Biology subjects

Perdew, G. H.

Publications and source records attributed to Perdew, G. H..

5 recordsLinked to original sources

bioRxiv2026

Interkingdom glycine conjugates of indole-3-carboxylates are Ah receptor ligands

Substituted indoles are conserved metabolites across all kingdoms of life and may function as a mediators of inter- and intra-species communication. Indole-3-carboxylates (indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA)) represent abundant tryptophan-derived AHR agonists in human serum, potentially influencing AHR-dependent physiology. LC-MS analysis of mouse serum, urine and cecal/fecal contents reveals that both IAA and IPA undergo host and microbial mediated glycine conjugation to facilitate urinary elimination. Notably, at physiologically detectable human serum concentrations (M), IAA-Glycine retains human AHR activation potential. Comparative in silico docking simulations corroborate IAA-Glycine as a direct ligand for the human AHR. Data suggest, in contrast to xenobiotic ligands, AHR activation by endogenous tryptophan metabolites is greater in humans than in mice. These results underscore the role of microbial and host-derived amino acid conjugation in generating bioactive metabolites. Thus, positioning interkingdom auxin chemistry within human physiology and revealing an unexpected link between plants, microbes, and humans.

biochemistry↗

bioRxiv2025

Fusobacterium nucleatum produces previously unappreciated AHR-activating metabolites and promotes CRC cell proliferation via the AHR-TERT axis

Fusobacterium nucleatum (Fn) is prevalently enriched in colorectal cancer (CRC), promoting CRC progression. However, Fn-derived small molecules and their host target pathways in CRC remain largely underexplored. Here, we identify that Fn produces previously unrecognized three indole-containing metabolites, fusotrisindoline (FTIN), streptindole (STIN), and trisindoline (TIN). Using AHR reporter, CYP1A1 mRNA induction, CYP1A enzyme assay, photoaffinity AHR-ligand competition, and in silico docking, we establish that these metabolites are bona fide agonists of the aryl hydrocarbon receptor (AHR), with FTIN being the most potent AHR ligand (EC50 [~]41 nM in HepG2 cells). Genetic and pharmacological perturbations demonstrate that FTIN-activated AHR promotes proliferation, migration, and invasion in EGFR blockade-responsive CRC cell lines, such as SNU-C4, but not in EGFR blockade-resistant cell lines, such as HCT116. We show that FTIN-activated AHR signaling is critical for Fn-mediated promotion of CRC cell growth. A {Delta}tnaA mutant defective in indole production lacked FTIN/STIN/TIN production and was unable to activate AHR or enhance CRC cell growth in vitro and SNU-C4 xenograft growth in vivo. RNA-seq and follow-up functional validation identified TERT as a key downstream effector of FTIN-activated AHR signaling. FTIN upregulated TERT transcription and telomerase activity, and TERT knockdown abrogated FTIN-promoted CRC cell proliferation. FTIN production was conserved across Fn subspecies, as well as other Fusobacterium species, and detected in additional CRC- associated genera. In 30 patient pairs of CRC-matched normal colon tissues, FTIN was quantifiable in most CRC tissues and significantly enriched relative to matched normal colon tissues, whereas STIN/TIN were undetectable. Our findings reveal a metabolite-centered FTIN-AHR-TERT axis by which intratumoral bacteria, such as Fn, accelerate CRC growth and uncover FTIN as a potential biomarker in CRC.

microbiology↗

bioRxiv2023

Complex chemical signals dictate Ah receptor activation through the gut-lung axis

The aryl hydrocarbon receptor (AHR) mediates intestinal barrier homeostasis. Many AHR ligands are also CYP1A1/1B1 substrates, which can result in the rapid clearance within the intestinal tract, limiting AHR activation. This led us to the hypothesis that there are dietary substrates of CYP1A1/1B1 that increase the half-life of potent AHR ligands. We examined the potential of urolithin A (UroA) as a CYP1A1/1B1 substrate to enhance AHR activity in vivo. UroA is a competitive substrate for CYP1A1/1B1 in an in vitro competition assay. A broccoli-containing diet promotes the gastric formation of the potent hydrophobic AHR ligand and CYP1A1/1B1 substrate, 5,11-dihydroindolo[3,2-b]carbazole (ICZ). Dietary exposure to UroA in a broccoli diet led to a coordinated increase in duodenal, cardiac, and pulmonary AHR activity, but no increase in activity in liver. Thus, CYP1A1 dietary competitive substrates can lead to intestinal "escape", likely through the lymphatic system, increasing AHR activation in key barrier tissues.

biochemistry↗

bioRxiv2023

Contribution of circulating host and microbial tryptophan metabolites towards Ah receptor activation

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of cell-based models for cancer and rheumatoid arthritis. We present data here that reframe AHR biology to include the presence of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.

biochemistry↗

bioRxiv2019

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

The human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as first-in-class non-cytotoxic PXR agonists, as a proof-of-concept for microbial metabolite mimicry. The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space.

biochemistry↗