Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron

Keller, Laura J.; Nguyen, Taylor H.; Liu, Lawrence J.; Hurysz, Brianna; Lakemeyer, Markus; Guerra, Matteo; Gelsinger, Danielle J.; Chanin, Rachael B.; Ngo, Nhi; Lum, Kenneth M.; Faucher, Franco F.; Ipock, Phillip; Niphakis, Micah J.; Bhatt, Ami S.; O’Donoghue, Anthony J.; Huang, Kerwyn Casey; Bogyo, Matthew

doi:10.1038/s41589-023-01357-8

Cited by 8 publications

(18 citation statements)

References 69 publications

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“…In the latter respect, the conserved and consensus GWSPGGF motif (GWSYGGY in eukaryotes) present in the bacterial DPP4 homolog has led to the assignment of this peptidase to the S9B family of serine peptidases according to the MEROPS database [23]. Our results are in agreement with recent findings showing the presence of DPP4-like enzymes in several species of Bacteroides [14,16].…”

Section: Discussionsupporting

confidence: 91%

“…For vildagliptin, concordant results in mice showed that the drug abolished DPP4 activity in the contents of the cecum and feces [38]. However, our results contrast with the recently characterized DPP4-like enzyme from B. thetaiotaomicron, which is inhibited in the nanomolar range (10 -8 range) by saxagliptin and in the micromolar range by sitagliptin (10 -6 range) and linagliptin (10 -5 range) [14]. These different inhibition patterns could be explained by the extensive sequence diversity of bacterial DPP4-like enzymes, resulting in a large repertoire of proteins with differing abilities to bind gliptins and affect their catalytic activity.…”

Section: Discussioncontrasting

confidence: 56%

“…We recently demonstrated the ability of the gut microbiota to produce DPP4-like activity in germ-free and conventionally colonized mice, leading us to propose that gut microbes are potential mediators of incretin inactivation [13]. Subsequent studies have identified the primary sources of human DPP4 (hsDPP4) homologs in species of the genera Bacteroides, Parabacteroides and Porphyromonas [14][15][16]. In addition, a peptidase activity complementary to that of DPP4, termed Xaa-Pro dipeptidyl-peptidase (PepX), has been identified in lactic acid bacteria commonly found in fermented foods and the human gut, such as Lactobacillus spp., Lactococcus spp.…”

Section: Introductionmentioning

confidence: 99%

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Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation

Olivares,

Hernandez-Calderon,

Cardenas-Brito

et al. 2023

Preprint

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BackgroundThe gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigated whether microbiota DPP4-like counterparts perform the same function.ResultsWe identified novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations betweenParabacteroidesandPorphyromonasDPP4-like genes and type 2 diabetes (T2D). We also found that the DPP4-like enzyme from the gut symbiontParabacteroides merdaemimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) hormonesin vitro.Importantly, administration ofE. colioverexpressing theP. merdaeDPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduced active GIP and GLP-1 levels, which was attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observed that linagliptin, saxagliptin, sitagliptin and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme fromP. merdae.ConclusionsOur findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation

Olivares,

Hernandez-Calderon,

Cardenas-Brito

et al. 2023

Preprint

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“…Whereas the functional characterization of these enzymes is still ongoing, we were able to characterize FphB as a novel virulence factor whose function can be specifically blocked with a small molecule inhibitor (Lentz et al 2018 ), and FphH appears to be linked to stress response (Fellner et al 2023 ). ABPP studies have also identified SHs in other microorganisms (Ortega et al 2016 , Tallman et al 2016 , Keller et al 2020 , 2023 , Babin et al 2022 , Li et al 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…The serine protease E has been, together with gelatinase E, associated with virulence in Enterococcus faecalis (Sifri et al 2002 , Engelbert et al 2004 ), while in E. faecium their roles in virulence are still unclear. In a recent chemoproteomic study where the FP-probe identified a dipeptidyl peptidase homolog in the gut commensal Bacteroides thetaiotaomicron , Keller et al ( 2023 ) also performed a bioinformatic prediction of SHs in human gut commensals. This analysis was based on homology with SH-associated Pfam domains and predicted a total number of 36 SHs in E. faecium ATCC BAA-472 and 37 in E. faecalis V583 (Keller et al 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Activity-based protein profiling of serine hydrolases and penicillin-binding proteins in Enterococcus faecium

Grunnvåg,

Hegstad,

Lentz

2024

FEMS Microbes

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Enterococcus faecium is a gut commensal bacterium that is gaining increasing relevance as an opportunistic, nosocomial pathogen. Its high level of intrinsic and acquired antimicrobial resistance is causing a lack of treatment options, particularly for infections with vancomycin-resistant strains, and prioritizes the identification and functional validation of novel druggable targets. Here, we use activity-based protein profiling (ABPP), a chemoproteomics approach using functionalized covalent inhibitors, to detect active serine hydrolases across 11 E. faecium and Enterococcus lactis strains. Serine hydrolases are a big and diverse enzyme family, that includes known drug targets such as penicillin-binding proteins (PBPs), whereas other subfamilies are underexplored. Comparative gel-based ABPP using Bocillin-FL revealed strain- and growth condition dependent variations in PBP activities. Profiling with the broadly serine hydrolase-reactive fluorescent probe fluorophosphonate-TMR showed a high similarity across E. faecium clade A1 strains, but higher variation across A2 and E. lactis strains. To identify these serine hydrolases, we used a biotinylated probe analog allowing for enrichment and identification via liquid chromatography-mass spectrometry. We identified 11 largely uncharacterized targets (α,β-hydrolases, SGNH-hydrolases, phospholipases, amidases, peptidases) that are druggable and accessible in live vancomycin-resistant E. faecium E745 and may possess vital functions that are to be characterized in future studies.

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Funktionelle Charakterisierung der Darmflora und ihrerhydrolytisch aktiven Enzyme ‐Trendbericht Biochemie 2024 (2/3)

Lakemeyer,

Seidel

2024

Nachr Chem

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Chemische Proteinsynthese: Neue Techniken in der Durchflusschemie und selektive Ligationsmethoden ermöglichen, komplexe und präzise modifizierte Peptide und Proteine für biologische Anwendungen herzustellen. Funktionelle Charakterisierung: Mit Methoden aus Mikrobiologie, chemischer Biologie und Biochemie untersuchen Forschende die molekulare Funktion bakterieller Enzyme des Mikrobioms und decken so deren Relevanz bei der Entwicklung von Darmerkrankungen auf. DNA‐Origami: Biomoleküle auf mikro‐ und nanoskopischer Ebene zu untersuchen soll helfen, neue Therapeutika zu entwickeln, herzustellen und an ihren Zielort zu bringen. Besonders die Interaktionen von Proteinen miteinander und mit Ligandenmolekülen sind dabei wichtig.

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Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron

Cited by 8 publications

References 69 publications

Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation

Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation

Activity-based protein profiling of serine hydrolases and penicillin-binding proteins in Enterococcus faecium

Funktionelle Charakterisierung der Darmflora und ihrerhydrolytisch aktiven Enzyme ‐Trendbericht Biochemie 2024 (2/3)

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