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Joseph P. Noel

 

Joseph P. Noel

Joseph P. Noel

Professor
Jack H. Skirball Center for Chemical Biology and Proteomics & Howard Hughes Medical Institute

"Most people are familiar with the word biodiversity, but "chemodiversity"—the extraordinary tapestry of natural chemicals found in plants—is just as important for life and the survival of many different ecosystems on the earth. I am particularly interested in the 'chemical factories' or biosynthetic pathways that give rise to these vital molecules."

Stuck where the seed germinates, plants have to make the best of their real estate. They rely on an impressive arsenal of volatile molecules, which diffuse easily through the membranes of the cells that produce them, to communicate and interact with the outside world. Often highly aromatic and exceedingly specific for a particular ecological niche, these chemicals attract pollinators, summon natural predators of pests, defend against competitors, or mobilize their antimicrobial properties to provide protection against natural plant pathogens such as fungi and bacteria.

In one system, Noel's lab has been probing the metabolic pathways that members of the nightshade family, which includes tobacco, tomatoes, potatoes, peppers, and henbane, use to produce terpenes—compounds that impart aromatic odors and flavors to foods. In many cases, terpenes are also modified in the plant to produce so-called phytoalexins, which are natural forms of antifungal and antimicrobial compounds found in many different plants.

Henbane and tobacco each rely on a different phytoalexin to successfully defend themselves against fungi typical for their habitat. Yet the more than 500 amino acids that make up the chemical factories in each that are known as enzymes are nearly identical to each other, with very minor differences accumulated over approximately a million years of evolutionary change. Using structure analyses, Noel and his colleagues discovered that changing only nine of the 550 amino acids shifts the production from tobacco-specific phytoalexins to the henbane versions and vice versa. Making fewer changes leads to a mixture of both, explaining how plants can tinker with their chemical cocktail and adjust it to a changing environment without shutting down intracellular chemical factories completely.

Studies like this one not only give scientists a glimpse of the plants' evolutionary past but may help Noel and others to fine-tune the production of natural and environmentally friendly fungicides and pesticides by turning "enzymatic knobs" in the right direction.

Lab Photo

Left to right:
Back row: Michael Hothorn, Charles Stewart, Paul O'Maille, Gordon Louie, Mike Austin, Stephane Richard, Tom Baiga Front row: Nikki Dellas, June Brennan, Marianne Bowman, Michele Auldridge, Monica Tello, Joe Noel

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Joseph P. Noel

Faculty

Joseph P. Noel

Joseph P. Noel

Professor
Jack H. Skirball Center for Chemical Biology and Proteomics & Howard Hughes Medical Institute

Mechanistic, Structural and Evolutionary Basis for Chemical Complexity in Nature

Research Goals

The focus of the research in our laboratory is to decipher the core principles influencing evolutionary change in proteins and protein networks particularly enzymes and metabolic pathways underlying the emergence and rapid expansion of chemical diversity in living systems. We ultimately hope to understand the chemical, structural and evolutionary tenets governing this extraordinary form of biodiversity and biocomplexity. In addition to probing the fundamental nature of molecular evolution, we also aim to exploit what we learn to direct our efforts at harnessing and altering these pathways to generate chemical "scaffolds" for the development of small molecule tools modulating proteins, cells and organisms.

Evolutionary Rationale

We study sessile organisms such as plants and microbes and the molecular basis for how they 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. 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.

So why are these metabolic pathways useful for understanding the molecular roots of biodiversity, biocomplexity and evolution? The means by which organisms acquire, improve and exploit diverse metabolic systems to generate a rich repertoire of chemically complex natural products play key roles in the rapid expansion of many ecosystems, and therefore, hold incredible adaptive significance for the diversity of life. While seemingly insignificant, specialized metabolites often serve as key mediators of intra- and interspecies interactions resulting in speciation, survival and ecological homeostasis. Under the evolutionary restraints of chemically established adaptation, diverse molecular changes associated with specialized metabolism are often preserved genetically in a particular species' genome and are discerned at a functional and structural level. These often ecotype specific genomes are the direct result of the increased fitness of host organisms "chemically" adapted to specific ecological niches. Therefore, these specialized metabolic pathways and their "chemical output" present us with a rich evolutionary record of where biosynthetic pathways, natural chemicals and biosynthetic enzymes have been (vestigial biochemical traits), what adaptive advantages these complex enzymatic systems hold in the present (emergent function), and ultimately where these pathways may be heading in the future (functional plasticity).

Metabolic Adaptation, Synthetic Evolutionary Lineages and Natural Chemicals

Currently, we are mapping the adaptive molecular changes that have occurred in enzymes and metabolic pathways of specialized metabolism as these enzymes and enzyme networks emerged and subsequently evolved from their ancestral roots in primary metabolism billions of years ago. Unlike enzymes of specialized metabolism, the modern day versions of these ancestral proteins are little changed in a functional sense since the primeval split with specialized metabolic enzymes. In short, functional change in primary metabolism is generally counter productive or even lethal since these enzyme networks often fulfill little changed catalytic roles pivotal for producing universally conserved primary metabolites essential to life. Our work to date has concentrated instead on specialized metabolites and their biosynthetic machinery encompassing three classes of natural chemicals with ancestral origins in primary metabolism, namely polyketides, isoprenoids and hybrid polyketide-isoprenoids.

Moreover, while these specialized metabolic pathways are ideal systems for exploring fundamental principles of natural selection including evolutionary landscapes linking structurally related proteins during the course of enzyme evolution, they also provide novel and rare chemical scaffolds for use in drug development and for engineering the metabolism of organisms. The structural and mechanistic foundation for evolutionary change in these systems provides us with a more cogent starting point to harness and alter biosynthetic pathways for the production of regio- and stereo-chemically complex molecular scaffolds. Notably, these natural products often possess diverse and extant bioactivities selected for over billions of years, a fact historically exploited during the search for new pharmaceuticals.

Genetically Encoded Medicinal Chemistry and Healthy Plant Based Diets

More recently, we have turned our attention to genetically encoding rationally designed "synthetic" metabolic pathways to facilitate our experimental search for definitive health related roles associated with natural plant compounds (nutraceuticals) including flavonoids and stilbenes (resveratrol) found in plant-rich diets. By genetically encoding existing and newly designed pathways, we can employ model organisms such as worms, flies and mice as heterologous hosts for our newly assembled metabolic pathways. In this way, understanding the detailed structures and functions of the enzymes that produce these compounds, how these enzyme structures change during the course of evolution, and how these enzymes organize themselves spatially and temporally in cells, we can judiciously engineer "synthetic" versions of the biosynthetic pathways now linked to an artificial gene or a set of genes. These "synthetic" and genetically encoded pathways can then be introduced and precisely regulated in new hosts to locally produce bioactive compounds starting from universal metabolic building blocks available in all organisms. With this level of control, we can then rigorously address, in a cellular and tissue specific context, the role played by these dietary compounds in slowing the progression of human maladies such as aging, aberrant fat metabolism, diabetes and various neurodegenerative diseases, all of which have been circumstantially curbed by plant derived flavonoids and stilbenes. Moreover, by harnessing a repository of biosynthetic reactions that alter these compounds in cells, we can genetically encode the chemical modification of existing compounds to improve their potency and activity entirely in living animals.

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