The convergence of biosynthesis and biocatalysis is unlocking a new paradigm for the efficient construction of functional molecules, such as natural products and pharmaceuticals. By elucidating biosynthetic pathways, including all valuable enzymatic transformations that originate from biological systems, chemists can directly access powerful natural enzymes or engineer them via directed evolution to address long-standing synthetic challenges. This perspective explores the synergistic opportunities arising from integrating biosynthesis and biocatalysis. We highlight how enzymes derived from natural product biosynthetic pathways—such as Diels-Alderases—and tailored enzymes serve as powerful biocatalytic tools, with their utility further expanded through protein engineering. This convergence, by merging nature’s biosynthetic logic with modern chemo-catalytic concepts, enables new-to-nature reactivities. We further discuss how unmet synthetic demands are reshaping biosynthetic research, driving the discovery of enzymes with novel catalytic functions. We conclude by outlining future directions, including AI-driven enzyme discovery and engineering, as well as automated high-throughput experimentation, which will accelerate the translation of these integrating approaches into scalable and sustainable manufacturing solutions.
Bile acids are a class of cholesterol-derived metabolites that have long been recognized for their essential roles in dietary lipid absorption and cholesterol homeostasis. Over the past two decades, however, bile acids have emerged as crucial signaling molecules that regulate diverse physiological and pathological processes, including metabolism, inflammation, immunity, host–microbiota interactions, and liver diseases. Dysregulation of bile acid homeostasis has been implicated in a broad spectrum of human disorders, making bile acid signaling pathways attractive targets for therapeutic intervention. Despite substantial progress in identifying bile acid receptors and transporters, a fundamental challenge remains: how can we systematically decode the biological functions of structurally diverse bile acids and translate the knowledge into therapeutic opportunities?
In this Account, we summarize our 10-year mechanism-driven research effort to address this challenge through an integrated translational chemical biology strategy that combines chemoproteomics, metabolomics, structural biology, and medicinal chemistry. We first developed chemoproteomic platforms to globally profile bile-acid-interacting proteins in mammalian cells and bacteria, revealing an extensive bile-acid interactome that extends beyond canonical receptors and transporters. These studies uncovered hundreds of candidate interactors and identified previously unrecognized bile-acid-sensing mechanisms in host cells and gut microbes, providing a systems-level framework for understanding bile acid biology.
Building upon these discoveries, we focused on elucidating the molecular basis of cholestatic itch, a debilitating symptom frequently associated with liver diseases. We identified the G-protein-coupled receptor MRGPRX4 (hX4) as a human bile acid receptor mediating cholestatic pruritus and demonstrated that sulfated bile acids are key endogenous pruritogens that accumulate in patients with cholestasis. Through cryo-electron microscopy (cryo-EM), we determined the structure of hX4 in complex with a bile acid agonist and elucidated the molecular mechanism underlying receptor activation. These mechanistic insights revealed the critical role of the bile acid 3-hydroxyl group in receptor recognition and signaling.
Importantly, a mechanistic understanding of bile acid signaling enabled the rational design of therapeutics. Guided by structural information, we developed a modified bile acid derivative that retains therapeutic efficacy for liver diseases while minimizing itch-related side effects. Furthermore, through high-throughput screening, medicinal chemistry optimization, structural analysis, and preclinical evaluation, we discovered HEP-50768, a potent inverse agonist of hX4 that has advanced toward clinical development for cholestatic itch. In parallel, we determined the cryo-EM structure of the bile acid transporter OSTα/β and uncovered its transport mechanism, providing new insights into the regulation of bile acid homeostasis.
Collectively, these studies illustrate how decoding bile acid function at the molecular level can uncover previously unrecognized biological mechanisms and accelerate drug discovery. We anticipate that the continued integration of chemical biology, structural biology, and translational pharmacology will enable the construction of a comprehensive functional atlas of bile acids and facilitate the development of next-generation therapeutics targeting bile acid signaling networks.
