Joseph Noel probes the adaptive changes that have occurred in plant-specialized metabolism as these enzyme networks emerged and evolved from their ancestral roots in primary metabolism at the dawn of terrestrial plants nearly 500 million years ago. His lab continues studies of sessile organisms such as plants, and more recently, microbes that form important relationships with non-motile plants. His research focuses on probing the molecular basis for how these sessile organisms, residing at the base of the global food chain, acquired and evolved specialized biosynthetic networks classified as secondary metabolic pathways, the output of which are regio- and stereo-chemically complex small molecule natural products including isoprenoids, flavonoids, polyketides and alkaloids. These chemicals of secondary metabolism, or more appropriately specialized metabolism, serve as chemical languages in ecosystems and impart a species-specific chemical “signature” on the parent organism in an ecologically specific context. Functionally, these natural chemicals often confer protective or symbiotic characteristics on their hosts allowing sessile organisms to survive and prosper in a multitude of challenging ecological niches.
Grants from the National Institutes of Health and theNational Science Foundation provided partial support for these projects.
Noel Research Abstract Slideshow
Figure 1: Specialized chemical diversity from nature. Examples of bioactive natural products resulting from specialized metabolism. The top panel illustrates a range of polyketides, from simple to complex. The middle panel details bioactive terpenes. The bottom panel illustrates representative hybrid isoprenoids from actinomycetes. Although the chemical complexity of these molecules varies, the enzymatic principle governing their biosynthesis is an evolutionary trait that is conserved across kingdoms.
Image: Joseph Noel.
Figure 2: Structure, coenzyme A (CoA) binding, and overall reaction of chalcone synthase (CHS). The left panel depicts each monomer of the physiological dimer, colored gold and blue, respectively. The N and C termini for each monomer are indicated. CoA is depicted as a stick diagram; the position of the active-site cysteine is highlighted by *s. The bottom section of the left panel shows the overall reaction catalyzed by CHS, with the malonyl-derived portions of chalcone shown in red. The right panel illustrates the molecular surface representation of the CHS-CoA complex.
Image: Michael Austin.
Figure 3: Schematic representation of hybrid fatty acid synthase–polyketide synthase (FAS-PKS) multidomain enzyme from Dictyostelium discoideum. KS, ketoacyl synthase; AT, acyltransferase; DH, dehydratase; ER, enol-CoA reductase; KR, ketoreductase; ACP, acyl carrier protein. CHS (chalcone synthase) highlights the type III PKS C-terminal domain. Conventional type I FASs and PKSs usually contain a TE (thioesterase) domain in place of the depicted CHS domain. The TE domain off-loads covalently attached fatty acids and polyketides from the ACP domain. The domain organization of STEELY 1 and 2 suggests that the CHS-like domain off-loads product from ACP in a manner reminiscent of the off-loading mechanism of CHS. In the case of CHS, an elongated tetraketide undergoes a Claisen cyclization reaction, which results in both trihydroxyphenyl ring formation and cleavage of the thioester bond that links the tetraketide to the CHS active site.
Image: Michael Austin.
Figure 4: Overall structure of TEAS bound to a product analog. The catalytic domain is formed by a series of ahelices that mold an aromatic-rich surface in the gold-colored C-terminal domain. One catalytically essential Mg2+ ion is shown as an aqua sphere. The loop labeled J-K undergoes a large conformational change that seals off the active site from surrounding solvent when a farnesyl diphosphate substrate binds.
Image: Courtney Starks.
Figure 5: Chemical mechanisms for the biosynthesis of 5-epi-aristolochene and premnaspirodiene by TEAS and HPS, respectively. The solid box and arrow highlight the TEAS-specific leg of the mechanistic pathway; the dotted box and arrow highlight the HPS leg. A critical branch point occurs at the eudesmane carbocation, and the choice of which direction to proceed depends maximally on nine amino acids that modulate the structure and dynamics of the active-site surface.
Image: Joseph Noel.
Figure 6: Summary of the strategy to link specific structural modifications of the conserved terpene synthase (cyclase) fold with specific sesquiterpene end products.
Image: Paul O'Maille.
Figure 7: Novel sesquiterpene-derived pharmacophores. The top panel illustrates the three-dimensional structures and models for FXR (farnesoid-X receptor). The top left panel depicts the experimentally determined structure of FXR bound to a synthetic agonist, fexaramine, previously determined by our laboratory. The top middle panel illustrates the results of a comprehensive set of computer-assisted docking runs for FXR and a series of sesquiterpenes. Shown is the complex with premnaspirodiene, which was the highest scoring complex generated in silico. The top right panel is a superpositioning of the fexaramine complex (gold) on the modeled premnaspirodiene complex (purple). The bottom panel schematically illustrates the use of premnaspirodiene and further chemical elaboration to explore agonism and antagonism in nuclear hormone receptors such as FXR.
Top panel, Paul O'Maille. Bottom panel, Thomas Baiga.
Figure 8: Structural evolution from ligand binding to efficient and stereospecific catalyst. Approximately 500 MYA, Chalcone Isomerase (CHI) evolved from a non-enzymatic Fatty Acid-binding protein (FAP) into a highly efficient, stereospecific catalyst for the conversion of naringenin chalcone into (2S)-naringenin; an early committed step of the plant flavanoid pathway. To understand the structural basis for the emergence of this novel enzyme activity, we have adapted a directed evolution approach to identify key substitutions in the evolutionary history of CHI. Through the use of protein X-ray crystallography and protein NMR, we are characterizing how enhanced activity is enabled through iterative changes to protein structure and dynamics, with the goal demystifying underlying principles that govern interplay between the evolution of protein structure and function.
Image: Jason Burke.