Bacteria often produce siderophores - small molecules with high affinity for Fe(III) - to acquire the iron that they need to grow. After transport of the Fe(III)-siderophore across the outer membrane of Gram-negative bacteria, a periplasmic binding protein (PBP) generally shuttles the Fe(III)-siderophore through the periplasm to the inner membrane. The fish pathogen Yersinia ruckeri synthesizes the oligoester tris-catecholate siderophore ruckerbactin, (DHB-Arg-Ser) (1), to acquire iron during infection. Its biosynthetic gene cluster encodes a single PBP, RupB, which was presumed to bind Fe(III)-ruckerbactin, however, previous fluorescence quenching titrations revealed RupB does not bind Fe(III)-ruckerbactin nor the Fe(III) complexes of its hydrolysis products - the bis- and mono-catecholate siderophores, 2 and 3, respectively - with biologically relevant affinities. Instead, RupB binds the complex of the structurally-related siderophore enterobactin, (DHB-Ser), which is surprising since enterobactin is not biosynthesized by Y. ruckeri. RupB inverts the chirality of the Δ-Fe(III)-enterobactin to Λ upon binding. A second PBP, YiuA, which is encoded elsewhere in the genome was established previously to bind the 1:2 Fe(III) complex of the mono-catecholate DHB-Arg-Ser (3), Fe(III)-(3), as well as the diastereomeric complex Fe(III)-(4) with nanomolar affinities, in which 4 is the monocatechol DHB-Arg-Ser. We show that YiuA recognizes similar siderophore scaffolds containing the alternative cationic amino acids (Lys, Orn), suggesting a broader role in xenosiderophore uptake. YiuA binds its substrate in the Λ isomer regardless of the chirality of the complex presented to it.

Ru265, [Ru(μ-N)(NH)Cl]Cl, is a potent nanomolar inhibitor of the mitochondrial calcium uniporter (MCU), the transporter that mediates Ca uptake into the mitochondria. This compound and related MCU inhibitors are promising therapeutic agents and chemical biology tools for studying intracellular Ca dynamics. Axial ligand modification of these Ru-based complexes provides a facile way to tune their properties and make prodrugs. In this study, the use of axial phosphonate and phosphinate ligands was explored within this compound class, yielding [Ru(μ-N)(NH)(OPO(OH)Me)](CFSO) (1) and [Ru(μ-N)(NH)(OPOPh)](CFSO) (2). Both complexes were characterized by multinuclear NMR spectroscopy, revealing downfield shifts of the P resonances of the coordinated ligands. The crystal structure of 1 was also obtained, which confirmed coordination of the methylphosphonate ligands to the axial sites of the Ru core. The aquation of 1 and 2 were studied by NMR and UV-vis spectroscopy. Unexpectedly, compound 1 undergoes partial aquation, arresting at a final product in which only one axial methylphosphonate is displaced by water. By contrast, 2 loses both diphenylphosphinates via aquation (t = 1.7 h) under physiological conditions. The in vitro biological investigations of 1 and 2 in HeLa cells showed that neither demonstrate high cytotoxicity nor depolarize the mitochondrial membrane potential. Both compounds exhibit nanomolar inhibitory activity against mitochondrial Ca uptake in permeabilized HEK293T cells and modest inhibitory activity against this process in intact HeLa cells. Notably, 1 shows pH-dependent activity for MCU inhibition, with greater inhibition in more acidic conditions, while 2 shows improvement in cellular uptake efficiency.

Although widely used clinically, the extensive nephrotoxicity and drug resistance of platinum-based metallic anticancer drugs have spurred the research and development of non‑platinum-based metallic anticancer drugs. Half-sandwich iridium(III) (Ir) complexes have become a research hotspot in this field due to their excellent anticancer activity, structural tunability, and unique mechanism of action different from that of cisplatin. Then two half-sandwich Ir xanthate complexes with a simple structure were prepared in this study. In vitro anti-proliferative evaluation showed that these two complexes enjoyed favorable activity towards A549 lung cancer cells in comparison to cisplatin, and could also effectively inhibit cell migration. Further research showed that Ir1 could target lysosomes (PCC: 0.85) and lead to lysosomal damage, then disturbing the cell cycle arrest (G/G phase), decreasing mitochondrial membrane potential and inducing the improvement of intracellular reactive oxygen species levels. Western blotting also confirmed the existence of a lysosomal-mitochondrial apoptotic anticancer pathway. Collectively, these structurally simple yet highly active Ir complexes provide a valuable foundation for the rational design and development of novel non‑platinum-based metallic anticancer drugs.

