Jing-Ke Weng

Early plants began colonizing the terrestrial earth approximately 450 million years ago. Their success on land has been attributed to the evolution of elaborate specialized metabolic systems from core metabolic pathways, the former yielding a panoply of functionally diverse chemicals to cope with a myriad of biotic and abiotic ecological pressures.

Our lab has broad interests in understanding the origin and evolution of plant specialized metabolism at enzyme, pathway, and systems levels, as well as how plants exploit discrete small molecules to interact with their surrounding biotic and abiotic environments. Our work in plant metabolic evolution impacts a fundamental question in biology - how do complex traits evolve in a Darwinian fashion? In addition, we actively seek opportunities to utilize plant as a unique model system to study human diseases, including metabolic syndromes and protein-misfolding diseases. In the long run, we also aim at elucidating the molecular mechanisms underlying the "matrix effect" known from many traditional herbal remedies used for thousands of years. We believe that basic scientific research motivated by curiosity will be key to address the societal challenges of tomorrow.

Metabolic evolution has resulted in an explosion of chemodiversity present in modern-day terrestrial plants, which arose from aquatic environment 450 million years ago.

Plants produce a repository of functionally diverse chemicals as a means to adapt to challenging environments. These so-called specialized metabolites protect plants against various abiotic stresses in terrestrial ecosystems, and mediate an array of interspecies interactions, ranging from seduction of pollinators and seed dispersers to defense against pathogens and herbivores. In addition, several classes of plant specialized metabolites also serve as hormones, perceived by complementary signaling networks in host plants to trigger physiological changes in response to environmental cues. Furthermore, many plant-derived specialized metabolites, e.g. paclitaxel, artemisinin, and resveratrol, also possess unique pharmacological properties that directly impact human health. The remarkable chemodiversity in plants is backdropped by rapidly evolving specialized metabolic systems, offering a fascinating platform to understand how complex traits arose in life.

We are interested in addressing five fundamental questions regarding the origin and evolution of chemodiversity in plants: (I) What are the evolutionary trajectories through which multistep specialized metabolic pathways and specific hormone-receptor pairs were assembled? (II) What is the structural and mechanistic basis for the divergence or convergence of catalytic functions in evolving specialized enzymes? (III) What roles do neutral mutation, catalytic promiscuity, protein dynamics, and stability play in natural evolution of new enzyme functions? (IV) Are there distinct biophysical constraints imposed on the same protein fold shaping the differential evolvability in primary and specialized metabolic enzymes? (V) Can we uncover missing genetic and epigenetic components facilitating the rapid evolution of specialized metabolic systems in plants?

More detailed description of research programs in Weng lab is listed below.

Hormone metabolism, biased ligands, and complex signaling

Traditional views of cell signaling often depict hormone perception mechanisms as simple on-off switches in a one-ligand-one-receptor model, wherein a particular receptor protein is activated solely by its pairing hormone with perfected binding kinetics. However, an increasing body of evidences suggests that hormone-receptor interactions in vivo are more sophisticated than previously thought, which may involve dynamic interactions between a series of structurally related hormone molecules and a family of divergent receptor proteins subject to spatial and temporal regulation. Hormone metabolism not only gives rise to the biosynthesis of one active hormone form, but also yield a series of related metabolites, including the precursor intermediates preceding hormone biosynthesis as well as the compounds that are further metabolized from the most commonly recognized active hormone form. Historically, the signaling properties of these additional hormone-related metabolites were at large overlooked without much scrutiny, yet some of these metabolites have indeed been exploited evolutionarily to serve as new signaling molecules, often in a “biased fashion”, contributing to the signaling complexity within the same organism or across divergent lineages. Using several classical phytohormone systems, we investigate the role of biased ligands, derived from evolutionarily elaborated hormone metabolic systems, in complex signaling regulation in plants.

Structural, energetic, and mechanistic determinants of enzyme evolvability

Specialized metabolic enzymes originated from primary metabolism, yet their catalytic properties differ significantly from their counterparts in primary metabolism. Whereas primary metabolic enzymes are highly specific and exhibit low levels of mechanistic elasticity, specialized metabolic enzymes, on average, display greater catalytic promiscuity and evolvability. Comparative study of structurally related primary and specialized metabolic enzyme families offers unique opportunities to unveil determining factors of enzyme evolvability. Combining bioinformatics, structural biology, synthetic biology, and biochemistry, we aim to decipher networks consist of energetically coupled residues across a protein fold, which dictate important parameters regarding enzyme evolution, such as protein folding stability and catalytic properties.

