Dongshan Wu, Sanshan Wang, Haowen Zhang, Han Ke, Zeying Sun, Shuhan Xie, Yihui Gao, Jun Yang, Bingwu Wang, and Xiaoguang Lei*
J. Am. Chem. Soc. 2025, doi:10.1021/jacs.5c05656
Due to the invaluable properties of organofluorine compounds, incorporating a fluorinated unit has become necessary in pharmaceuticals, agrochemicals, and materials. However, achieving asymmetric fluorination such as trifluoromethylation through chemo- or biocatalysis has been a synthetic challenge. Here, we introduce a unique cooperative photoenzymatic catalysis for the enantioselective fluoroalkylation/cyclization cascade. This method, utilizing the engineered flavin-dependent “ene”-reductases (EREDs) and an exogenous photocatalyst (PC), produces a variety of fluorinated cyclic ketones with high yield and enantioselectivity. The discovery of stereocomplementary enzymes that provide access to both enantiomers of the cyclized products further enhances the synthetic applications of our method. The radical-trapping, spectroscopic, and kinetic studies have substantiated the interaction mode between the PC and the enzyme and demonstrated a cascade reaction mechanism involving a unique intermolecular addition of fluorinated radicals and a stereocontrolled intramolecular cyclization. Isotopic labeling experiments support flavin as the source of the hydrogen atom. Molecular dynamics simulations reveal that the binding interaction of the enzyme and the intermediate triggers the photoinduced enantioselective cyclization. This work underscores the potential of enzymes for the asymmetric synthesis of fluorinated compounds.
Dongshan Wu,† Zeying Sun,† Sanshan Wang, Jun Yang, Jingyuan He, and Xiaoguang Lei*
JACS Au 2025, doi:10.1021/jacsau.5c00633
Organic nitriles are significant in pharmaceuticals, agrochemicals, cosmetics, and materials. Although numerous cyanidation methods have been developed, more eco-friendly and green protocols for manufacturing alkyl nitriles are in high demand. Here, we report a photoenzymatic enantioselective intermolecular hydrocyanoalkylation of alkenes catalyzed by flavin-dependent “ene”-reductases. The discovery of stereocomplementary enzymes that provide access to both enantiomers of the high-value nitriles further showcases the synthetic applications of this method. Radical trapping, isotopic labeling, and spectroscopic experiments have elucidated the formation of a charge transfer complex at the protein active site. The single-electron reduction of the cyanoalkyl radical precursor by flavin hydroquinone yields a cyanoalkyl radical, which then undergoes intermolecular radical addition. This active site can stereoselectively control the radical-terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic nitriles. This work further expands the reactivity repertoire of biocatalytic transformations via non-natural radical mechanisms.
Auxin regulates many aspects of plant growth and development, featuring polar auxin transport mediated by auxin efflux and influx carriers. AUX1 is the prominent auxin importer that actively takes up natural and synthetic auxins. However, the precise mechanisms by which AUX1 recognizes and transports auxin remain elusive. Here, we describe the cryo-electron microscopy structures of Arabidopsis thaliana AUX1 in apo and auxin-bound forms, revealing the structural basis for auxin recognition. AUX1 assumes the LeuT-like fold in an inward conformation. The auxin analogue 2,4-D is recognized by polar residues in the middle of AUX1. We identify a putative cation site in AUX1, which plays a role in stabilizing the inward-facing conformation. His249 undergoes a large conformational shift, and mutation of it completely abolished transport activity, suggesting a crucial role of His249 in AUX1 gating. Together, this study provides a structural foundation for a deeper comprehension of auxin influx by AUX1-like carriers.