Sn pollution poses significant risks to ecosystems and human health, necessitating the development of simple detection methods for accurate monitoring of Sn dynamics. Here, we developed a conceptually distinct strategy that exploits the Sn-mediated reduction of organic azides rather than conventional chelation mechanism, and constructed a series of azide-based fluorescent probes (A-G) operating via turn-on, ratiometric, or fluorescence resonance energy transfer modality with emissions spanning blue to near-infrared for specific sensing of Sn. These probes exhibit exceptional selectivity for Sn over Sn and other biologically relevant species, sub-micromolar detection limits (as low as 13.7 nM), fast response kinetics (t < 1 min), and full aqueous compatibility. The reduction mechanism was confirmed through radical trapping and product isolation. Probe B enabled direct quantify Sn in real water samples with good recovery (93.5-103.3 %). All designed probes facilitated high-contrast in-situ imaging of Sn in living cells. This work provides a robust platform for deciphering the environmental fate and biological roles of Sn.

The Mo-dependent enzyme human sulfite oxidase (HSO) oxidises highly neurotoxic sulfite to benign sulfate in the final step of cysteine catabolism. Although sulfite is its only known physiological substrate, HSO has been suggested to play a role in the generation of nitric oxide (NO) from nitrite under ischemic conditions. In this work we have investigated the electrochemically driven nitrite reductase activity of HSO mediated by the benzyl viologen radical cation. We show that HSO can act as an effective nitrite reductase with a K value of 3.5 mM at pH 7. A heme-free variant of HSO behaves similarly. We also demonstrate electrochemically driven tandem sulfite oxidation and nitrite reduction with HSO using a known Fe coordination compound as mediator. Significant pH-dependence of catalytic activity is found.

Triazolam (TRZ) is a representative benzodiazepine sedative-hypnotic drug that has gradually been abused due to the increasing societal pressures. To further provide a theoretical basis for the rationale use of TRZ and obtain more information for its metabolic process, in this study, human CYP3A4 was employed as the metabolic enzyme to investigate the metabolic mechanism of TRZ by multiple computational methods. Here, three types of substrate-binding conformations related to the diversity of TRZ metabolites are identified (pose A, pose B and pose C). The "sandwich" structure and the π-π stacking between TRZ and F304/porphyrin ring may be the key factors in dominating three substrate-binding conformations. Furthermore, we discovered pose A is the predominant binding mode, with Cα-H serving as the key metabolic site and CYP3A4-catalyzed Cα-H hydroxylation follows a hydrogen abstraction-rebound mechanism. More importantly, in hydroxylation process, the spin states of iron can regulate the metabolic reaction rate of TRZ and the highest rate of metabolism (5.96 s) is found in the quartet spin states. Based on our findings, it can be suggested that rational incorporating aromatic groups into TRZ could improve its metabolic stability. Meanwhile, the transition of the heme iron from a low-spin to a high-spin state appears to accelerate TRZ metabolism, potentially leading to the accumulation of α-OH triazolam in vivo, which may pose risks to human health. These results could enhance our understanding of CYP3A4-mediated regioselective metabolism of TRZ and provide a theoretical foundation and new perspective for studies on the metabolism of other triazole drugs.

Tryptophan radicals are relevant to charge transport and catalysis in several enzymes. The radical is produced by the removal of an electron and proton from tryptophan. Despite its prevalence, tools to probe tryptophan radicals in biological systems remain limited. Fluorination of the indole ring of tryptophan induces changes in the redox potential, pK and absorption spectrum, thus making fluorotryptophans attractive residues to probe the transient role of tryptophan radicals in biological systems. A series of N-acylated mono-fluorotryptophan amide analogs have been synthesized. Fluorine substitution at the 4 to 7 positions on the indole ring expands the a pK of the indole proton from 4.6 to 3.8-4.0 and a shift in reduction potential of 70 to 115 mV in the pH independent region (pH < 4) and 33 to 72 mV in the pH dependent regime that is accessible to most proteins (pH 6 to 9). Spectral shifts between 550 and 620 nm for the fluorotryptophan radical cation and between 495 and 550 nm for the neutral fluorotryptophan radical, respectively, allow their transient formation to be differentiated from background tryptophans in protein systems. The red shift of the radical cation as compared to the neutral radical is captured by DFT calculations and is shown to arise primarily from the stabilization of the radical cation SOMO. With the emergence of genetic code expansion techniques for incorporating fluorotryptophans in proteins, the mono-fluorotryptophans reported herein will be useful unnatural amino acids for examining tryptophan radicals in biology.

