November 2011

JBC: Formation of radical for DNA generation


Ribonucleotide reductases are essential in all living organisms, because they supply the raw material for DNA synthesis. The class IA ribonucleotide reductases are iron-dependent enzymes that create deoxyribonucleotides from ribonucleotides. In humans, the enzymes are successful targets of several chemotherapy drugs, such as gemcitabine and clofarabine. The enzymes have two homodimeric subunits, α2 and β2. The β2 subunit contains a di-iron cluster that generates a tyrosyl radical that is essential in making deoxyribonucleotides. The cluster in the resting state is a diferric-tyrosyl radical, Fe3+-Y·. The tyrosyl radical has a fleeting existence in humans, hanging around for only 20 minutes. Some chemotherapy drugs target this radical to destroy it and inactivate the enzyme. But as Mingxia Huang at the University of Colorado School of Medicine and JoAnne Stubbe at the Massachusetts Institute of Technology explain, the biosynthesis of the cluster and its maintenance  “in an active form inside the cell has been a major unsolved problem.” In a recent Journal of Biological Chemistry "Paper of the Week," the duo led a team to explore how this important iron center is formed in the β2 subunit of yeast. The investigators suggest that there are two proteins involved in the process: Grx3/Grx4, a protein complex that may be involved in some way with iron delivery, and Dre2/Tah18, which may provide the reducing equivalents. The investigators explain that understanding how the Fe3+-Y· cluster forms and finding out whether there is a pathway to regenerate the radical may provide new cancer therapeutic strategies.

Rajendrani Mukhopadhyay, Ph.D., ( is the senior science writer for ASBMB Today and technical editor for JBC. 

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