Xiaojiao Guo, Lei Gao, Shiwei Li, Jing Gao, Yuanyuan Wang, Jing Lv, Jiayi Wei, Jing Yang, Han Ke, Qi Ding, Jun Yang, Fusheng Guo, Haowen Zhang, Xiaoguang Lei & Le Kang
Nature (2025). DOI： 10.1038/s41586-025-09110-y
Aggregation pheromone, 4-vinylanisole (4VA), is specifically released by gregarious migratory locusts, and is crucial in forming locust swarms that cause destructive plagues1. Control of locust plagues relies heavily on the extensive application of chemical pesticides, which has led to severe environmental and health issues2. As pheromones are primary mediators of insect communication and behaviour3, exploring their biosynthesis can provide important cues to develop innovative behavioural regulators, potentially reducing the reliance on chemical pesticides. Here we resolve the biosynthesis of 4VA and behavioural responses of locusts when enzymes in the 4VA biosynthetic pathway are manipulated. The process initiates with phenylalanine derived from food plants and proceeds through three precursors: cinnamic acid, p-hydroxycinnamic acid and 4-vinylphenol (4VP). Notably, the conversion from 4VP to 4VA through methylation is unique to gregarious locusts. This step is catalysed by two crucial methyltransferases, 4VPMT1 and 4VPMT2. Guided by the X-ray co-crystal structure of 4VPMT2 bound with 4VP and S-adenosyl-L-methionine, we developed 4-nitrophenol as a substrate surrogate. We identified several chemicals that can block 4VA production by inhibiting the enzymatic activities of 4VPMT proteins, thereby suppressing locust aggregative behaviour. The findings uncover the chemical logic behind 4VA biosynthesis and pinpoint two crucial enzymes as novel targets for locust swarm management.
Jun Yang, Yuling Zhu, Yunxi Han, Han Ke, Jing Zhang, Ming-Wei Wang, Xiaoguang Lei*
ACS Catal. 2025, 15, 11664–11672
Trichothecenes, particularly T-2 toxin (T-2), pose significant threats to food safety as well as to both animal and human health. Although Fhb7 and its variants have been utilized for deoxynivalenol degradation, no enzyme with efficient T-2 degradation activity has been reported. Herein, we generated five enzymes derived from Fhb7 that are capable of T-2 degradation via ancestral sequence reconstruction. Among these, N1, N2, and N4 exhibited superior catalytic activity toward T-2 compared to the parent enzyme Fhb7 and its variants. Structural analyses revealed that residue F27 provides a hydrophobic environment for accommodation of the unique 3-methylbutyryl group of T-2. In addition, the long insertion loop of N2 plays a key role in its improved substrate preference. Furthermore, all the ancestors displayed remarkable thermostability, with N2 and N4 displaying superior thermal tolerance (Tm values are 54 and 59 °C, respectively, and their half-life times are longer than 90 h), positioning them as a promising candidate for industrial applications. This work introduces a promising enzymatic approach for T-2 degradation and lays a foundation for developing robust biocatalysts for the environmental and industrial bioremediation of mycotoxins.
With the continuous elucidation of biosynthetic enzymes for natural products, the application of enzymes asunique biological resources in the total synthesis of natural products has become increasingly widespread, driving thechemoenzymatic strategy to emerge as a research hotspot in this field. The use of enzymes not only enhances theprecision and efficiency of natural product synthesis but also expands the boundaries of traditional chemical synthesis,promoting the in-depth development and utilization of natural product resources. Based on the research practices of ourgroup and representative work from other domestic groups over the past three years, this article systematicallysummarizes the three major application dimensions of enzyme-catalyzed reactions in natural product synthesis:providing new synthetic starting points, driving the construction of complex scaffolds, and facilitating precise late-stagemodifications. This provides a reference for the further application of enzyme resources in natural product synthesis.
Transcription factors (TFs) play essential roles in cancer and metabolic diseases, and targeting TFs with small molecules remains a significant challenge. The TF PU.1 is critical for maintaining leukemia initiation cells (LICs) “stemness” in acute T cell lymphoblastic leukemia (T-ALL) and is also a key regulator of fibroblast polarization and organ fibrosis. Herein we rationally designed and synthesized a variety of diamidines with rigid and AT-selective linkers as PU.1 inhibitors. The compound PKU0140 displayed the highest potency in reducing the expression of PU.1 target genes. Significantly, PKU0140 allosterically disrupted the PU.1-chromatin interaction by binding to the minor groove of DNA. In the Pten-null T-ALL mouse model, PKU0140, combined with rapamycin, could significantly decrease leukemic blasts and LICs, alleviate leukemia progression, and prolong the survival of mice. Furthermore, PKU0140 showed preventive and therapeutic effects on fibrotic lesions in various organs by inhibiting the activation of myofibroblasts. This work provides a new small-molecule PU.1 inhibitor with the potential for the treatment of T-ALL and organ fibrosis.