Molecular mechanisms associated with protein misfolding in plants

Random mutations are generally thought to have deleterious effects on protein folding and function. Although proteins are marginally stable and exhibit a level of mutational robustness, they do misfold under excessive environmental stresses or mutations. In human, continual aggregation of certain misfolded proteins could lead to pathology, including many neurodegenerative diseases such as Alzheimer’s, Huntington, Parkinson’s, and the prion maladies. Plants contain rapidly evolving specialized metabolic system, and presumably encounter destabilized evolutionary intermediates along their mutational trajectories. Have plants evolved unique molecular mechanisms that assist folding of those destabilized proteins and/or mitigate proteotoxicity arising from protein misfolding? We use the model plant Arabidopsis thaliana to examine the in vivo function and behavior of mutant enzymes that exhibit broadened product promiscuity and/or decreased folding stability in vitro. We attempt to identify genetic components involved in cellular mechanisms that assist folding or alter product profile of these mutant enzymes.

Personalized cocktail medicine inspired by traditional herbal remedies

Plants have long been recognized for their pharmacological properties as evidenced by the extensive use of herbal medicines and tonics by many indigenous cultures. The earliest documentation of herb-based treatments appeared in Shen Nong Ben Cao Jing (The Divine Farmer’s Materia Medica) in 2737 BC. Despite a long history of herbal remedies, the scientific basis underpinning their efficacy in treating various maladies is lacking. Except for a limited number of successful cases, individual compounds isolated from their host species often lack expected therapeutic activities, a phenomenon previously attributed to matrix effect. In traditional Chinese herbal medicine, a prescription typically consists of a handful of ingredients mixed in a given ratio, whereas many of these ingredients are indeed referred to as efficacy-enhancing ingredients. Using a combination of quantitative metabolomics, mathematics, analytic chemistry, genomics and biochemistry, we decipher the molecular mechanisms underlying the matrix effect of traditional herbal remedies. We believe this project will potentially provide new systems-level insights into disease mechanisms, and further instruct new therapies of complex diseases through personalized cocktail medicine.

  1. Weng JK. (2013) The evolutionary paths towards complexity: a metabolic perspective. New Phytol. (In press)
  2. Weng JK and Noel JP. (2013) Chemodiversity in Selaginella: a reference system for parallel and convergent metabolic evolution in terrestrial plants. Front Plant Sci. 4:119.
  3. Weng JK and Noel JP. (2012) The remarkable pliability and promiscuity of specialized metabolism. Cold Spring Harb Symp Quant Biol.77:309-320.
  4. Weng JK, Philippe RN, Noel JP. (2012) The rise of chemodiversity in plants. Science. 336:1667-1670.
  5. Weng JK, Li Y, Mo H, Chapple C. (2012) Assembly of an evolutionarily new pathway for α-pyrone biosynthesis in Arabidopsis. Science. 337: 960-964.
  6. Weng JK, Akiyama T, Ralph J, Chapple C. (2011) Independent recruitment of an O-methyltransferase for syringyl lignin biosynthesis in Selaginella moellendorffii. Plant Cell. 23: 2708–2724.
  7. Weng JK, Mo H, Chapple C. (2010) Over-expression of F5H in COMT-deficient Arabidopsis leads to enrichment of an unusual lignin and disruption of pollen wall formation. Plant J. 64:898-911.
  8. Weng JK, Akiyama T, Bonawitz ND, Li X, Ralph J, Chapple C. (2010) Convergent evolution of syringyl lignin via distinct biosynthetic pathways in the lycophyte Selaginella and flowering plants. Plant Cell. 22:1033-1045.
  9. Weng JK and Chapple C. (2010) The origin and evolution of lignin biosynthesis. New Phytol. 187:273-285.
  10. Weng JK, Li X, Stout J, Chapple C. (2008) Independent origins of syringyl lignin in vascular plants. Proc Natl Acad Sci U S A. 105:7887-7892.
  11. Weng JK, Li X, Bonawitz ND, Chapple C. (2008) Emerging strategies of lignin engineering and degradation for cellulosic biofuel production. Curr Opin Biotechnol. 19:166-172.