Plants are a vast reservoir of natural products with diverse structural scaffolds, making them an invaluable source for discovering novel enzymes that catalyze unique and evolutionarily specialized metabolic transformations in biosynthetic pathways. Rapid advances in genomics, metabolomics, protein structure prediction, and heterologous pathway reconstruction have enabled the identification of numerous cryptic biosynthetic enzymes responsible for key scaffold-forming and tailoring reactions in metabolism. Particularly notable are the discoveries of plant-derived enzymes that catalyze challenging chemical transformations, including oxidative carbon-carbon bond rearrangements, atypical cycloadditions, radical-mediated coupling reactions, and iterative scaffold remodeling. This review summarizes major advances in enzyme discovery in plant natural product biosynthesis in recent years, focusing on emerging catalytic mechanisms, strategies for elucidating pathways, and evolutionary relationships, and highlights their implications for synthetic biology, metabolic engineering, and the sustainable production of valuable natural products.
Ruyao Tang, Fusheng Guo, Jinyi Bai, Xiaoguang Lei
JACS Au (2026)
https://doi.org/10.1021/jacsau.6c01025.
Antibody-drug conjugates (ADCs) represent an emerging pharmaceutical category that leverages antibodies to facilitate drug delivery to target cells. A key challenge for ADCs is increasing the drug-antibody ratio (DAR) to improve efficacy without compromising their properties, such as pharmacokinetics. Here, we present a novel polypeptide-based platform that substantially increases the DAR of antibody-payload ADCs while minimally compromising the ADCs’ inherent characteristics. A polypeptide-based antibody-drug conjugate lead (polypeptide ADC 6c), capable of achieving a DAR of up to 61, was synthesized using the versatile click reaction method based on our polypeptide-based platform. 6c could efficiently recognize antigens, be subsequently endocytosed, and achieve subnanomolar activity at the cellular level. Moreover, 6c exhibited excellent pharmacokinetic parameters and potent antitumor efficacy in mice. Collectively, this study provides and characterizes a highly variable polypeptide backbone platform that can be used to efficiently develop innovative ADCs with high payloads for the treatment of various cancers.
Yaqing Ma, Han Zhang, Jinping Bao, Wei Kang, Dongyu Tang, Rongchang Chen, Yang Jin, Xinying Qu, Tong Zhang, Cui Liu, Lujia Yang, Juzhang Yan, Hongwu Ma, Chaochao Zhang, Lande Fu, Jianfei Hu, Chengsen Cui, Xiaoguang Lei, Shu-Shan Gao
Angew Chem Int Ed Engl (2026)
https://doi.org/10.1002/anie.330777
Tertiary amines are privileged motifs in bioactive molecules. However, their chemical synthesis lacks sustainability, and biocatalytic alternatives remain underdeveloped. Therefore, there is an urgent need to develop innovative catalytic strategies. We herein disclose the engineering of a wild-type imine reductase into a tandem aminase for consecutive intermolecular reductive aminations, designated AHTanAm. The tandem aminase and its variants exhibit dual catalytic advantages, enabling one-pot synthesis of hundreds of tertiary amines from broadly available primary amine precursors, and exerting precise stereochemical control over multiple stereocenters. Mechanistic dissection via x-ray crystallography and mutagenesis revealed that enzyme-pocket alterations amplify the second-step amination's activity, which serves as the driving force for successful tandem catalysis. In summary, this study bridges the critical synthetic challenge in accessing tertiary amines by creating the first tandem aminase, to the best of our knowledge, via imine-reductase redesign.
The human gut microbiota is now established as a vital contributor to drug metabolism and therapeutic efficacy. Nevertheless, the interaction between gut microbes and pharmaceutical agents is inherently complex, posing significant challenges to the use of the microbiota to reduce toxicity and improve efficacy. Gaining a deeper understanding of the complex role of the gut microbiota in regulating drug metabolism and influencing treatment outcomes is essential for enhancing diagnostic accuracy, prognostic stratification, and therapeutic approaches. This review systematically summarizes recent advances in gut microbiota-mediated drug metabolism and effectiveness and assesses the potential of targeting microbial communities to improve drug performance. The insights provided here are set to advance personalized medicine and promote the development of microbiota-targeted therapies.