Six platinum(IV) prodrugs incorporating 5-fluorouracil (5FU) derivatives in the axial positions were synthesised, purified, fully characterised, and their biological activity assessed. The 5FU derivatives, 5FU-acetate and 5FU-methoxybutanoate, were successfully coordinated to [Pt(P)(1S,2S-diaminocyclohexane)(OH)₂] scaffolds, where P = 1,10-phenanthroline (Phen) or 5,6-dimethyl-1,10-phenanthroline (56Me₂Phen). All complexes exhibited exceptional in vitro cytotoxicity across a broad panel of cancer cell lines, with [Pt(56MePhen)(1S,2S-diaminocyclohexane)(5FU-methoxybutanoate)(OH)](NO) (6) demonstrating the lowest GI₅₀ of 1 nM against the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 6 being up to 1400-fold more active in selected cancer cell lines. Complexes incorporating the 5FU-methoxybutanoate ligand (5 and 6) were notably more cytotoxic and lipophilic than their 5FU-acetate analogues (1-3), with 6 also exhibiting ∼2-fold greater potency than its platinum(II) precursor. Further studies in the HT29 colon cancer cell line revealed that 5 and 6 induced sustained elevations in reactive oxygen species (ROS) and substantial reductions in mitochondrial membrane potential, indicating that oxidative stress and mitochondrial dysfunction contributed to their cytotoxicity. Collectively, these findings demonstrate that the incorporation of 5FU into platinum(IV) prodrugs enhances both potency and mechanistic activity, with prodrug 6 emerging as a highly promising anticancer candidate.

Auranofin (AF) is a clinically approved gold(I) metallodrug with recognized anti-inflammatory and anticancer properties, whose mechanism of action relies on the covalent binding at key selenoproteins and thiols causing their irreversible deactivation. While the final covalent binding event is well-documented, the initial non-covalent recognition phase that precedes it, and which likely governs the drug's selectivity, remains poorly characterized by experimental methods. To address this gap, we employed density functional theory (DFT) calculations to systematically investigate the weak, pre-covalent interactions between auranofin (AF) or its chlorido derivative, Au(PEt)Cl (AFCl), with model protein residues. Our results reveal distinct non-covalent interactions preferences for each drug: AF shows a stronger affinity for charged amino acid residues, while AFCl exhibits a marked preference for aromatic and some charged residues. We demonstrate that these initial non-covalent interactions induce a significant redistribution of electron density. This effect alters the local electronic properties of the gold center and its bond to the labile ligand, effectively priming the drug for subsequent covalent attack. We then utilized the computationally derived geometric assets to perform a comprehensive motif search within the Protein Data Bank (PDB) database, which identified ten protein targets with significant therapeutic relevance. This bioinformatic analysis provided a general picture of how these gold compounds navigate their biological environment and led to the identification of targets. This pre-covalent interaction with protein is not a random anchoring process but a crucial preparatory step for the targeted attachment of gold-based drugs.

Three novel unsymmetrically substituted 2,2'-bipyridine ligands were prepared by introducing a 2-hydroxyphenyl group at the 6-position and either a 4-methoxyphenyl, 3,4-dimethoxyphenyl or 3,4-methylenedioxyphenyl group at the 4-position, using a modified Kröhnke protocol. Their corresponding rhenium(I) tricarbonyl iodido complexes, fac-[Re(L)(CO)I], 1-3, were synthesized and comprehensively characterized by single-crystal X-ray diffraction (SCXRD), H and C nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, cyclic voltammetry (CV), high-resolution mass spectrometry (HRMS), and elemental analysis. The common 6-(2-hydroxyphenyl) moiety predominantly influences the spectroscopic and redox properties of the complexes. SCXRD confirms the facial arrangement of the fac-[Re(CO)NI] core in all three cases, although solid-state conformational isomerism was observed only in complex 1. In contrast, two NMR-distinguishable isomers are observed in solution for all three complexes. The cytotoxicity of 1-3 was evaluated by MTT assay after 48 h of continuous exposure in several human tumor cell lines (HeLa, PANC-1, MDA-MB-231, A549) and in non-malignant human lung fibroblasts (MRC-5). Notably, all three complexes displayed low-micromolar IC values comparable to cisplatin, with the highest activity observed in HeLa cells (5.11-7.45 μM). However, significant activity was also recorded in MRC-5 cells (IC = 8.19-8.95 μM), suggesting higher overall toxicity and weaker selectivity compared to cisplatin. Analysis in HeLa cells using bright-field microscopy confirmed a substantial antiproliferative effect.

