Chemoproteomic identification of a dipeptidyl peptidase 4 (DPP4) homolog in Bacteroides thetaiotaomicron important for envelope integrity and fitness

Serine hydrolases play important roles in signaling and human metabolism, yet little is known about the functions of these enzymes in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human protease dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Functional studies reveal that BT4193 is a true homolog of hDPP4 while the other is misannotated and is a proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and is inhibited by FDA-approved type 2 diabetes drugs that target hDPP4. Loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. Taken together, our findings suggest that serine hydrolases contribute to gut microbiota dynamics and may be off-targets for existing drugs that could cause unintended impact on the microbiota.

• Publication year

  2022

• Venue

  bioRxiv

• Publication date

  2022-07-26

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1101/2022.07.25.501481
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Quantitative Metaproteomics and Activity-based Protein Profiling of Patient Fecal Microbiome Identifies Host and Microbial Serine-type Endopeptidase Activity Associated With Ulcerative Colitis

  2022cited by this paper
• Resource competition predicts assembly of in vitro gut bacterial communities

  2022cited by this paper
• Establishment and characterization of stable, diverse, fecal-derived in vitro microbial communities that model the intestinal microbiota.

  2022cited by this paper
• Functional genetics of human gut commensal Bacteroides thetaiotaomicron reveals metabolic requirements for growth across environments

  2021cited by this paper
• Multi-omics analyses of the Ulcerative Colitis gut microbiome link Bacteroides vulgatus proteases with disease severity

  2021cited by this paper
• Identification of covalent inhibitors that disrupt M. tuberculosis growth by targeting multiple serine hydrolases involved in lipid metabolism.

  2021cited by this paper
• Identification of cell wall synthesis inhibitors active against Mycobacterium tuberculosis by competitive activity-based protein profiling

  2021cited by this paper
• Bioaccumulation of therapeutic drugs by human gut bacteria

  2021cited by this paper
• Trends in Diabetes Treatment and Control in U.S. Adults, 1999-2018.

  2021cited by this paper
• Xenosiderophore Utilization Promotes Bacteroides thetaiotaomicron Resilience during Colitis.

  2020cited by this paper
• Role of gut microbiota in type 2 diabetes pathophysiology

  2020cited by this paper
• Characterization of serine hydrolases across clinical isolates of commensal skin bacteria Staphylococcus epidermidis using activity-based protein profiling.

  2020cited by this paper
• How to use the MEROPS database and website to help understand peptidase specificity

  2020cited by this paper
• Gut microbiota in human metabolic health and disease

  2020cited by this paper
• Loss of Bacterial Cell Pole Stabilization in Caulobacter crescentus Sensitizes to Outer Membrane Stress and Peptidoglycan-Directed Antibiotics

  2019cited by this paper
• A higher throughput and physiologically relevant two-compartmental human ex vivo intestinal tissue system for studying gastrointestinal processes.

  2019cited by this paper
• Metaproteomics of the human gut microbiota: Challenges and contributions to other OMICS.

  2019cited by this paper
• Mapping human microbiome drug metabolism by gut bacteria and their genes

  2019cited by this paper
• Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases

  2019cited by this paper
• Chemoproteomic Profiling of Gut Microbiota-Associated Bile Salt Hydrolase Activity

  2019cited by this paper
• SignalP 5.0 improves signal peptide predictions using deep neural networks

  2019cited by this paper
• Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism

  2019cited by this paper
• Author Correction: A surface endogalactanase in Bacteroides thetaiotaomicron confers keystone status for arabinogalactan degradation

  2019cited by this paper
• Activity based probes for functional interrogation of 1 retaining-glucuronidases 2

  2018cited by this paper
• A Commensal Dipeptidyl Aminopeptidase with Specificity for N-Terminal Glycine Degrades Human-Produced Antimicrobial Peptides in Vitro.

  2018cited by this paper
• The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice

  2018cited by this paper
• Extensive impact of non-antibiotic drugs on human gut bacteria

  2018cited by this paper
• The Biosynthesis of Lipooligosaccharide from Bacteroides thetaiotaomicron

  2018cited by this paper
• An Antibacterial β-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis.

  2018cited by this paper
• Identification of a S. aureus virulence factor by activity-based protein profiling (ABPP)

  2018cited by this paper
• A Probe-Enabled Approach for the Selective Isolation and Characterization of Functionally Active Subpopulations in the Gut Microbiome.

