Proteomics

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Characterizing metabolic drivers of Clostridioides difficile infection with activity-based hydrazine probes


ABSTRACT: Many enzymes require post-translational modifications or cofactor machinery for primary function. As these catalytically essential moieties are highly regulated, they act as dual sensors and chemical handles for context-dependent metabolic activity. Clostridioides difficile is a major nosocomial pathogen that infects the colon. Energy generating metabolism, particularly through amino acid Stickland fermentation, is central to colonization and persistence of this pathogen during infection. Here using activity-based protein profiling (ABPP), we revealed Stickland enzyme activity is a biomarker for C. difficile infection (CDI) and annotated two such cofactor-dependent Stickland reductases. We, for the first time, structurally assigned proline reductase and glycine reductase as cysteine-derived pyruvoyl-dependent enzymes and showed through cofactor monitoring that their activity is regulated by their respective amino acid substrates. Proline reductase was consistently active in toxigenic C. difficile, confirming the enzyme to be a major metabolic driver of CDI. Further, activity-based hydrazine probes were shown to be active site directed inhibitors of proline reductase. As such, this enzyme activity, via its druggable cofactor modality, is a promising therapeutic target that could allow for the repopulation of bacteria that compete with C. difficile for proline and therefore restore colonization resistance against C. difficile in the gut.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Clostridioides Difficile Atcc 43255

SUBMITTER: Megan Matthews  

LAB HEAD: Megan L. Matthews

PROVIDER: PXD039143 | Pride | 2023-03-11

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20201207_KBVI73_4.mzXML Mzxml
20201207_KBVI73_4.raw Raw
20201207_KBVI73_4_DTASelect-filter.mzid.gz Mzid
20210113_KBVI128_1.mzXML Mzxml
20210113_KBVI128_1.raw Raw
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Publications

Characterizing metabolic drivers of <i>Clostridioides difficile</i> infection with activity-based hydrazine probes.

Bustin Katelyn A KA   Abbas Arwa A   Wang Xie X   Abt Michael C MC   Zackular Joseph P JP   Matthews Megan L ML  

Frontiers in pharmacology 20230126


Many enzymes require post-translational modifications or cofactor machinery for primary function. As these catalytically essential moieties are highly regulated, they act as dual sensors and chemical handles for context-dependent metabolic activity. <i>Clostridioides difficile</i> is a major nosocomial pathogen that infects the colon. Energy generating metabolism, particularly through amino acid Stickland fermentation, is central to colonization and persistence of this pathogen during infection.  ...[more]

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