22nd Annual Stauffer Lectureship (Day 2 of 2): Professor JoAnne Stubbe, MIT
22nd Annual Stauffer Lectureship (Day 2 of 2): Professor JoAnne Stubbe, MIT
About the Seminar
"Ribonucleotide Reductases: Self-Preservation Strategy for a 35 Å Oxidation"
Ribonucleotide reductases (RNRs) catalyze the conversion of nucleotides to deoxynucleotides in all organisms playing an essential role in DNA replication and repair. The class I RNRs are composed of two homodimeric subunits: R1 (a2) and R2(b2) that form a transient, active a2b2 complex. b2 contains the di-iron tyrosyl radical (Y122•) cofactor essential for activity. a2 contains the active site where nucleotide reduction occurs and the effector sites that control the specificity and rate of nucleotide reduction. Studies have revealed that the Y122• in b2 generates a transient thiyl radical on a2 (C439) to initiate the reduction process via an oxidation that occurs over 35 Å involving a specific pathway (Y122• D [W48] D Y356 in b2 to Y731 D Y730 D C439 in a2). Rate-limiting conformational gating of this radical transfer (RT) process requires perturbation to examine the chemistry. FnY (n = 2-4) and other unnatural amino acids site-specifically incorporated in place each pathway Y in conjunction with kinetic studies and detection of intermediates by paramagnetic resonance methods (HF-EPR, -ENDOR and -PELDOR) have been carried out. The studies reveal an uphill (> 200 mv) thermodynamic landscape of the RT pathway in the forward direction. Negative stain EM of F3Y122•/E52Q-b2/a2/GDP/TTP provide the first “picture” of an asymmetric a2b2 and holds promise for the first molecular details of this machine.
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