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journal article·2026-06Open access

Enzymatic Basis for the Oxidative Branch of Aromatic Amino Acid Fermentation Leading to p ‐cresol Formation

Li Jiang, Yifeng Wei, Xumei Liu, Dazhi Liu, Zhenyu Liu, Yang Tong, Jinyu Yin, Ankanahalli N. Nanjaraj Urs, Meining Xing, Mark A. Harrison, Chuyuan Zhang, Sheng Yang, Yunzi Luo, Ee Lui Ang, Huimin Zhao, Yan Zhang

Advanced Science· Volume 13· Issue 34
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Abstract

ABSTRACT The phenolic metabolite p ‐cresol is a byproduct of tyrosine fermentation by certain strictly anaerobic bacteria, including the human gut pathogen Clostridium difficile , with toxic effects on the host and intestinal microbiota. The only enzyme in this biochemical pathway characterized to date is the glycyl radical enzyme p ‐hydroxyphenylacetate (HPA) decarboxylase (HPAD), which catalyzes the terminal step. Here we report the identification and characterization of enzymes for anaerobic degradation of tyrosine to HPA in the model p‐ cresol‐producing bacterium Clostridium scatologenes . In this pathway, tyrosine is first converted to p‐ hydroxyphenylpyruvate (HPP), followed by net oxidation to HPA by a trio of enzymes HPP: ferredoxin oxidoreductase (HpdDEFG), phosphate HPA‐transferase (HpdJ) and HPA kinase (HpdK). Each step is thermodynamically reversible, and the pathway is coupled to net generation of ATP and reduced ferredoxin. A bioinformatics search reveals that gene clusters containing a similar trio of enzymes are widespread in anaerobic Firmicutes bacteria, suggesting analogous pathways for the degradation of other amino acids. These findings clarify the oxidative pathways by which anaerobic gut bacteria convert aromatic amino acids into a major class of aromatic metabolites including HPA and p ‐cresol, deepening our understanding of microbiota–host metabolic interactions.
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Research context

Catalysis & surfaces

OpenAlex topics: Clostridium difficile and Clostridium perfringens research · Biochemical and biochemical processes · Microbial bioremediation and biosurfactants

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

New Cornerstone Science Laboratory School of Pharmaceutical Science and Technology Tianjin University Tianjin China

Tianjin Key Laboratory For Modern Drug Delivery & High‐Efficiency Collaborative Innovation Center of Chemical Science and Engineering School of Pharmaceutical Science and Technology Tianjin University Tianjin China

Frontiers Science Center For Synthetic Biology (Ministry of Education) Tianjin University Tianjin China

Singapore Institute of Food and Biotechnology Innovation Agency for Science Technology and Research (A^{∗}STAR) Singapore

Key Laboratory of Systems Bioengineering (Ministry of Education) School of Chemical Engineering and Technology Tianjin University Tianjin China

Department of Infection Biology London School of Hygiene and Tropical Medicine London UK

Key Laboratory of Synthetic Biology Center For Excellence of Molecular Plant Science Chinese Academy of Sciences Shanghai China

Department of Chemical and Biomolecular Engineering University of Illinois at Urbana‐Champaign Urbana Illinois USA

School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai China

Funding

National Natural Science Foundation of China

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