Plants employ immune receptors to perceive pathogen-associated molecular patterns (PAMPs) to trigger immune signaling. How plants impede pathogen progression following successful signal transduction, however, has remained largely elusive. Plants produce diverse secondary metabolites, called phytoalexins, in response to pathogen infections. Various phytoalexins show strong lineage specificity and are believed to act upon microbes by growth inhibition or toxicity. Whether any phytoalexins protect plants by targeting specialized virulence machinery of pathogens has not been well studied. For instance, numerous gram-negative bacterial pathogens employ the type III secretion system (T3SS), a multiprotein injectisome, to deliver virulence proteins into animal and plant host cells for pathogenesis. Immune-activated plants are known to possess activity that inhibits the bacterial T3SS, although the nature of this activity and underlying mechanism remain unknown. This immune-induced anti-T3SS activity serves as a model to investigate potential antivirulence phytoalexins in plants.
Junping Fan*, Wenjun Xie, Han Ke, Jing Zhang, Jin Wang, Haijun Wang, Nianxin Guo, Yingjie Bai, Xiaoguang Lei*
JACS Au 2025, https://doi.org/10.1021/jacsau.4c01188
The urate transporter 1 (URAT1) is the primary urate transporter in the kidney responsible for urate reabsorption and, therefore, is crucial for urate homeostasis. Hyperuricemia causes the common human disease gout and other pathological consequences. Inhibition of urate reabsorption through URAT1 has been shown as a promising strategy in alleviating hyperuricemia, and clinical and preclinical drug candidates targeting URAT1 are emerging. However, how small molecules inhibit URAT1 remains undefined, and the lack of accurate URAT1 complex structures hinders the development of better therapeutics. Here, we present cryoelectron microscopy structures of a humanized rat URAT1 bound with benzbromarone, lingdolinurad, and verinurad, elucidating the structural basis for drug recognition and inhibition. The three small molecules reside in the URAT1 central cavity with different binding modes, locking URAT1 in an inward-facing conformation. This study provides mechanistic insights into the drug modulation of URAT1 and sheds light on the rational design of potential URAT1-specific therapeutics for treating hyperuricemia.
Recently, ligand-promoted Au(I)/Au(III)-catalyzed cross-coupling reactions with aryl iodides have garnered considerable attention. Here, we report the first visible-light-driven gold-catalyzed cross-couplings of challenging aryl bromides. In the presence of a (P, N)-gold(I) catalyst and an acridinium photocatalyst under blue LED irradiation, C–O coupling of aryl bromides with carboxylic acids was achieved, and soon it was found that this photoinduced gold-catalyzed cross-coupling of aryl bromides was appliable for other C–C, C–N, and C–S bond formation. Experimental and computational studies suggest that this visible-light-driven gold-catalyzed cross-couplings of aryl bromides involves two discrete photoinduced energy transfer (EnT) events: first, energy transfer (EnT) from a photosensitizer produces an excited-state gold(I) complex that allows the bottleneck oxidative addition of aryl bromides to form an aryl Au(III) complex and second, the reductive elimination of aryl-Au(III) complex to regenerate Au(I). Collectively, the new synergistic catalytic method developed here highlights the tremendous potential of photochemical gold catalysis via excited-state organogold complexes, as well as its potential to facilitate drug discovery due to the biocompatibility and mildness of the reaction conditions.
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Cooperative Photoenzymatic Catalysis for Enantioselective Fluoroalkylation/Cyclization Cascade
Dongshan Wu, Sanshan Wang, Haowen Zhang, Han Ke, Zeying Sun, Shuhan Xie, Yihui Gao, Jun Yang,
Bingwu Wang, and Xiaoguang Lei*
J. Am. Chem. Soc. 2025, doi:10.1021/jacs.5c05656
Due to the invaluable properties of organofluorine compounds, incorporating a fluorinated unit has become necessary in pharmaceuticals, agrochemicals, and materials. However, achieving asymmetric fluorination such as trifluoromethylation through chemo- or biocatalysis has been a synthetic challenge. Here, we introduce a unique cooperative photoenzymatic catalysis for the enantioselective fluoroalkylation/cyclization cascade. This method, utilizing the engineered flavin-dependent “ene”-reductases (EREDs) and an exogenous photocatalyst (PC), produces a variety of fluorinated cyclic ketones with high yield and enantioselectivity. The discovery of stereocomplementary enzymes that provide access to both enantiomers of the cyclized products further enhances the synthetic applications of our method. The radical-trapping, spectroscopic, and kinetic studies have substantiated the interaction mode between the PC and the enzyme and demonstrated a cascade reaction mechanism involving a unique intermolecular addition of fluorinated radicals and a stereocontrolled intramolecular cyclization. Isotopic labeling experiments support flavin as the source of the hydrogen atom. Molecular dynamics simulations reveal that the binding interaction of the enzyme and the intermediate triggers the photoinduced enantioselective cyclization. This work underscores the potential of enzymes for the asymmetric synthesis of fluorinated compounds.
