About

Yousong Ding, Ph.D., is a professor of medicinal chemistry at the University of Florida College of Pharmacy. He received his B.S. in applied chemistry from Peking University, followed by an M.S. in fungal secondary metabolite biosynthesis from the University of Nebraska under Dr. Liangcheng Du. He completed his Ph.D. training with Dr. David Sherman at the University of Michigan, where he expanded his expertise in natural products. Dr. Ding then worked as a postdoctoral scholar in Dr. Frances H. Arnold’s laboratory at the California Institute of Technology, applying principles of protein engineering and synthetic biology to develop biocatalysts for the production of valuable chemicals and to understand herbicide metabolism. His long-term interests in drug development led him to a position at Pfizer, where he gained experience in pharmaceutical bioprocess development and generated biocatalysts used in bio-routes for lowering manufacturing costs of drugs. Since 2013, he has been an assistant professor at the University of Florida, focusing his research on natural product biosynthesis, drug discovery and development, synthetic biology, protein engineering, and chemical biology. His laboratory aims to discover and develop small molecules and biologics as therapeutic leads for unmet medical needs such as obesity, cardiovascular diseases, cancer, and infectious diseases. The research involves deciphering biosynthetic logics of natural products, employing biosynthetic systems from microbial genome data, heterologous production, structure determination, and bioactivity evaluation, as well as developing biocatalysts for value-added chemical production. Dr. Ding's work spans organic chemistry, medicinal chemistry, biochemistry, microbiology, molecular biology, cell biology, protein engineering, synthetic biology, and bioprocess development.

Research topics

• Biology
• Biochemistry
• Microbiology
• Genetics
• Botany
• Computer Science
• Chemistry
• Artificial Intelligence
• Ecology
• Organic chemistry
• Bioinformatics
• Virology
• Pathology
• Medicine
• Data science
• Stereochemistry
• Fishery
• Zoology
• Computational biology

Selected publications

• Molecular Basis of α-Glycine C–H Activation by a Nonheme Fe(II)/2-Oxoglutarate Dioxygenase

  Biochemistry · 2026-04-28

  articleOpen accessSenior author

  performs this unusual chemistry during mycosporine-like amino acid biosynthesis, converting mono- and disubstituted precursors into palythines and revealing unexpected substrate tolerance. Kinetic isotope effects, detection of a transient hydroxylated intermediate, and glyoxylate byproduct formation support an α-hydroxylation-initiated mechanism. High-resolution crystal structures, complemented by molecular docking, molecular dynamics simulations, and site-directed mutagenesis, define an active-site architecture that positions the glycyl substrate in a near-transition-state geometry. Hybrid QM/MM calculations reveal a low-barrier hydrogen-atom-transfer step followed by hydroxyl rebound and implicate a conserved Trp125 in an electron-transfer network that lowers the activation barrier. Together, these findings establish a mechanistic framework for protein-directed α-glycine C-H activation by nonheme iron enzymes and provide a blueprint for engineering Fe/2-OG dioxygenases to expand the chemical diversity of mycosporines and related natural products.

  PublisherOA PDFDOI

• Aldoximes serve as auxin precursors and repress phenylpropanoid metabolism in tomato

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-12

  articleOpen access

  Abstract Aldoximes are amino acid-derived metabolites that serve as precursors of auxins and modulate phenylpropanoid production in Arabidopsis. However, the enzymes responsible for aldoxime production in Solanaceae remain unknown. Here, we report the identification of aldoxime-producing enzymes in tomato ( Solanum lycopersicum ) and examine how altered aldoxime production affects auxin production and phenylpropanoid metabolism. Through homology-based analysis, we identified five putative CYP79 homologs in tomato, among which SlCYP79DB32 and SlCYP79DB52 exhibited aldoxime-producing activity toward multiple amino acids, including phenylalanine and tryptophan. SlCYP79DB32 and SlCYP79DB52 converted phenylalanine into phenylacetaldoxime (PAOx), whereas only SlCYP79DB52 converted tryptophan into indole-3-acetaldoxime (IAOx). Stable isotope-labeled feeding experiments revealed that IAOx and PAOx can be converted to the auxins indole-3-acetic acid (IAA) and phenylacetic acid (PAA), respectively. Consistently, tomato plants engineered to overproduce IAOx and PAOx accumulated elevated levels of IAA and PAA. These plants also accumulated lower levels of phenylpropanoids. In Brassicaceae plants such as Arabidopsis and Camelina, aldoxime accumulation represses phenylpropanoid production by promoting degradation of phenylalanine ammonia-lyase (PAL). However, aldoxime accumulation did not reduce PAL activity in tomato, suggesting an alternative mechanism in this species. Transcriptome analysis revealed extensive transcriptional reprogramming in aldoxime-overaccumulating tomato plants, including upregulation of stress– and defense-related genes. Despite the observed reduction in phenylpropanoid levels, transcript levels of most phenylpropanoid biosynthetic genes were not decreased, suggesting possible post-transcriptional regulation of this repression. Together, our findings demonstrate that aldoximes can serve as intermediates in auxin biosynthesis in tomato and reveal that aldoxime-mediated repression of phenylpropanoid metabolism extends beyond Brassicaceae.

