly referred to as dietary fiber. Instead, microbes inhabiting the human intestinal system—the gut microbiota—digest those polysaccharides, generating energy to support microbial growth and releasing metabolic products that may be beneficial to humans.

The combined genomes of the gut microbiota—the gut microbiome—include an abundant assortment of genes involved in polysaccharide metabolism. For example, one of the best-studied members of the human gut microbiota, Bacteroides thetaiotamicron, dedicates 20% of its genome to polysaccharide utilization. Virtually all of these genes are arranged in 88 polysaccharide utilization loci (PUL), each encoding a set of enzymes necessary for the complete degradation of one specific carbohydrate. Due to the lack of homologous genes in databases and the sheer size of the gut microbiome, many genes, including those involved in polysaccharide degradation, are yet to be classified and characterized. Two recent papers from the PSI JCSG contribute to filling this gap.

Godzik and colleagues focused on B. thetaiotaomicron protein BT1012, a member of a group of microbiota proteins with unknown function. Sequence and Pfam analyses indicated that BT1012 belongs to the glycoside hydrolase family 5 and contains two domains: an N-terminal domain similar to the TIM barrel glycoside hydrolase superfamily (Pfam PF13204) and a C-terminal domain currently annotated as a collagen-binding domain (Pfam PF12904). These domains are abundant in the gut microbiome and virtually always associated with each other. The authors solved the crystal structure of BT1012 at 2.1-Å resolution (PDB 3KZS). The N-terminal domain is similar to members of the β-glycanase SCOP superfamily, and structural alignment with an endo-beta-mannanase identified a putative catalytic site. The C-terminal domain is related to the C-terminal domain of a human α-galactosidase and expected to either stabilize or regulate the catalytic N-terminal domain. Phylogenetic and structural comparisons suggest that BT1012 is the first member of a new family of glycoside hydrolases, with around 150 homologs currently present in microbiome databases.

Rigden and colleagues studied a protein domain overrepresented in the PULs of gut microbes, GxGYxYP. B. thetaiotamicron has four proteins that contain GxGYxYP domains in two different PULs, including one with unknown carbohydrate specificity. The authors focused on a protein from the latter PUL, BT2193, containing two GxGYxYP domains. The crystal structure solved at 1.25-Å resolution (PDB 3SGG) revealed that BT2193 represents a new family of glycoside hydrolases, with two GxGYxYP domains connected by a linker. Structure-function analyses predicted a carbohydrate-binding cavity located between the two domains and a putative catalytic site that resembles those of cellulases.

The analyses presented in these reports support the involvement of these novel protein families in polysaccharide utilization and provide clues into their specific activities. The next challenge will be to determine their substrate specificity using biochemical experiments.

Claudia Lupp

References

  1. A. Sheydina et al. Structural genomics analysis of uncharacterized protein families overrepresented in human gut bacteria identifies a novel glycoside hydrolase.
    BMC Bioinformatics. 15, 112 (2014). doi:10.1186/1471-2105-15-112

  2. D.J. Rigden et al. Structure- and context-based analysis of the GxGYxYP family reveals a new putative class of Glycoside Hydrolase.
    BMC Bioinformatics. 15, 196 (2014). doi:10.1186/1471-2105-15-196

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