Moracins are a distinct class of benzofuran natural products, primarily found in Moraceae plants. Despite their varying biological activities and interesting chemical structures, little is known about their biosynthesis. Here, we elucidate the biosynthetic pathway of moracin M, a common intermediate in moracin biosynthesis. Using thermal proteome profiling, we identified a noncanonical laccase from Morus alba (MaLAC) that catalyzes an unprecedented oxidative cyclization of oxyresveratrol to moracin M. Distinct from other plant laccases, MaLAC is the first plant laccase shown to catalyze an intramolecular oxidative cyclization reaction in natural product biosynthesis. Mechanistic studies revealed a copper-mediated radical cyclization, providing guidance for engineering laccases to catalyze synthetically valuable intramolecular oxidative cyclization. The biosynthetic pathway for moracin M was heterologously constructed in Nicotiana benthamiana. This work not only provides important insights into moracin biosynthesis, laying the foundation for manufacturing bioactive moracins via metabolic engineering strategies, but also demonstrates the power of label-free chemoproteomics in elucidating unknown biosynthetic pathways of plant secondary metabolites.
Cephalotaxine-type and homoerythrina-type alkaloids are structurally unique and biologically important natural products isolated from endangered species that belong to the genus Cephalotaxus. Among them, homoharringtonine (HHT [1]) is a marketed drug used to treat leukemia. However, the scalable production of HHT is significantly hindered by limited natural resources. Despite intensive investigation over half a century, the complete biosynthetic pathways of these alkaloids remain unknown. Here, we applied a comprehensive multi-omics analysis and used a set of chemically synthesized standard compounds to identify the missing enzymes required for the biosynthesis of cephalotaxinone and homoerythratine. We also uncovered a rare case of divergent oxidation catalyzed by two highly homologous cytochrome P450 enzymes, CfCYP2 and CfCYP3, in the biosynthesis of two structurally distinct alkaloids. We further identified the key residues that significantly affect the divergent oxidation outcomes and ultimately reconstituted the complete biosynthetic pathways for producing these two alkaloids in N. benthamiana.
Isothiocyanates (ITCs) are a unique class of electrophilic natural products that exert biological effects by reacting with proteinous cysteines to generate thionoacyl adducts. However, the identification of ITCs’ target sites is still an unmet task due to the high lability of such adducts. Here, we report an unexpected chemistry through which the ITC-protein adduct forms a stable N-terminal dihydrothiazole peptide adduct during proteolysis. This proteolysis-assisted cyclization (PAC) reaction can be harnessed for developing affinity-based and activity-based chemoproteomic methods to site-specifically profile targets of ITCs. Applying these methods not only adds further complexity to the known polypharmacological landscape of sulforaphane but also expands the ligandable cysteinome with site-level resolution through a 55-member ITC library. Given the promising chemopreventive and therapeutic effects of ITCs, the PAC-based chemoproteomic platform may lay the groundwork for elucidating their mechanisms of action and ultimately diversifying cysteine targetability for drug discovery.
Zhanli Wang, Lu Han, Lei Gao*, Liyun Zhang, Yan Xie, Hanwu Liu, Junping Fan, Ming Wu, Ning Yue, Yan Wang, Meng Han, Tongcan Sun, Qi Ding, Xiyin Zheng, Jidong Cao, Xueqi Shen, Haijun Wang, Tuxunaili Aizitili, Chunyan Wu, Xuehong Wu, Zhenhua Liu, Yiguo Hong, Xiaoguang Lei*, and Yule Liu*
Cell, Available online 8 May 2026
https://doi.org/10.1016/j.cell.2026.04.021
Phytoalexins are core components of plant chemical defense against pathogens. However, the genetic basis and regulatory mechanisms governing their biosynthesis remain preliminary. Debneyol is a well-defined, broad-spectrum fungicidal phytoalexin. Here, we elucidate its biosynthetic pathway, key regulators, and activity against multiple pathogens. We show that debneyol is synthesized from farnesyl pyrophosphate (FPP) through three steps catalyzed by 5-epi-aristolochene synthase (EAS), 5-epi-aristolochene epoxidase (EAE), and epoxide hydrolase-1 (EH1). MCD1 (miR1919-targeted cell death-factor-1) interacts with EAS and EAE, enhancing their association and EAE activity and promoting debneyol biosynthesis. Increased MCD1expression confers plant resistance not only against fungal but also viral and bacterial pathogens. Our work reveals a complete plant phytoalexin-based chemical defense machinery, opening avenues for engineering broad-spectrum plant resistance and industrial-scale debneyol production via synthetic biology.
