Dr. Guang-Lei Ma

Anthraquinone-fused enediynes (AQEs) are renowned for their distinctive molecular architecture, reactive enediyne warhead, and potent anticancer activity. Although the first members of AQEs, i.e., dynemicins, were discovered three decades ago, how their nitrogen-containing carbon skeleton is synthesized by microbial producers remains largely a mystery. In this study, we showed that the recently discovered sungeidine pathway is a “degenerative” AQE pathway that contains upstream enzymes for AQE biosynthesis. Retrofitting the sungeidine pathway with genes from the dynemicin pathway not only restored the biosynthesis of the AQE skeleton but also produced a series of novel compounds likely as the cycloaromatized derivatives of chemically unstable biosynthetic intermediates. The results suggest a cascade of highly surprising biosynthetic steps leading to the formation of the anthraquinone moiety, the hallmark C8–C9 linkage via alkyl–aryl cross-coupling, and the characteristic epoxide functionality. The findings provide unprecedented insights into the biosynthesis of AQEs and pave the way for examining these intriguing biosynthetic enzymes.

19 December 2025 in Acta Pharmaceutica Sinica B

Journal Article

Exploring specialized metabolic pathways in medicinal plants with single-cell and spatial omics

Guo Li

Miaomiao Cai

Xinhao Liao

Guang-Lei Ma

Xiaohui Fan

Medicinal plants synthesize an immense diversity of specialized metabolites that play crucial roles in ecological interactions and serve as valuable pharmaceutical resources. However, the biosynthetic pathways responsible for this chemical diversity remain largely uncharacterized. These pathways are often complex, involving multiple steps that are spatially and temporally orchestrated within highly specialized or rare cell types. Classical bulk omics approaches obscure such cellular heterogeneity by averaging signals across tissues, limiting their utility in resolving cell-specific metabolic processes. Recent advances in single-cell and spatial omics technologies have revolutionized the ability to investigate plant metabolism at high spatiotemporal resolution, as exemplified by monoterpene indole alkaloids and Taxol biosynthesis. In this review, we highlight key technological advances in plant single-cell and spatial omics, examine their applications in pathway discovery and partitioning, and discuss emerging directions for harnessing these tools in plant synthetic biology and metabolic engineering. These developments promise to accelerate the systemic mapping of plant metabolic networks and facilitate their biotechnological exploitation for pharmaceutical development.

9 August 2024 in JACS Au

Journal Article

An Enzymatic Oxidation Cascade Converts δ-Thiolactone Anthracene to Anthraquinone in the Biosynthesis of Anthraquinone-Fused Enediynes

Guang-Lei Ma

Wan-Qiu Liu

Huawei Huang

Xin-Fu Yan

Wei Shen

Zhao-Xun Liang

Anthraquinone-fused enediynes are anticancer natural products featuring a DNA-intercalating anthraquinone moiety. Despite recent insights into anthraquinone-fused enediyne (AQE) biosynthesis, the enzymatic steps involved in anthraquinone biogenesis remain to be elucidated. Through a combination of in vitro and in vivo studies, we demonstrated that a two-enzyme system, composed of a flavin adenine dinucleotide (FAD)-dependent monooxygenase (DynE13) and a cofactor-free enzyme (DynA1), catalyzes the final steps of anthraquinone formation by converting δ-thiolactone anthracene to hydroxyanthraquinone. We showed that the three oxygen atoms in the hydroxyanthraquinone originate from molecular oxygen (O₂), with the sulfur atom eliminated as H₂S. We further identified the key catalytic residues of DynE13 and A1 by structural and site-directed mutagenesis studies. Our data support a catalytic mechanism wherein DynE13 installs two oxygen atoms with concurrent desulfurization and decarboxylation, whereas DynA1 acts as a cofactor-free monooxygenase, installing the final oxygen atom in the hydroxyanthraquinone. These findings establish the indispensable roles of DynE13 and DynA1 in AQE biosynthesis and unveil novel enzymatic strategies for anthraquinone formation.

About Me

Dr. Guanglei Ma received his Ph.D. in Medicinal Chemistry from School of Pharmacy, Fudan University, in 2018. Shortly thereafter, he joined the School of Biological Sciences at Nanyang Technological University, Singapore, as a postdoctoral research fellow. In 2023, he returned to China and was appointed as a Research Professor and Doctoral Supervisor at Zhejiang University. He is also a core young faculty member of State Key Laboratory for Innovative Chinese Medicine. Dr. Ma’s research is positioned at the intersection of natural product chemistry, biosynthesis, and synthetic biology. His work focuses on mining biosynthetic gene clusters, elucidating enzymatic mechanisms, and refactoring biosynthetic pathways to discover and engineer medicinally valuable natural products. By integrating multi-omics analysis, enzymology, and synthetic biology tools, his group aims to uncover novel bioactive molecules and reconstruct their biosynthetic logic in microbial and plant systems. His long-term goal is to employ the language of chemistry to decipher biological questions underlying the biosynthesis of secondary metabolites, with a particular emphasis on the biosynthetic mechanisms and artificial creation of active ingredients in traditional Chinese medicine. To date, Dr. Ma has published more than 40 research papers in leading international journals, including Journal of the American Chemical Society, JACS Au, and Chemical Communications.

Dr. Guang-Lei Ma

Dr. Guang-Lei Ma

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