Enantioselective Radical Hydrocyanoalkylation of Alkenes via Photoenzymatic Catalysis
Dongshan Wu,† Zeying Sun,† Sanshan Wang, Jun Yang, Jingyuan He, and Xiaoguang Lei*
JACS Au 2025, doi:10.1021/jacsau.5c00633
Organic nitriles are significant in pharmaceuticals, agrochemicals, cosmetics, and materials. Although numerous cyanidation methods have been developed, more eco-friendly and green protocols for manufacturing alkyl nitriles are in high demand. Here, we report a photoenzymatic enantioselective intermolecular hydrocyanoalkylation of alkenes catalyzed by flavin-dependent “ene”-reductases. The discovery of stereocomplementary enzymes that provide access to both enantiomers of the high-value nitriles further showcases the synthetic applications of this method. Radical trapping, isotopic labeling, and spectroscopic experiments have elucidated the formation of a charge transfer complex at the protein active site. The single-electron reduction of the cyanoalkyl radical precursor by flavin hydroquinone yields a cyanoalkyl radical, which then undergoes intermolecular radical addition. This active site can stereoselectively control the radical-terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic nitriles. This work further expands the reactivity repertoire of biocatalytic transformations via non-natural radical mechanisms.
Structural basis of auxin recognition and transport in plant influx carrier AUX1
Huiwen Chen1, Junping Fan1, Cheng Chi1, Jun Zhao, Di Wu, Xiaoguang Lei*, Xingwang Deng*, Daohua Jiang*
Molecular Plant, 2025.
doi.org/10.1016/j.molp.2025.06.015
Auxin regulates many aspects of plant growth and development, featuring polar auxin transport mediated by auxin efflux and influx carriers. AUX1 is the prominent auxin importer that actively takes up natural and synthetic auxins. However, the precise mechanisms by which AUX1 recognizes and transports auxin remain elusive. Here, we describe the cryo-electron microscopy structures of Arabidopsis thaliana AUX1 in apo and auxin-bound forms, revealing the structural basis for auxin recognition. AUX1 assumes the LeuT-like fold in an inward conformation. The auxin analogue 2,4-D is recognized by polar residues in the middle of AUX1. We identify a putative cation site in AUX1, which plays a role in stabilizing the inward-facing conformation. His249 undergoes a large conformational shift, and mutation of it completely abolished transport activity, suggesting a crucial role of His249 in AUX1 gating. Together, this study provides a structural foundation for a deeper comprehension of auxin influx by AUX1-like carriers.
Decoding 4-vinylanisole biosynthesis and pivotal enzymes in locusts
Xiaojiao Guo, Lei Gao, Shiwei Li, Jing Gao, Yuanyuan Wang, Jing Lv, Jiayi Wei, Jing Yang, Han Ke, Qi Ding, Jun Yang, Fusheng Guo, Haowen Zhang, Xiaoguang Lei & Le Kang
Nature (2025). DOI： 10.1038/s41586-025-09110-y
Aggregation pheromone, 4-vinylanisole (4VA), is specifically released by gregarious migratory locusts, and is crucial in forming locust swarms that cause destructive plagues1. Control of locust plagues relies heavily on the extensive application of chemical pesticides, which has led to severe environmental and health issues2. As pheromones are primary mediators of insect communication and behaviour3, exploring their biosynthesis can provide important cues to develop innovative behavioural regulators, potentially reducing the reliance on chemical pesticides. Here we resolve the biosynthesis of 4VA and behavioural responses of locusts when enzymes in the 4VA biosynthetic pathway are manipulated. The process initiates with phenylalanine derived from food plants and proceeds through three precursors: cinnamic acid, p-hydroxycinnamic acid and 4-vinylphenol (4VP). Notably, the conversion from 4VP to 4VA through methylation is unique to gregarious locusts. This step is catalysed by two crucial methyltransferases, 4VPMT1 and 4VPMT2. Guided by the X-ray co-crystal structure of 4VPMT2 bound with 4VP and S-adenosyl-L-methionine, we developed 4-nitrophenol as a substrate surrogate. We identified several chemicals that can block 4VA production by inhibiting the enzymatic activities of 4VPMT proteins, thereby suppressing locust aggregative behaviour. The findings uncover the chemical logic behind 4VA biosynthesis and pinpoint two crucial enzymes as novel targets for locust swarm management.