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Opportunities for merging biosynthesis and biocatalysis
Dongshan Wu, Jin Wang, Xiaoguang Lei
Chem 12, October 8, 2026
https://doi.org/10.1016/j.chempr.2026.103254
The convergence of biosynthesis and biocatalysis is unlocking a new paradigm for the efficient construction of functional molecules, such as natural products and pharmaceuticals. By elucidating biosynthetic pathways, including all valuable enzymatic transformations that originate from biological systems, chemists can directly access powerful natural enzymes or engineer them via directed evolution to address long-standing synthetic challenges. This perspective explores the synergistic opportunities arising from integrating biosynthesis and biocatalysis. We highlight how enzymes derived from natural product biosynthetic pathways—such as Diels-Alderases—and tailored enzymes serve as powerful biocatalytic tools, with their utility further expanded through protein engineering. This convergence, by merging nature’s biosynthetic logic with modern chemo-catalytic concepts, enables new-to-nature reactivities. We further discuss how unmet synthetic demands are reshaping biosynthetic research, driving the discovery of enzymes with novel catalytic functions. We conclude by outlining future directions, including AI-driven enzyme discovery and engineering, as well as automated high-throughput experimentation, which will accelerate the translation of these integrating approaches into scalable and sustainable manufacturing solutions.
Decoding the Biological Function of Bile Acids for Drug Discovery
Jun Yang and Xiaoguang Lei
Accounts of Chemical Research (2026)
https://doi.org/10.1021/acs.accounts.6c00477
Bile acids are a class of cholesterol-derived metabolites that have long been recognized for their essential roles in dietary lipid absorption and cholesterol homeostasis. Over the past two decades, however, bile acids have emerged as crucial signaling molecules that regulate diverse physiological and pathological processes, including metabolism, inflammation, immunity, host–microbiota interactions, and liver diseases. Dysregulation of bile acid homeostasis has been implicated in a broad spectrum of human disorders, making bile acid signaling pathways attractive targets for therapeutic intervention. Despite substantial progress in identifying bile acid receptors and transporters, a fundamental challenge remains: how can we systematically decode the biological functions of structurally diverse bile acids and translate the knowledge into therapeutic opportunities?
In this Account, we summarize our 10-year mechanism-driven research effort to address this challenge through an integrated translational chemical biology strategy that combines chemoproteomics, metabolomics, structural biology, and medicinal chemistry. We first developed chemoproteomic platforms to globally profile bile-acid-interacting proteins in mammalian cells and bacteria, revealing an extensive bile-acid interactome that extends beyond canonical receptors and transporters. These studies uncovered hundreds of candidate interactors and identified previously unrecognized bile-acid-sensing mechanisms in host cells and gut microbes, providing a systems-level framework for understanding bile acid biology.
Building upon these discoveries, we focused on elucidating the molecular basis of cholestatic itch, a debilitating symptom frequently associated with liver diseases. We identified the G-protein-coupled receptor MRGPRX4 (hX4) as a human bile acid receptor mediating cholestatic pruritus and demonstrated that sulfated bile acids are key endogenous pruritogens that accumulate in patients with cholestasis. Through cryo-electron microscopy (cryo-EM), we determined the structure of hX4 in complex with a bile acid agonist and elucidated the molecular mechanism underlying receptor activation. These mechanistic insights revealed the critical role of the bile acid 3-hydroxyl group in receptor recognition and signaling.