  PublisherDOI

• Targeted genome mining with GATOR-GC maps the evolutionary landscape of biosynthetic diversity

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-28 · 1 citations

  preprintOpen access

  Gene clusters, groups of physically adjacent genes that work collectively, are pivotal to bacterial fitness and valuable in biotechnology and medicine. While various genome mining tools can identify and characterize gene clusters, they often overlook their evolutionary diversity, a crucial factor in revealing novel cluster functions and applications. To address this gap, we developed GATOR-GC, a targeted genome mining tool that enables comprehensive and flexible exploration of gene clusters in a single execution. We show that GATOR-GC identified a diversity of over 4 million gene clusters similar to experimentally validated biosynthetic gene clusters (BGCs) that other tools fail to detect. To highlight the utility of GATOR-GC, we identified previously uncharacterized co-occurring conserved genes potentially involved in mycosporine-like amino acid biosynthesis and mapped the taxonomic and evolutionary patterns of genomic islands that modify DNA with 7-deazapurines. Additionally, with its proximity-weighted similarity scoring, GATOR-GC successfully differentiated BGCs of the FK-family of metabolites (e.g., rapamycin, FK506/520) according to their chemistries. We anticipate GATOR-GC will be a valuable tool to assess gene cluster diversity for targeted, exploratory, and flexible genome mining. GATOR-GC is available at https://github.com/chevrettelab/gator-gc.

  PublisherOA PDFDOI

• Green genes from blue greens: challenges and solutions to unlocking the potential of cyanobacteria in drug discovery

  Natural Product Reports · 2025-07-15 · 5 citations

  reviewOpen access

  Cyanobacteria are prolific producers of biologically active compounds that are important in influencing ecology, behavior of interacting organisms, and as leads in drug discovery efforts. Here we discuss the challenges faced by all natural product researchers, especially those that focus on cyanobacteria, and then describe progress that has been made in these areas. We also propose some solutions, paths forward, and thoughts for consideration on these challenges.

  PublisherDOI

• Biosynthesis, Chemical Synthesis, and Pharmacological Evaluation of Lyngbyapeptin A as a GPCR Antagonist of Motilin, Cannabinoid, and Amylin Receptors

  Journal of Natural Products · 2025-10-17

  articleOpen access

  to the GPCR hits were further investigated using molecular modeling.

  PublisherOA PDFDOI

• Biocatalytic potential of microbial CYP450s in the degradation of selected environmental pollutants

  Medicinal Chemistry Research · 2025-08-18 · 2 citations

  articleSenior author
  PublisherDOI

• Bacterial Cytochrome P450 for Oxidative Halogenated Biaryl Coupling

  ACS Catalysis · 2025-12-19

  articleOpen accessSenior authorCorresponding

  Biaryl motifs are fundamental structural elements in many pharmaceuticals, agrochemicals, and advanced materials. Traditional synthetic approaches for biaryl bond formation often require harsh conditions, costly catalysts, and prefunctionalized starting materials, which limit their efficiency, sustainability, and substrate scope. Enzymatic catalysis offers a more environmentally benign alternative. However, biocatalysts capable of directly coupling halogenated biaryl compounds remain largely underexplored. Here, we report the functional characterization of the marine-derived cytochrome P450 enzyme Bmp7, which catalyzes the formation of halogenated biaryls. We began by defining the product profile of recombinant Bmp7 using its native substrate 2,4-dibromophenol (1) and confirmed the dominant ortho-ortho C–C homocoupled product as MC21-A. Screening a halogenated aromatic substrate library revealed that Bmp7 binds and catalyzes the coupling of 17 halogenated phenols, as evidenced by spectral shift assays, LC-HRMS, HRMS/MS, and GC-MS analyses. Two homocoupled products were structurally confirmed by NMR analysis to possess ortho–ortho C–C linkages. In addition to efficient homocoupling, Bmp7 catalyzed heterocoupling reactions between substrate 1 and 16 other substrates, producing mixtures of homocoupled and heterocoupled halogenated biphenols. X-ray crystallography revealed the binding of two substrate 1 molecules within the active site, while DFT calculations supported a single-radical reaction mechanism, shedding light on the mechanistic basis of the coupling reaction. Together, these findings establish a foundation for future efforts in enzyme engineering and the development of biocatalytic strategies for synthetic applications.