Developing Fhb7-Derived Enzymes with High Thermostability for Detoxification of T-2 Toxin through Ancestral Sequence Reconstruction
Jun Yang, Yuling Zhu, Yunxi Han, Han Ke, Jing Zhang, Ming-Wei Wang, Xiaoguang Lei*
ACS Catal. 2025, 15, 11664–11672
Trichothecenes, particularly T-2 toxin (T-2), pose significant threats to food safety as well as to both animal and human health. Although Fhb7 and its variants have been utilized for deoxynivalenol degradation, no enzyme with efficient T-2 degradation activity has been reported. Herein, we generated five enzymes derived from Fhb7 that are capable of T-2 degradation via ancestral sequence reconstruction. Among these, N1, N2, and N4 exhibited superior catalytic activity toward T-2 compared to the parent enzyme Fhb7 and its variants. Structural analyses revealed that residue F27 provides a hydrophobic environment for accommodation of the unique 3-methylbutyryl group of T-2. In addition, the long insertion loop of N2 plays a key role in its improved substrate preference. Furthermore, all the ancestors displayed remarkable thermostability, with N2 and N4 displaying superior thermal tolerance (Tm values are 54 and 59 °C, respectively, and their half-life times are longer than 90 h), positioning them as a promising candidate for industrial applications. This work introduces a promising enzymatic approach for T-2 degradation and lays a foundation for developing robust biocatalysts for the environmental and industrial bioremediation of mycotoxins.
The application of enzyme resources in the synthesis of natural products
Jin Wang, Haoran Dong, Xiaoguang Lei
SCIENTIA SINICA Chimica, 2025, 55(5): 1196-1202.
With the continuous elucidation of biosynthetic enzymes for natural products, the application of enzymes asunique biological resources in the total synthesis of natural products has become increasingly widespread, driving thechemoenzymatic strategy to emerge as a research hotspot in this field. The use of enzymes not only enhances theprecision and efficiency of natural product synthesis but also expands the boundaries of traditional chemical synthesis,promoting the in-depth development and utilization of natural product resources. Based on the research practices of ourgroup and representative work from other domestic groups over the past three years, this article systematicallysummarizes the three major application dimensions of enzyme-catalyzed reactions in natural product synthesis:providing new synthetic starting points, driving the construction of complex scaffolds, and facilitating precise late-stagemodifications. This provides a reference for the further application of enzyme resources in natural product synthesis.
Small-Molecule Inhibitors of Transcription Factor PU.1 for the Treatment of Acute T Cell Lymphoblastic Leukemia and Organ Fibrosis
Xin Wang, Liuzhen Zhang, Fusheng Guo, Ningning Yao, Zhenpeng Wu, Libing He, Dan Xu,Haichuan Zhu, Zhou Gong, Shuai Yang, Wenjun Xie, Yafen Wang, Liyun Zhang, Xiang Zhou10, Chun Tang,Rong Mu, Hong Wu* & Xiaoguang Lei*
CCS Chem. 2025, Just Published.
Transcription factors (TFs) play essential roles in cancer and metabolic diseases, and targeting TFs with small molecules remains a significant challenge. The TF PU.1 is critical for maintaining leukemia initiation cells (LICs) “stemness” in acute T cell lymphoblastic leukemia (T-ALL) and is also a key regulator of fibroblast polarization and organ fibrosis. Herein we rationally designed and synthesized a variety of diamidines with rigid and AT-selective linkers as PU.1 inhibitors. The compound PKU0140 displayed the highest potency in reducing the expression of PU.1 target genes. Significantly, PKU0140 allosterically disrupted the PU.1-chromatin interaction by binding to the minor groove of DNA. In the Pten-null T-ALL mouse model, PKU0140, combined with rapamycin, could significantly decrease leukemic blasts and LICs, alleviate leukemia progression, and prolong the survival of mice. Furthermore, PKU0140 showed preventive and therapeutic effects on fibrotic lesions in various organs by inhibiting the activation of myofibroblasts. This work provides a new small-molecule PU.1 inhibitor with the potential for the treatment of T-ALL and organ fibrosis.