Importantly, a mechanistic understanding of bile acid signaling enabled the rational design of therapeutics. Guided by structural information, we developed a modified bile acid derivative that retains therapeutic efficacy for liver diseases while minimizing itch-related side effects. Furthermore, through high-throughput screening, medicinal chemistry optimization, structural analysis, and preclinical evaluation, we discovered HEP-50768, a potent inverse agonist of hX4 that has advanced toward clinical development for cholestatic itch. In parallel, we determined the cryo-EM structure of the bile acid transporter OSTα/β and uncovered its transport mechanism, providing new insights into the regulation of bile acid homeostasis.
Collectively, these studies illustrate how decoding bile acid function at the molecular level can uncover previously unrecognized biological mechanisms and accelerate drug discovery. We anticipate that the continued integration of chemical biology, structural biology, and translational pharmacology will enable the construction of a comprehensive functional atlas of bile acids and facilitate the development of next-generation therapeutics targeting bile acid signaling networks.
Recent discovery of new enzymes in plant natural product biosynthesis
Zheng-Xi Zhang, Han Ke, Jin Wang, Xiaoguang Lei
Curr Opin Chem Biol. 94:102752 (2026).
http://doi.org/10.1016/j.cbpa.2026.102752
Plants are a vast reservoir of natural products with diverse structural scaffolds, making them an invaluable source for discovering novel enzymes that catalyze unique and evolutionarily specialized metabolic transformations in biosynthetic pathways. Rapid advances in genomics, metabolomics, protein structure prediction, and heterologous pathway reconstruction have enabled the identification of numerous cryptic biosynthetic enzymes responsible for key scaffold-forming and tailoring reactions in metabolism. Particularly notable are the discoveries of plant-derived enzymes that catalyze challenging chemical transformations, including oxidative carbon-carbon bond rearrangements, atypical cycloadditions, radical-mediated coupling reactions, and iterative scaffold remodeling. This review summarizes major advances in enzyme discovery in plant natural product biosynthesis in recent years, focusing on emerging catalytic mechanisms, strategies for elucidating pathways, and evolutionary relationships, and highlights their implications for synthetic biology, metabolic engineering, and the sustainable production of valuable natural products.
Development of a Polypeptide-Based Platform to Construct Antibody-Drug Conjugates with High Potency
Ruyao Tang, Fusheng Guo, Jinyi Bai, Xiaoguang Lei
JACS Au (2026)
https://doi.org/10.1021/jacsau.6c01025.
Antibody-drug conjugates (ADCs) represent an emerging pharmaceutical category that leverages antibodies to facilitate drug delivery to target cells. A key challenge for ADCs is increasing the drug-antibody ratio (DAR) to improve efficacy without compromising their properties, such as pharmacokinetics. Here, we present a novel polypeptide-based platform that substantially increases the DAR of antibody-payload ADCs while minimally compromising the ADCs’ inherent characteristics. A polypeptide-based antibody-drug conjugate lead (polypeptide ADC 6c), capable of achieving a DAR of up to 61, was synthesized using the versatile click reaction method based on our polypeptide-based platform. 6c could efficiently recognize antigens, be subsequently endocytosed, and achieve subnanomolar activity at the cellular level. Moreover, 6c exhibited excellent pharmacokinetic parameters and potent antitumor efficacy in mice. Collectively, this study provides and characterizes a highly variable polypeptide backbone platform that can be used to efficiently develop innovative ADCs with high payloads for the treatment of various cancers.