  PublisherOA PDFDOI

• BGC-MAC and BGC-MAP: Attention-Based Models for Biosynthetic Gene Cluster Classification and Product Matching

  Journal of Chemical Information and Modeling · 2025-12-18

  articleOpen access

  Natural products, synthesized via enzymes encoded by biosynthetic gene clusters (BGCs), represent a major source of therapeutic agents. Accurate BGC annotation is essential to unlocking the vast potential of natural product diversity. However, BGC annotation remains challenging due to our incomplete understanding of the enzymatic logic underlying biosynthesis. Here, we present two deep learning models trained on experimentally validated BGC-natural product pairs to advance BGC annotation. The BGC-multihead attention classifier (BGC-MAC) classifies BGCs by natural product class, outperforming antiSMASH and DeepBGC. The BGC-multihead attention product-matcher (BGC-MAP) associates BGCs with product structures, demonstrating potential to prioritize candidate BGCs given a natural product or to identify potential natural products from a given BGC. Importantly, the models' cross-attention mechanisms enable explainable AI, identifying key protein domains and revealing BGC-substructure relationships in the biosynthesis without requiring prior annotations. Together, BGC-MAC and BGC-MAP establish a data-driven, explainable AI framework that enhances BGC annotation, deepens biosynthetic insight, and accelerates the discovery of new natural products. The software is available at https://github.com/EvoCatalysis/BGC_annotation.

  PublisherOA PDFDOI

• Synthetic biology strategies for cyanobacterial systems to heterologously produce cyanobacterial natural products

  Natural Product Reports · 2025-01-01 · 13 citations

  reviewOpen accessSenior authorCorresponding

  sp. PCC 7120, and emerging hosts. Advances in BGC cloning, combinatorial biosynthesis, transcriptional and translational regulation, and host engineering are also highlighted. Together, these synthetic biology developments provide a powerful framework for expanding cyanobacterial natural product discovery and production.

  PublisherOA PDFDOI

• Structure Determination and Biosynthesis of Dapalides A–C, Glycosylated Kahalalide F Analogues from the Marine Cyanobacterium <i>Dapis</i> sp

  Journal of Natural Products · 2025-08-26 · 2 citations

  articleOpen access

  Kahalalides were originally isolated from the marine mollusk Elysia rufescens and its green algal diet Bryopsis sp., but the true producer was revealed as the obligate bacterial symbiont Candidatus Endobryopsis kahalalidefaciens, residing within Bryopsis sp. The most notable is kahalalide F, a broad-spectrum antitumor depsipeptide that entered the clinic but failed from lack of efficacy. We have isolated three new glycosylated analogues of kahalalide F, termed dapalides A–C (1–3), from a marine cyanobacterium, Dapis sp., collected from Guam. The planar structures were determined by extensive NMR coupled with mass spectrometry. Acid hydrolysis of 1 using amino acid analysis revealed the absolute configuration of singlet and a mixture of duplicate amino acids. Metagenomic analysis unveiled a biosynthetic gene cluster (BGC) with a nonribosomal peptide synthetase (NRPS) system and downstream glycosylation enzymes, which assisted the configurational assignment through epimerization domain analysis. The discovered BGC, termed dap, was assigned to a high-quality metagenome-assembled genome of the Dapis sp. Dapalide A (1) was subjected to phenotypic bioassays and exhibited weak anticancer cytotoxicity. This discovery expands the chemical diversity of the kahalalide F family, suggests their broad ecological role across diverse organisms, and presents an intriguing case of natural product biosynthesis evolution.

  PublisherOA PDFDOI

Recent grants

• Integrative Multidisciplinary Discovery Platform to Unlock Marine Natural Products Therapeutic Opportunities

  NIH · $7.1M · 2022–2027

• Accessing and expanding microbial bioactive chemical diversity by synthetic biology and new enzymology

  NIH · $3.1M · 2018–2028

• Novel Imine Formation by ATP Grasp Enzymes

  NSF · $480k · 2021–2025

Frequent coauthors

• David H. Sherman

  University of Michigan–Ann Arbor

  70 shared

• Robert M. Williams

  68 shared

• Thomas J. Greshock

  United States Military Academy

  65 shared

• Kenneth A. Miller

  Fort Lewis College

  49 shared

• Jennifer M. Finefield

  Colorado State University

  32 shared

• Man‐Yun Chen

  Central South University

  18 shared

• Timothy R. Welch

  17 shared

• Ran Zuo

  Jiangsu University

  17 shared

Labs

• Department of Cellular and Systems PharmacologyPI

Education

• B.S., Applied Chemistry

  Peking University

• M.S., Fungal Secondary Metabolite Biosynthesis

  University of Nebraska

• Ph.D., Natural Product Field

  University of Michigan

• Other, Protein Engineering and Synthetic Biology

  California Institute of Technology