A widespread plant defense compound disarms bacterial type III injectisome assembly
Pei Miao†, Haijun Wang†, Wei Wang†, Zhengdong Wang, Han Ke, Hangyuan Cheng, Jinjing Ni, Jingnan Liang, Yu-Feng Yao, Jizong Wang, Jian-Min Zhou*, Xiaoguang Lei*
Science, 2025, 387, eads0377.
Plants employ immune receptors to perceive pathogen-associated molecular patterns (PAMPs) to trigger immune signaling. How plants impede pathogen progression following successful signal transduction, however, has remained largely elusive. Plants produce diverse secondary metabolites, called phytoalexins, in response to pathogen infections. Various phytoalexins show strong lineage specificity and are believed to act upon microbes by growth inhibition or toxicity. Whether any phytoalexins protect plants by targeting specialized virulence machinery of pathogens has not been well studied. For instance, numerous gram-negative bacterial pathogens employ the type III secretion system (T3SS), a multiprotein injectisome, to deliver virulence proteins into animal and plant host cells for pathogenesis. Immune-activated plants are known to possess activity that inhibits the bacterial T3SS, although the nature of this activity and underlying mechanism remain unknown. This immune-induced anti-T3SS activity serves as a model to investigate potential antivirulence phytoalexins in plants.
Structural Basis for Inhibition of Urate Reabsorption in URAT1
Junping Fan*, Wenjun Xie, Han Ke, Jing Zhang, Jin Wang, Haijun Wang, Nianxin Guo, Yingjie Bai, Xiaoguang Lei*
JACS Au 2025,
https://doi.org/10.1021/jacsau.4c01188
The urate transporter 1 (URAT1) is the primary urate transporter in the kidney responsible for urate reabsorption and, therefore, is crucial for urate homeostasis. Hyperuricemia causes the common human disease gout and other pathological consequences. Inhibition of urate reabsorption through URAT1 has been shown as a promising strategy in alleviating hyperuricemia, and clinical and preclinical drug candidates targeting URAT1 are emerging. However, how small molecules inhibit URAT1 remains undefined, and the lack of accurate URAT1 complex structures hinders the development of better therapeutics. Here, we present cryoelectron microscopy structures of a humanized rat URAT1 bound with benzbromarone, lingdolinurad, and verinurad, elucidating the structural basis for drug recognition and inhibition. The three small molecules reside in the URAT1 central cavity with different binding modes, locking URAT1 in an inward-facing conformation. This study provides mechanistic insights into the drug modulation of URAT1 and sheds light on the rational design of potential URAT1-specific therapeutics for treating hyperuricemia.
Photosensitized Gold-Catalyzed Cross-Couplings of Aryl Bromides
Jiawen Wu, Fusheng Guo, Chenju Yi, Rongjie Yang, Xiaoguang Lei, Zhonghua Xia*
J. Am. Chem. Soc. 2025, 147, 7, 5839–5850.
Recently, ligand-promoted Au(I)/Au(III)-catalyzed cross-coupling reactions with aryl iodides have garnered considerable attention. Here, we report the first visible-light-driven gold-catalyzed cross-couplings of challenging aryl bromides. In the presence of a (P, N)-gold(I) catalyst and an acridinium photocatalyst under blue LED irradiation, C–O coupling of aryl bromides with carboxylic acids was achieved, and soon it was found that this photoinduced gold-catalyzed cross-coupling of aryl bromides was appliable for other C–C, C–N, and C–S bond formation. Experimental and computational studies suggest that this visible-light-driven gold-catalyzed cross-couplings of aryl bromides involves two discrete photoinduced energy transfer (EnT) events: first, energy transfer (EnT) from a photosensitizer produces an excited-state gold(I) complex that allows the bottleneck oxidative addition of aryl bromides to form an aryl Au(III) complex and second, the reductive elimination of aryl-Au(III) complex to regenerate Au(I). Collectively, the new synergistic catalytic method developed here highlights the tremendous potential of photochemical gold catalysis via excited-state organogold complexes, as well as its potential to facilitate drug discovery due to the biocompatibility and mildness of the reaction conditions.