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.
Jun Yang#, Ruichao Shen#, Chunyu Wang#, Wenneng Zhu, Han Ke, Junping Fan, Mengna Zhang, Yingjun Liu, Shuai Li, Guochuan Li, Xiaoming Wang, Yulong Li, Can Cao*, Xiaoguang Lei*
Nature Chemical Biology (2026)
https://doi.org/10.1038/s41589-026-02195-0
Chronic itch, particularly in cholestatic and uremic conditions, poses a notable clinical burden, yet treatment options remain inadequate. MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor predominantly expressed in human sensory neurons, has emerged as a critical mediator of cholestatic pruritus. Here we identified and characterized HEP-50768, a potent and selective small-molecule inverse agonist of hX4 through high-throughput screening and structure–activity optimization. Structural elucidation through cryo-electron microscopy of the hX4–inverse agonist complex structure revealed the unique binding mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats, HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors. Comprehensive preclinical absorption, distribution, metabolism, excretion and safety profiling was performed in both rats and monkeys, and these findings establish HEP-50768 as a promising therapeutic candidate for chronic itch, supporting its advancement to clinical evaluation.
Glucosinolates (GLSs) play crucial roles in plant defense against herbivores. GTR1 facilitates the high-affinity transport of GLSs through a proton-dependent process. However, the molecular mechanism underlying GLS recognition and transport by GTR1 remains largely unknown. Here, we present four cryo-EM structures of Arabidopsis GTR1 in distinct states, namely, the outward-apo, inward-apo, 4MTB-bound and 3IMG-bound forms, revealing the structural basis for GLS and proton cotransport by GTR1. GTR1 consists of an MFS-like transmembrane domain and an intracellular domain (ICD). The ICD plays an essential role in GTR1 function by interacting with the gating helix, transmembrane helix 7. GLSs are recognized by the central cavity residues and directly interact with the conserved E1X1X2E2K motif. Our structural and functional analyses demonstrated that the E1X1X2E2K motif and Glu513 determine the proton coupling of GTR1. This study provides mechanistic insights into how GTR1 transports GLSs, which could aid in improving crop quality and enhancing resistance to herbivory.
Lei Gao#, Xiang Qiu#, Jun Yang#, Kangdelong Hu#, Peilin Li, Wei Li, Feng Gao, Fabrice Gallou, Florian Kleinbeck, Xiaoguang Lei*
Science 391,eadw3365 (2026)
https://doi.org/10.1126/science.adw336
Amide bond formation is widely used in pharmaceutical synthesis, typically involving stoichiometric coupling reagents to activate carboxylic acid substrates for a condensation reaction. As an alternative approach, we repurposed aldehyde dehydrogenases into oxidative amidases by creating a more hydrophobic and spacious catalytic pocket for amines to capture the thioester intermediate. This biocatalyst efficiently facilitates the formation of amide bonds between diverse aldehydes and amines. We also developed a two-step enzymatic cascade to synthesize amides from broadly available aliphatic alcohols. This biocatalytic strategy enabled the redesign of synthetic routes for five drug molecules. Our findings highlight the potential of oxidative amidases in advancing the synthesis of structurally diverse drug molecules through efficient amide bond formation.
Ke Wang, Junping Fan, Huiwen Chen, Bo Huang, Cheng Chi, Rui Yan, Di Wu, Feng Zhou, Wenhua Zhang, Juquan Jiang, Xiaoguang Lei & Daohua Jiang
Nature 651, 251–259 (2026)
https://doi.org/10.1038/s41586-025-09934-8
Bile acids (BAs) are crucial amphipathic surfactants that function as multifaceted regulators in various physiological processes, including nutrient absorption and distribution, lipid metabolism and inflammation. The human organic solute transporter αβ (OSTα–OSTβ; hereafter referred to as OSTα/β) is a BA transporter that has a key role in the secretion and distribution of BAs. Pathogenic mutations in OSTα/β have been associated with cholestasis. Despite the functional importance of OSTα/β in BA homeostasis, the stoichiometry and assembly of the complex and the molecular mechanism that underlies BA transport by OSTα/β remain unknown. Here we present cryo-electron microscopy structures of human OSTα/β in complex with cholesterols and an endogenous substrate, elucidating the structural basis for the function of OSTα/β. OSTα/β is assembled in a novel dimer-of-heterodimers manner: two OSTα units form the homodimeric core, with two OSTβ units bound to the periphery. OSTα adopts the G-protein-coupled-receptor (GPCR) fold and contains a unique cysteine-rich loop with seven palmitoylation sites; these cooperate with transmembrane helices 5 and 6, constituting a BA recognition site. A positive cavity in OSTα connects the BA site and facilitates the transmembrane translocation of BAs through OSTα/β. Together, this study reveals the architecture and transport mechanism of OSTα/β and provides insights into the structure–function relationships of this crucial transporter in BA homeostasis.
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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.
Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment
Jun Yang#, Ruichao Shen#, Chunyu Wang#, Wenneng Zhu, Han Ke, Junping Fan, Mengna Zhang, Yingjun Liu, Shuai Li, Guochuan Li, Xiaoming Wang, Yulong Li, Can Cao*, Xiaoguang Lei*
Nature Chemical Biology (2026)
https://doi.org/10.1038/s41589-026-02195-0
Chronic itch, particularly in cholestatic and uremic conditions, poses a notable clinical burden, yet treatment options remain inadequate. MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor predominantly expressed in human sensory neurons, has emerged as a critical mediator of cholestatic pruritus. Here we identified and characterized HEP-50768, a potent and selective small-molecule inverse agonist of hX4 through high-throughput screening and structure–activity optimization. Structural elucidation through cryo-electron microscopy of the hX4–inverse agonist complex structure revealed the unique binding mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats, HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors. Comprehensive preclinical absorption, distribution, metabolism, excretion and safety profiling was performed in both rats and monkeys, and these findings establish HEP-50768 as a promising therapeutic candidate for chronic itch, supporting its advancement to clinical evaluation.
Structural basis of glucosinolate recognition and transport by plant GTR1
Rui Yan#, Junping Fan#, Cheng Chi#, Bowen Zhang, Di Wu, Huiwen Chen, Jianke Gong*, Xiaoguang Lei*and Daohua Jiang*
Cell Discovery 12, 26 (2026);
https://doi.org/10.1038/s41421-026-00884-7
Glucosinolates (GLSs) play crucial roles in plant defense against herbivores. GTR1 facilitates the high-affinity transport of GLSs through a proton-dependent process. However, the molecular mechanism underlying GLS recognition and transport by GTR1 remains largely unknown. Here, we present four cryo-EM structures of Arabidopsis GTR1 in distinct states, namely, the outward-apo, inward-apo, 4MTB-bound and 3IMG-bound forms, revealing the structural basis for GLS and proton cotransport by GTR1. GTR1 consists of an MFS-like transmembrane domain and an intracellular domain (ICD). The ICD plays an essential role in GTR1 function by interacting with the gating helix, transmembrane helix 7. GLSs are recognized by the central cavity residues and directly interact with the conserved E1X1X2E2K motif. Our structural and functional analyses demonstrated that the E1X1X2E2K motif and Glu513 determine the proton coupling of GTR1. This study provides mechanistic insights into how GTR1 transports GLSs, which could aid in improving crop quality and enhancing resistance to herbivory.
Engineered aldehyde dehydrogenases for amide bond formation
Lei Gao#, Xiang Qiu#, Jun Yang#, Kangdelong Hu#, Peilin Li, Wei Li, Feng Gao, Fabrice Gallou, Florian Kleinbeck, Xiaoguang Lei*
Science 391,eadw3365 (2026)
https://doi.org/10.1126/science.adw336
Amide bond formation is widely used in pharmaceutical synthesis, typically involving stoichiometric coupling reagents to activate carboxylic acid substrates for a condensation reaction. As an alternative approach, we repurposed aldehyde dehydrogenases into oxidative amidases by creating a more hydrophobic and spacious catalytic pocket for amines to capture the thioester intermediate. This biocatalyst efficiently facilitates the formation of amide bonds between diverse aldehydes and amines. We also developed a two-step enzymatic cascade to synthesize amides from broadly available aliphatic alcohols. This biocatalytic strategy enabled the redesign of synthetic routes for five drug molecules. Our findings highlight the potential of oxidative amidases in advancing the synthesis of structurally diverse drug molecules through efficient amide bond formation.
Structure and mechanism of the human bile acid transporter OSTα–OSTβ
Ke Wang, Junping Fan, Huiwen Chen, Bo Huang, Cheng Chi, Rui Yan, Di Wu, Feng Zhou, Wenhua Zhang, Juquan Jiang, Xiaoguang Lei & Daohua Jiang
Nature 651, 251–259 (2026)
https://doi.org/10.1038/s41586-025-09934-8
Bile acids (BAs) are crucial amphipathic surfactants that function as multifaceted regulators in various physiological processes, including nutrient absorption and distribution, lipid metabolism and inflammation. The human organic solute transporter αβ (OSTα–OSTβ; hereafter referred to as OSTα/β) is a BA transporter that has a key role in the secretion and distribution of BAs. Pathogenic mutations in OSTα/β have been associated with cholestasis. Despite the functional importance of OSTα/β in BA homeostasis, the stoichiometry and assembly of the complex and the molecular mechanism that underlies BA transport by OSTα/β remain unknown. Here we present cryo-electron microscopy structures of human OSTα/β in complex with cholesterols and an endogenous substrate, elucidating the structural basis for the function of OSTα/β. OSTα/β is assembled in a novel dimer-of-heterodimers manner: two OSTα units form the homodimeric core, with two OSTβ units bound to the periphery. OSTα adopts the G-protein-coupled-receptor (GPCR) fold and contains a unique cysteine-rich loop with seven palmitoylation sites; these cooperate with transmembrane helices 5 and 6, constituting a BA recognition site. A positive cavity in OSTα connects the BA site and facilitates the transmembrane translocation of BAs through OSTα/β. Together, this study reveals the architecture and transport mechanism of OSTα/β and provides insights into the structure–function relationships of this crucial transporter in BA homeostasis.