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A structurally unique Fusobacterium nucleatum tannase provides detoxicant activity against gallotannins and pathogen resistance.

ABSTRACT: Colorectal cancer pathogenesis and progression is associated with the presence of Fusobacterium nucleatum and the reduction of acetylated derivatives of spermidine, as well as dietary components such as tannin-rich foods. We show that a new tannase orthologue of F. nucleatum (TanBF_nn ) has significant structural differences with its Lactobacillus plantarum counterpart affecting the flap covering the active site and the accessibility of substrates. Crystallographic and molecular dynamics analysis revealed binding of polyamines to a small cavity that connects the active site with the bulk solvent which interact with catalytically indispensable residues. As a result, spermidine and its derivatives, particularly N⁸ -acetylated spermidine, inhibit the hydrolytic activity of TanBF_nn and increase the toxicity of gallotannins to F. nucleatum. Our results support a model in which the balance between the detoxicant activity of TanBF_nn and the presence of metabolic inhibitors can dictate either conducive or unfavourable conditions for the survival of F. nucleatum.

SUBMITTER: Mancheno JM

PROVIDER: S-EPMC8867971 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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A structurally unique Fusobacterium nucleatum tannase provides detoxicant activity against gallotannins and pathogen resistance.

Mancheño José Miguel JM Atondo Estíbaliz E Tomás-Cortázar Julen J Luís Lavín José J Plaza-Vinuesa Laura L Martín-Ruiz Itziar I Barriales Diego D Palacios Ainhoa A Daniel Navo Claudio C Sampedro Leticia L Peña-Cearra Ainize A Ángel Pascual-Itoiz Miguel M Castelo Janire J Carreras-González Ana A Castellana Donatello D Pellón Aize A Delgado Susana S Ruas-Madiedo Patricia P de Las Rivas Blanca B Abecia Leticia L Muñoz Rosario R Jiménez-Osés Gonzalo G Anguita Juan J Rodríguez Héctor H

Microbial biotechnology 20201218 2

Colorectal cancer pathogenesis and progression is associated with the presence of Fusobacterium nucleatum and the reduction of acetylated derivatives of spermidine, as well as dietary components such as tannin-rich foods. We show that a new tannase orthologue of F. nucleatum (TanBF<sub>nn</sub> ) has significant structural differences with its Lactobacillus plantarum counterpart affecting the flap covering the active site and the accessibility of substrates. Crystallographic and molecular dynami ...[more]

PMID: 33336898

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Project description:BackgroundInfection with the periodontal pathogen Fusobacterium nucleatum (F. nucleatum) has been associated with gastric cancer. The present study is aimed at uncovering the putative biological mechanisms underlying effects of F. nucleatum-mediated neutrophil transcriptional deregulation in gastric cancer.Materials and methodsA gene expression dataset pertaining to F. nucleatum-infected human neutrophils was utilized to identify differentially expressed genes (DEGs) using the GEO2R tool. Candidate genes associated with gastric cancer were sourced from the "Candidate Cancer Gene Database" (CCGD). Overlapping genes among these were identified as link genes. Functional profiling of the link genes was performed using "g:Profiler" tool to identify enriched Gene Ontology (GO) terms, pathways, miRNAs, transcription factors, and human phenotype ontology terms. Protein-protein interaction (PPI) network was constructed for the link genes using the "STRING" tool, hub nodes were identified as key candidate genes, and functionally enriched terms were determined.ResultsThe gene expression dataset GEO20151 was downloaded, and 589 DEGs were identified through differential analysis. 886 candidate gastric cancer genes were identified in the CGGD database. Among these, 36 overlapping genes were identified as the link genes. Enriched GO terms included molecular function "enzyme building," biological process "protein folding,'" cellular components related to membrane-bound organelles, transcription factors ER71 and Sp1, miRNAs miR580 and miR155, and several human phenotype ontology terms including squamous epithelium of esophagus. The PPI network contained 36 nodes and 53 edges, where the top nodes included PH4 and CANX, and functional terms related to intracellular membrane trafficking were enriched.ConclusionF nucleatum-induced neutrophil transcriptional activation may be implicated in gastric cancer via several candidate genes including DNAJB1, EHD1, IER2, CANX, and PH4B. Functional analysis revealed membrane-bound organelle dysfunction, intracellular trafficking, transcription factors ER71 and Sp1, and miRNAs miR580 and miR155 as other candidate mechanisms, which should be investigated in experimental studies.

Dataset Information

A structurally unique Fusobacterium nucleatum tannase provides detoxicant activity against gallotannins and pathogen resistance.

Publications

A structurally unique Fusobacterium nucleatum tannase provides detoxicant activity against gallotannins and pathogen resistance.

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