Johnstown, Pennsylvania, is better known for its coal and steel industries and the great flood of 1889 than it is for inspiring scientists embarking on a future in chemistry and biology. But when Nobel laureate Max Perutz, the founding father of protein x-ray crystallography and the modern discipline of structural biology, spoke to the chemistry majors at the University of Pittsburgh at Johnstown, Joe Noel's life and future career changed forever. Perutz lingered after his lecture to talk with the undergraduates about their own research, becoming a role model for the budding structural biologist and biochemist.
Now Noel seeks to understand the intricate biosynthetic pathways plants and microbes use to produce a vast array of compounds that allow them to survive and prosper in the multitude of challenging ecosystems found on Earth. Some of these natural chemicals are used for communication with other species in their local environment and some are used for their own defense—both as natural chemical weapons against other organisms or as chemical strategies to adapt to challenging physical environments. Such compounds are a rich source of new drugs. Noel's aim is to understand the chemistry and evolutionary principles that underlie this extraordinary biological diversity, as well as to harness and alter these pathways to produce chemical "scaffolds" that can provide the starting point for the development of new drugs.
His work has concentrated on the biosynthetic machinery for three important classes of natural compounds: polyketides, terpenes, and hybrid terpene-polyketides. These chemicals have played an important role in the pharmaceutical industry as sources of new drugs. Noel's studies focus on understanding the structures and functions of the enzymes that produce these compounds, how these structures have evolved over time, and how they organize themselves in space and time to form complex metabolic pathways. Using this knowledge, Noel seeks to engineer new versions of the biosynthetic enzymes and pathways that can create altered compounds as a potential source of new biological tools and pharmaceuticals.
Noel's work has improved our understanding of the structure and function of key biosynthetic enzymes, called polyketide synthases, involved in producing chain-like polyketide molecules. His future studies will utilize chemistry and structural biology to investigate newly discovered polyketide synthases in bacteria, fungi, and plants to understand their basic architectural and mechanistic principles. Such studies will provide insight into how these characteristics evolve to create immense chemical complexity in organisms.
He has also made major advances in understanding sesquiterpene synthases, which are key to the synthesis of terpenes, the most diverse family of natural compounds known. The extraordinary complexity of terpenes and their myriad biological activities has made them a major challenge for chemists seeking to understand how they are synthesized.
More recently, Noel's lab has discovered the structural and chemical principles underlying an entirely new class of enzymes that create hybrid natural chemicals possessing both polyketide and terpene portions, providing access to an even greater diversity of potent biologically active natural chemicals.
To harness the chemical complexity of nature resulting from hundreds of millions of years of evolutionary change and natural selection, Noel and his colleagues have developed a technique called structure-based combinatorial protein engineering (SCOPE), to create large libraries of mutant versions of these enzymes, which they can then screen for unique catalytic properties. These methods are key to understanding the evolutionary processes that continue to expand nature's biosynthetic toolbox for creating immense chemical diversity. This diversity plays a central role in how organisms adapt and prosper.
To aid drug development research using rare terpenes, polyketides, and hybrid terpene-polyketides, Noel is developing bioreactors and heterologous organisms as chemical factories to produce large quantities of these starting compounds. He integrated synthetic chemistry with enzymes to create diverse chemical variants of these rare, highly structured, and bioactive chemical scaffolds.
Dr. Noel is also Professor and Director of the Jack H. Skirball Center for Chemical Biology and Proteomics at the Salk Institute for Biological Studies and Adjunct Professor of Chemistry and Biochemistry at the University of California, San Diego.
RESEARCH ABSTRACT SUMMARY:
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 research examines the evolutionary principles underlying the biosynthesis of plant natural products, including isoprenoids, phenylpropanoids, polyketides, and fatty acid–derived metabolites.
View Research Abstract
Photo: John Hayes/AP, © HHMI