In 1984, a synthetic model system for certain molybdenum oxotransferase enzymes was reported. These reports claimed that an oxygen atom could be extracted from a designed dioxomolybdenum(VI) complex to produce a monoxomolybdenum(IV) complex without the formation of an oxo-bridged molybdenum(V) binuclear species. The reduced product was shown to accept oxygen atoms from substrates such as dimethylsulfoxide with substrate saturation kinetics. Fifteen years later, it was demonstrated that the reduced product was, in fact, the oxo-bridged molybdenum(V) binuclear species. Here, it is shown that the kinetic data can be reinterpreted in terms of rate-limiting disproportionation of the oxo-bridged molybdenum(V) binuclear species to form a highly reactive monoxomolybdenum(IV) complex. The second order rate constant for oxygen atom transfer from dimethyl sulfoxide to this complex is more than 100,000 times higher than those reported for other monoxomolybdenum(IV) complexes. The five-coordinate molybdenum sites in the dioxomolybdenum(VI) and presumed monoxomolybdenum(IV) complexes are quite similar to those observed for eukaryotic nitrate reductase enzymes and this model system shows relatively rapid reduction of nitrate through a similar mechanistic scheme.

This research presents the design, synthesis, structural characterization, and evaluation of the anticancer activities of three new pyrimidylanthrahydrazone cobalt(II) complexes: 1) 9-MPMAH-Co, 2) 9-FPMAH-Co, and 3) 9-PMAH-Co. Single-crystal X-ray diffraction analysis confirmed that all three complexes adopt a hexacoordinate mononuclear geometry. However, differences in their coordination modes were observed due to variations in the ligand substituents (-CH, -F, -H). Spectroscopic DNA interaction studies indicated that all three cobalt complexes exhibit varying levels of DNA intercalation. Topoisomerase I inhibition assays revealed that 9-PMAH-Co demonstrates significant enzyme inhibition at a low concentration of 1 μM. In vitro antiproliferative assays confirmed that 9-PMAH-Co exhibits potent cytotoxic activity against SK-OV-3 and HeLa-229 cancer cell lines, with IC₅₀ values of 4.99 ± 0.18 μM and 8.09 ± 1.13 μM, respectively, while showing reduced toxicity toward normal liver cells (HL-7702) compared to cisplatin. Further investigation through cell cycle analysis indicated that 9-PMAH-Co induces G2/M phase arrest in SK-OV-3 cells, with a population increase to 91.37 % (Δ = 76.59 %). Studies on the structural-activity relationship suggest that the synergistic interactions between the ligand substituents and the cobalt center play a crucial role in modulating biological activity, highlighting 9-PMAH-Co as a promising lead compound for the development of targeted anticancer agents.

The evolution of oxidative metabolism has shaped life on Earth, from ancient anaerobic microorganisms to modern eukaryotes. Central to aerobic life is the ability of metalloproteins to regulate and utilize dioxygen through tightly controlled biochemical processes. Beginning with the emergence of oxygenic photosynthesis and aerobic respiration, the pivotal roles of metalloenzymes in dioxygen activation, utilization and detoxification are then highlighted. Bridging perspectives from bioinorganic chemistry, enzymology, synthetic biology and microbiome science, we discuss how studies of biomimetic molecular complexes and natural and artificial metalloproteins illuminate the structural and functional strategies used to manage dioxygen reactivity. We further consider the systemic roles of metal ions in maintaining redox balance, shaping host-microbe interactions, and contributing to pathological outcomes when misregulated. A foundation is established for understanding the critical roles that metal ions play in dioxygen chemistry that underpins both healthy metabolism and oxidative stress related diseases.