An Engineered Enzyme Catalyzing Tandem Reductive Aminations for Synthesizing Tertiary Amines
Yaqing Ma, Han Zhang, Jinping Bao, Wei Kang, Dongyu Tang, Rongchang Chen, Yang Jin, Xinying Qu, Tong Zhang, Cui Liu, Lujia Yang, Juzhang Yan, Hongwu Ma, Chaochao Zhang, Lande Fu, Jianfei Hu, Chengsen Cui, Xiaoguang Lei, Shu-Shan Gao
Angew Chem Int Ed Engl (2026)
https://doi.org/10.1002/anie.330777
Tertiary amines are privileged motifs in bioactive molecules. However, their chemical synthesis lacks sustainability, and biocatalytic alternatives remain underdeveloped. Therefore, there is an urgent need to develop innovative catalytic strategies. We herein disclose the engineering of a wild-type imine reductase into a tandem aminase for consecutive intermolecular reductive aminations, designated AHTanAm. The tandem aminase and its variants exhibit dual catalytic advantages, enabling one-pot synthesis of hundreds of tertiary amines from broadly available primary amine precursors, and exerting precise stereochemical control over multiple stereocenters. Mechanistic dissection via x-ray crystallography and mutagenesis revealed that enzyme-pocket alterations amplify the second-step amination's activity, which serves as the driving force for successful tandem catalysis. In summary, this study bridges the critical synthetic challenge in accessing tertiary amines by creating the first tandem aminase, to the best of our knowledge, via imine-reductase redesign.
Gut microbiota alters drug metabolism and therapeutic outcomes
Fusheng Guo, Yingjie Bai, and Xiaoguang Lei*
Cell Host & Microbe, 34 (7), 1262-1272 (2026)
https://doi.org/10.1016/j.chom.2026.06.001.
The human gut microbiota is now established as a vital contributor to drug metabolism and therapeutic efficacy. Nevertheless, the interaction between gut microbes and pharmaceutical agents is inherently complex, posing significant challenges to the use of the microbiota to reduce toxicity and improve efficacy. Gaining a deeper understanding of the complex role of the gut microbiota in regulating drug metabolism and influencing treatment outcomes is essential for enhancing diagnostic accuracy, prognostic stratification, and therapeutic approaches. This review systematically summarizes recent advances in gut microbiota-mediated drug metabolism and effectiveness and assesses the potential of targeting microbial communities to improve drug performance. The insights provided here are set to advance personalized medicine and promote the development of microbiota-targeted therapies.
Characterization of the biosynthetic enzymes of the Morus alba benzofuran natural products
Xinshui Yu, Nianxin Guo, Teng Long, Yuling Zhu, Han Ke, Qi Ding, Lei Gao, Xiaoguang Lei
Sci. Adv. 12, eaec4824(2026).
http://dor.org/10.1126/sciadv.aec4824
Moracins are a distinct class of benzofuran natural products, primarily found in Moraceae plants. Despite their varying biological activities and interesting chemical structures, little is known about their biosynthesis. Here, we elucidate the biosynthetic pathway of moracin M, a common intermediate in moracin biosynthesis. Using thermal proteome profiling, we identified a noncanonical laccase from Morus alba (MaLAC) that catalyzes an unprecedented oxidative cyclization of oxyresveratrol to moracin M. Distinct from other plant laccases, MaLAC is the first plant laccase shown to catalyze an intramolecular oxidative cyclization reaction in natural product biosynthesis. Mechanistic studies revealed a copper-mediated radical cyclization, providing guidance for engineering laccases to catalyze synthetically valuable intramolecular oxidative cyclization. The biosynthetic pathway for moracin M was heterologously constructed in Nicotiana benthamiana. This work not only provides important insights into moracin biosynthesis, laying the foundation for manufacturing bioactive moracins via metabolic engineering strategies, but also demonstrates the power of label-free chemoproteomics in elucidating unknown biosynthetic pathways of plant secondary metabolites.
