22nd Annual Stauffer Lectureship (Day 1 of 2): Professor JoAnne Stubbe, MIT

22nd Annual Stauffer Lectureship (Day 1 of 2): Professor JoAnne Stubbe, MIT

About the Seminar

"Radicals: Your Life is in Their Hands"

If one Googles “causes of the aging process or disease”, one will find the most common culprits identified as FREE RADICALS.  In fact there are now many videos on YouTube, which describe the chemical nature of a free radical  (a molecule that has lost an electron and is desperately trying to find another one) and its inherent instability and reactivity.  “Bad” free radicals can be generated as a byproduct of normal metabolic processes: for example, when sugar from our diets is converted to metabolic energy via respiration or when plants oxidize water to oxygen with the help of sunlight.  Nature has thus evolved enzymes (super-catalysts) that are able to inactivate the “bad” free radicals directly or are able to repair the damage done to our DNA if the radicals escape that first line of defense.  Nature has also evolved antioxidants such as Vitamin C and Vitamin E that provide the electron the radical is so desperately seeking, reducing its reactivity.  Thus, in general, radicals are vilified.  They are associated with uncontrollable reactivity leading to mutations in DNA and consequent changes in proteins that inevitably contribute to the aging process and diseased states. 

It will thus come as a surprise to many scientists, even chemists, that Nature also uses free radical chemistry in essential metabolic pathways. She has figured out how to harness the considerable reactivity of these species to carry out very difficult chemical transformations with exquisite specificity. 

In this talk, I will discuss the role of “good” radicals in biology, a problem that my lab has investigated for 30 years.  Ribonucleotide reductases (RNRs) are a group of enzymes that serve as a paradigm for Nature’s use of controlled radical chemistry.  In all organisms, these enzymes catalyze the conversion of nucleotides, the building blocks of RNA, to deoxynucleotides, the building blocks of DNA, and consequently supply the monomeric precursors required for DNA replication and repair.  While this chemical transformation, cleavage of a carbon-hydroxyl (C-OH) bond of one of four nucleotide substrates and formation of a carbon-hydrogen (C-H) bond, appears to be very “simple”, nothing could be farther from the truth. The class Ia RNRs were the first enzymes shown to require an amino acid free radical for function by Peter Reichard in 1978.  This radical, located on the amino acid tyrosine adjacent to the metal cluster involved in its formation, resides in one of the two protein subunits that make up the active enzyme.  It initiates unprecedented chemistry via oxidation of a cysteine located in a second subunit positioned 35 Å away.   The resulting cysteine radical then initiates complex free radical chemistry to convert the nucleotide substrate to the deoxynucleotide.  One fascinating aspect of cysteine oxidation is the range of metallo-cofactors (FeS, FeFe, MnMn, MnFe and Co) essential for this purpose in different RNR classes, providing underappreciated examples of post-translational modification of proteins and the importance of controlled metallations in biology.

The central role of RNRs in nucleic acid metabolism has also made them the successful target of three drugs that are used clinically, including gemcitabine a mechanism based inhibitor rationally designed from our understanding of the mechanism of nucleotide reduction.   The involvement of protein radicals in enzymatic reactions, the unprecedented mechanism of radical-based nucleotide reduction, the diversity of metallo-cofactors used in generation of cysteine radicals, the success in targeting these enzymes with therapeutics in cancer treatment, and the central role of this enzyme in the evolution of an RNA world to a DNA world have enticed many investigators to study RNRs since their discovery.  A brief overview of the “good” radicals and their involvement in an essential enzyme mediated reaction in primary metabolism will be presented.

About the Speaker

JoAnne Stubbe (b. 1946) B. A. in Chemistry 1968, University of Pennsylvania; Ph.D in Organic Chemistry with George Kenyon, 1971, University of California Berkeley; Assistant Professor of Chemistry, Williams College 1971-75; Postdoctoral Fellow with Robert Abeles, Brandeis University 1975-7; Assistant Professor of Pharmacology at Yale University School of Medicine, 1977-1980; Assistant to Full Professor at University of Wisconsin, Madison, 1980-87; Ellen Swallow Richards Professor of Chemistry at MIT from 1987-92;  Professor of Biology,1990 to present; John C. Sheehan Professor of Chemistry,1992-1996; Novartis Professor of Chemistry,1996-2016; emeritus 9/1/2016.

Awards: Faculty prize in chemistry from the University of Pennsylvania; NIH predoctoral fellow, 9/69-9/71;  NIH postdoctoral fellow, 6/75-6/77;  NIH Career Development Award, 12/83-11/88;  H. I. Romnes Fellow, University of Wisconsin Madison, 3/85-3/87; Pfizer Award in Enzyme Chemistry, 1986;  ICI-Stuart Pharmaceutical Award for Excellence in Chemistry, 1989;  MIT Graduate Student Council Teaching Award, 1990; American Academy of Arts and Sciences, 1991; National Academy of Sciences, 1992; Cope Scholar Award, 1993; Richards Medal (Northeast Section of the ACS), 1996; Cotton Medal, 1997; Alfred Bader Award in Bioorganic and Bioinorganic Chemistry, 1997; Repligen Award from the Biological Chemistry Div of the ACS, 2004; American Philosophical Society, 2004;  John C. Scott Award, City of Philadelphia, 2005; National Academy of Sciences Award in Chemical Sciences, 2008; Emil Kaiser Award from the Protein Society, 2008; Kirkwood Medal, Yale University and New Haven ACS, 2008; Nakanishi Award from the ACS, 2009;  National Medal of Science, 2008 (awarded in 2009);  Prelog Medal, ETH Zurich, 2009; Franklin Institute Award in Chemistry, Philadelphia, 2010;  Murray Goodman Memorial Prize, Biophysical Society/ACS, 2010; Welch Award in Chemistry with Christopher Walsh HMS, 2010. MIT Killian Faculty Award, 2012; Yale First Distinguished Woman Science Award, 2013; Honorary Doctor of Science Harvard University, 2013; U. of Pennsylvania Alumnae Award, 2014; Remsen Award Maryland ACS, 2015; I. A. Scott Award, 2015; the Pearl Meister Greengard International Award to recognize Outstanding Women in Biomedial Science, 2017. 

General Research Interests:  My lab has helped explain the mechanisms of some of nature’s most complex and important enzymes. We use a wide range of tools and often work with outstanding collaborators to develop new techniques to reveal the otherwise inaccessible chemical complexity of these systems.  Perhaps our most noted work defines how nature harnesses the reactivity of free radicals to carry out difficult chemistry with exquisite specificity.   Bioinformatics now suggests that some >100000 enzymes use radical chemistry involved in a staggering diversity of reactions from methane production to nucleotide reduction.  We continue to unravel the free radical chemistry of ribonucleotide reductases, essential in the transformation of RNA building blocks to DNA building blocks. Our research also has explored in detail other major areas: the mechanism of bleomycin, a natural product antitumor antibiotic, used clinically; the mechanisms of iron and manganese metallation of proteins and regulation and prevention of mismetallation of metallo-cofactors in model organisms; and the biosynthetic pathways and mechanisms by which bacteria make polyoxoesters, biodegradable polymers with properties of thermoplastics