Neisseria gonorrhoeae is a pathogenic bacterium responsible for the disease gonorrhea, which has gained increasing attention in recent years due to the emergence of strains resistant to the currently used antibiotics. In the absence of a vaccine, understanding mechanisms that contribute to infection is imperative. One such mechanism is the reduction of hydrogen peroxide by the outer membrane bound bacterial peroxidase. Here, steady-state kinetics shows that cytochrome c, previously implicated in nitrite reduction, is an efficient electron donor to this enzyme, proving to be an alternative to the lipid-modified azurin. The cytochrome c-mediated peroxidase activity has a K of 0.74 ± 0.08 μM and a k of 18 ± 1 s for hydrogen peroxide, with an optimum pH at 7.7. The pH and ionic-strength dependence of this activity differs from that of azurin, suggesting that the two electron donors can play complementary roles depending on external conditions. Furthermore, the viscosity dependence of the activity suggests that protein-protein interactions are not purely diffusion-controlled but also governed by conformational changes required for complex formation and/or electron transfer, and docking analysis implies that cytochrome c binds near the exposed edge of the electron transferring heme of the bacterial peroxidase. This study improves our understanding of the periplasmic physiology of N. gonorrhoeae by demonstrating how the pathogen's flexibility in using electron donors enables it to maintain peroxidase activity and cope with oxidative stress in different host environments. These insights could inform future strategies aimed at disrupting redox homeostasis to combat antibiotic-resistant strains.

Both Mycobacterium smegmatis and M. abscessus secrete porphyrin throughout their growth, and other species of bacteria have also been shown to secrete porphyrin with various outcomes. However, how the secretion of a heme precursor alters heme levels remains to be seen. Herein we determined that porphyrin levels and heme levels in the mycobacteria are decoupled as an increase in intracellular or extracellular porphyrin does not alter intracellular heme levels. Our findings support a model for heme biosynthesis with multiple points of regulation, further our understanding of how to alter secretion and buildup of endogenous porphyrins in the mycobacteria, and suggest that mycobacteria have a biological purpose for porphyrin secretion.

This research aimed to compare the crystal structure, physicochemical, and biological properties of novel (acetylacetonate)(thiodiacetato)oxidovanadium(IV) complex salts, namely [QH][VO(acac)(tda)] (1) and [(acr)H][VO(acac)(tda)] (2) (acac = acetylacetonate, tda = thiodiacetate, Q = quinoline, acr = acridine) with previously reported oxydiacetate (oda) analogues: [QH][VO(acac)(oda)] (3) and [(acr)H][VO(acac)(oda)](HO) (4). A combination of experimental data, including X-ray crystallography, IR spectroscopy, potentiometric measurements and ESI-MS, and density functional theory (DFT) calculations enables thorough characterization of the complexes in the solid state and in solution. It has been demonstrated that the observed differences in the nature of VS (thioether) and VO (ether) dative bonds have only a slight impact on orbital energy levels and spin density distribution. At the same time, these minor differences do not significantly affect the thermodynamic stability of the complexes: logß {[VO(acac)(tda)]} = 16.91 and logß {[VO(acac)(oda)]} = 16.45. Additionally, the calculated thermodynamic parameters for the formation of these complexes (∆H, T∆S, ∆G in kcal mol, at 298 K) are -66.72, -16.38, and - 50.34 for [VO(acac)(tda)], and - 68.47, -15.64, and - 52.82 for [VO(acac)(oda)], respectively. The biological evaluations showed promising selective cytotoxic activity of the investigated complex salts against the human osteosarcoma cell line MG-63. The mechanism of biological action of these complexes appears to involve disruption of cell cycle regulation and induction of apoptosis. The counterions (acridine and quinoline) alone do not significantly affect cell cycle distribution, suggesting that the cytotoxic and cell cycle effects are primarily due to the [VO(acac)(tda)] and [VO(acac)(oda)] species.

Mixed-valence multi-metallic complexes, in which the metal is present in more than one oxidation state, provide crucial insight into how electron transfer operates in both biological proteins/enzymes and synthetic inorganic compounds. Nature offers striking examples, such as the oxygen-evolving complex (OEC) of photosystem II, where mixed valency plays an essential role in facilitating proton-coupled electron transfer (PCET) The degree of electronic delocalization between redox sites is subdivided into three groups (Class I, Class II, and Class III) by the Robin-Day classification. Elucidating electronic structure and the function of such systems serves as a foundation for the design of bioinspired catalysts. Nickel, with its rich redox flexibility, is well positioned to form mixed-valent binuclear complexes across several oxidation states, including Ni₂(I,0), Ni₂(I,II), and Ni₂(II,III) dinuclear complexes. Several such systems mirror the redox profiles of enzymes like acetyl-CoA synthase, which is central to C1 metabolism. This perspective highlights the emerging landscape of multinuclear nickel complexes, focusing on their structural classification and redox behavior. Special attention is given to a newly characterized family of Class III Ni₂(I,II) complexes, which exhibit fully delocalized valency. Collectively, this work underscores how mixed-valent states not only advance our understanding of electron transfer mechanisms but can also guide the development of new redox-active materials for catalysis.