Complete biosynthesis of the anticancer cephalotaxinone and homoerythratine
Runze Tian#, Feifan Lin#, Nianxin Guo#, Chendi Liu#, Kaiqi Chen, Yunxi Han, Ruiyun Lan, Qiang Li, Jianbin Yan*, and Xiaoguang Lei*
Cell. 2026
https://doi.org/10.1016/j.cell.2026.06.007
Cephalotaxine-type and homoerythrina-type alkaloids are structurally unique and biologically important natural products isolated from endangered species that belong to the genus Cephalotaxus. Among them, homoharringtonine (HHT [1]) is a marketed drug used to treat leukemia. However, the scalable production of HHT is significantly hindered by limited natural resources. Despite intensive investigation over half a century, the complete biosynthetic pathways of these alkaloids remain unknown. Here, we applied a comprehensive multi-omics analysis and used a set of chemically synthesized standard compounds to identify the missing enzymes required for the biosynthesis of cephalotaxinone and homoerythratine. We also uncovered a rare case of divergent oxidation catalyzed by two highly homologous cytochrome P450 enzymes, CfCYP2 and CfCYP3, in the biosynthesis of two structurally distinct alkaloids. We further identified the key residues that significantly affect the divergent oxidation outcomes and ultimately reconstituted the complete biosynthetic pathways for producing these two alkaloids in N. benthamiana.
Proteolysis-Assisted Cyclization Facilitates Site-Centric Target Deconvolution of Isothiocyanates
Jingyang He, Caiping Tian, Qiang Li, Jian Zhang, Jixiang He, Lingqiang Zhang, Xiaoguang Lei, Jing Yang
Angew. Chem. Int. Ed. 2026, e5512891
http://doi.org/10.1002/anie.5512891
Isothiocyanates (ITCs) are a unique class of electrophilic natural products that exert biological effects by reacting with proteinous cysteines to generate thionoacyl adducts. However, the identification of ITCs’ target sites is still an unmet task due to the high lability of such adducts. Here, we report an unexpected chemistry through which the ITC-protein adduct forms a stable N-terminal dihydrothiazole peptide adduct during proteolysis. This proteolysis-assisted cyclization (PAC) reaction can be harnessed for developing affinity-based and activity-based chemoproteomic methods to site-specifically profile targets of ITCs. Applying these methods not only adds further complexity to the known polypharmacological landscape of sulforaphane but also expands the ligandable cysteinome with site-level resolution through a 55-member ITC library. Given the promising chemopreventive and therapeutic effects of ITCs, the PAC-based chemoproteomic platform may lay the groundwork for elucidating their mechanisms of action and ultimately diversifying cysteine targetability for drug discovery.
Genetic basis of phytoalexin-mediated chemical defense in plants
Zhanli Wang, Lu Han, Lei Gao*, Liyun Zhang, Yan Xie, Hanwu Liu, Junping Fan, Ming Wu, Ning Yue, Yan Wang, Meng Han, Tongcan Sun, Qi Ding, Xiyin Zheng, Jidong Cao, Xueqi Shen, Haijun Wang, Tuxunaili Aizitili, Chunyan Wu, Xuehong Wu, Zhenhua Liu, Yiguo Hong, Xiaoguang Lei*, and Yule Liu*
Cell, Available online 8 May 2026
https://doi.org/10.1016/j.cell.2026.04.021
Phytoalexins are core components of plant chemical defense against pathogens. However, the genetic basis and regulatory mechanisms governing their biosynthesis remain preliminary. Debneyol is a well-defined, broad-spectrum fungicidal phytoalexin. Here, we elucidate its biosynthetic pathway, key regulators, and activity against multiple pathogens. We show that debneyol is synthesized from farnesyl pyrophosphate (FPP) through three steps catalyzed by 5-epi-aristolochene synthase (EAS), 5-epi-aristolochene epoxidase (EAE), and epoxide hydrolase-1 (EH1). MCD1 (miR1919-targeted cell death-factor-1) interacts with EAS and EAE, enhancing their association and EAE activity and promoting debneyol biosynthesis. Increased MCD1expression confers plant resistance not only against fungal but also viral and bacterial pathogens. Our work reveals a complete plant phytoalexin-based chemical defense machinery, opening avenues for engineering broad-spectrum plant resistance and industrial-scale debneyol production via synthetic biology.