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Joanne Stubbe

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Joanne Stubbe

Novartis Professor of √áhemistry emeritus
Massachussetts Institute of Technology

 Joanne Stubbe

One of Dr. Stubbe's major contributions has been to our understanding of the free radical chemistry of ribonucleotide reductases (RNRs), enzymes essential in the transformation of RNA building blocks to DNA building blocks.  These enzymes provide the dNTPs required for DNA replication and repair and play and essential role in the fidelity of these processes.  Dr. Stubbe has identified the importance of three unique types of thiyl-radicals in the nucleotide reduction process itself.  Her studies have led to the design of a mechanism-based inhibitor gemcitabine, currently used clinically.  We have elucidated an unprecedented 35 A oxidation by the stable tyrosyl radical in one subunit of RNR of a cysteine to a thiyl radical in the active site of the second subunit.  The oxidation involves multiple proton coupled electron transfer steps and three transient tryosyl radical intermediates.  Dr. Stubbe has elucidated the mechanism of biosynthesis and repair of the unprecedented diferric-tyrosyl radical cofactor essential for all class I RNR catalysis.

In 2010 Dr. Stubbe identified the first, dimanganese-tyrosyl radical cofactor in the class Ib RNRs.  These cofactors, distinct from the diferric-tyrosyl radical cofactors in human RNR, are likely unique to many pathogenenic organisms.  Dr. Stubbe has elucidated the biosynthetic pathways of this cluster that represents a new target from antibacterial therapeutics.   Most recently, Dr. Stubbe's focus has turned to the quaternary structure complexity of RNRs and its alteration by the clinically unsed drugs gemcitabine and clofarabine.