This paper reports the development of a complex between the antibiotic gentamicin sulfate (GEN), consisting of four major congeners, and zinc ions (Zn(II)GEN complex). The composition of the complex aligns well with the proposed molecular formula [Zn(L)(3H₂O)(2SO₄]. The Zn(II)GEN complex significantly enhanced inhibitory and bactericidal activity against S. aureus, E faecalis, P. aeruginosa, and E. coli. Unlike gentamicin sulfate alone, the Zn(II)-GEN complex did not induce drug-resistant mutants. Molecular modeling predicted predominantly hexacoordinated complexes involving three contact points with gentamicin and three with water, which agreed with the spectroscopic studies. The complexes adopted a restricted conformation of gentamicin, resulting in its hydrophilic groups being excluded from the solvent, which is consistent with the higher permeability. Molecular Modeling studies of the Zn(II)GEN complex with 16S RNA revealed a restricted bioactive conformation with stable interactions with residues A1493, G1494, and U1495, a structural requirement for antimicrobial activity. Free energy of binding analyses show that the Zn(II)GEN complex had better pharmacodynamic properties than the pure compound. A favored bioactive conformation formed upon the complexation of gentamicin sulfate with Zn(II) increased the complex's potency against bacteria and allowed it to penetrate bacterial cells. The complex also reduces the likelihood of antimicrobial resistance. The strategy is a good starting point for research into combating bacteria.

Due to cisplatin's limited efficacy and adverse effects on healthy tissues, particularly the kidneys, its use is restricted. The objective of this research was to investigate the impact of new Pt(IV) complexes that contain ethyl- propyl- and butyl-esters of the ethylenediamine-N,N'-di-S,S-(2,2'-dibenzyl) acetic acid, as well as possible advantages of resveratrol co-treatment, on the kidneys of female Wistar albino rats by detecting kidney injury markers, oxidative stress parameters and morphological tissue changes. The rats, divided into ten groups, received a single intraperitoneal dosage of cisplatin (7.5 mg/kg) or Pt(IV) complexes (10 mg/kg), and/or resveratrol (25 mg/kg), whereas the control animals received only an ip injection of saline. Acute complexes treatments increased Chl value while decreasing Gl, Cre, and Urea levels, suggesting kidney injury. Novel compounds considerably decreased the levels of O, HO and GSSG, while raising the levels of NO, LPO and GSH. In addition, the activities of SOD, GSH-Px, and GST were increased, while the activities of CAT and GR were alleviated. Regarding morphological changes in kidney tissue, they were mostly of mild intensity. Results indicate that used complexes might trigger an imbalance of redox equilibrium of kidney cells and that the renal tissue was more vulnerable to the negative effects of Pt(IV) complexes than to cisplatin. Resveratrol's nephroprotective benefits were not shown. Additionally, a prooxidative effect was registered after co-treatments. These findings could be useful for future studies in clarifying how the investigated compounds act in the estradiol-rich environment and how they affect the tissues of male rats.

Natural peroxidases use 4-halophenols either as substrates in oxidative chemistry or as inhibitors. Herein, we demonstrated that Fe-mimochrome VI*a (Fe-MC6*a), a miniaturized heme-enzyme, is a versatile catalyst as it integrates both these features. We previously reported that Fe-MC6*a catalyzes the chemo- and regio-selective oxidation of 4-halophenols, providing either dehalogenation or oligomerization products, depending on the nature of the halogen atom. In particular, 4-chlorophenol (4-CP) and 4-fluorophenol (4-FP) selectively led to dehalogenation and oligomerization products, respectively. Herein, spin-trapping studies and EPR analysis confirm the ability of Fe-MC6*a into processing halophenols as substrates and provide mechanistic hypothesis for the chemo-divergent reaction outcome. Further, in multiple substrate competition assays, 4-halophenols act as competitive inhibitors of Fe-MC6*a-catalyzed dehalogenation of 2,4,6-trichlorophenol (TCP). Nonetheless, the catalyst retains appreciable turnover in such complex substrate mixtures. Taken together, the combination of substrate-specific selectivity and resilience to the total inhibition position Fe-MC6*a as a promising bioremediation catalyst for simultaneous halophenol detoxification in wastewater-treatment applications.