  2018cited by this paper
• Gut microbiome structure and metabolic activity in inflammatory bowel disease

  2018cited by this paper
• The Potential Role of the Dipeptidyl Peptidase-4-Like Activity From the Gut Microbiota on the Host Health

  2018cited by this paper
• Synthesis of a HyCoSuL peptide substrate library to dissect protease substrate specificity

  2017cited by this paper
• Communication across the bacterial cell envelope depends on the size of the periplasm

  2017cited by this paper
• Activity-based protein profiling as a robust method for enzyme identification and screening in extremophilic Archaea

  2017cited by this paper
• Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling.

  2017cited by this paper
• A comprehensive and scalable database search system for metaproteomics

  2016cited by this paper
• Systematic Survey of Serine Hydrolase Activity in Mycobacterium tuberculosis Defines Changes Associated with Persistence.

  2016cited by this paper
• The Perseus computational platform for comprehensive analysis of (prote)omics data

  2016cited by this paper
• Chemoproteomic profiling of host and pathogen enzymes active in cholera

  2016cited by this paper
• Antibiotic Resistance and Regulation of the Gram-Negative Bacterial Outer Membrane Barrier by Host Innate Immune Molecules

  2016cited by this paper
• Analysis of the Outer Membrane Proteome and Secretome of Bacteroides fragilis Reveals a Multiplicity of Secretion Mechanisms

  2015cited by this paper
• The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis

  2015cited by this paper
• Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation

  2015cited by this paper
• Exopeptidases and gingipains in Porphyromonas gingivalis as prerequisites for its amino acid metabolism

  2015cited by this paper
• A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site.

  2013cited by this paper
• Structure, Function and Diversity of the Healthy Human Microbiome

  2012cited by this paper
• Global identification of peptidase specificity by multiplex substrate profiling

  2012cited by this paper
• The pharmacological landscape and therapeutic potential of serine hydrolases

  2012cited by this paper
• Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

  2010cited by this paper
• Superfamily-wide portrait of serine hydrolase inhibition achieved by library-versus-library screening

  2010cited by this paper
• Activity-based Proteomics of Enzyme Superfamilies: Serine Hydrolases as a Case Study*

  2010cited by this paper
• Identifying genetic determinants needed to establish a human gut symbiont in its habitat.

  2009cited by this paper
• Diversity of Serine Hydrolase Activities of Unchallenged and Botrytis-infected Arabidopsis thaliana*S

  2009cited by this paper
• MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification

  2008cited by this paper
• Metabolism And Excretion of the Dipeptidyl Peptidase 4 Inhibitor [14C]Sitagliptin in Humans

  2007cited by this paper
• Glycan Foraging in Vivo by an Intestine-Adapted Bacterial Symbiont

  2005cited by this paper
• New friendly tools for users of ESTHER, the database of the alpha/beta-hydrolase fold superfamily of proteins.

  2005cited by this paper
• Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation

  2004cited by this paper
• Predicting subcellular localization of proteins for Gram‐negative bacteria by support vector machines based on n‐peptide compositions

  2004cited by this paper
• Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog

  2003cited by this paper
• Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV.

  2003cited by this paper
• Expedient solid-phase synthesis of fluorogenic protease substrates using the 7-amino-4-carbamoylmethylcoumarin (ACC) fluorophore.

  2002cited by this paper
• Profiling serine hydrolase activities in complex proteomes.

  2001cited by this paper
• Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries.

  2000cited by this paper
• Enzymatic Properties of Dipeptidyl Aminopeptidase IV Produced by the Periodontal Pathogen Porphyromonas gingivalis and Its Participation in Virulence

  2000cited by this paper
• Formation of a dipeptidyl arylamidase by Bacteroides splanchnicus NCTC 10825 with specificities towards glycylprolyl-x and valylalanine-x substrates.

  1997cited by this paper
• Identification and characterization of a new gene of Escherichia coli K-12 involved in outer membrane permeability.

  1989cited by this paper
• Structural characterization of the lipid A component of Bacteroides fragilis strain NCTC 9343 lipopolysaccharide.

  1989cited by this paper
• Independent release of peptide YY (PYY) into the circulation and ileal lumen of the awake dog.

  1989cited by this paper
• Protein degradation by human intestinal bacteria.

  1986cited by this paper
• glycylprolyl β-naphthylamidase activity in human serum

  1975cited by this paper

• No citing papers are available for this paper.