Adjunct Professor of Chemistry and Biochemistry
Director & Professor, Jack H. Skirball Center for Chemical Biology and Proteomics (The Salk Institute for Biological Studies)
Investigator, Howard Hughes Medical Institute

Phone: 858-453-4100
Email: jnoel@ucsd.edu
Web: hhmi.org/research/investigators/noel.html

1993

Appointed as Adjunct Faculty

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 P