A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases

Bingsen Zhou, Jimin Shao, Leila Su, Yate Ching Yuan, Christina Qi, Jennifer Shih, Bixin Xi, Bernard Chu, Yun Yen

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)


Ribonucleotide reductase catalyzes the reduction of ribonucleotides to deoxyribonucleotides for DNA biosynthesis. A tyrosine residue in the small subunit of class I ribonucleotide reductase harbors a stable radical, which plays a central role in the catalysis process. We have discovered that an additional tyrosine residue, conserved in human small subunits hRRM2 and p53R2, is required for the radical formation and enzyme activity. Mutations of this newly identified tyrosine residue obliterated the stable radical and the enzymatic activity of human ribonucleotide reductases shown by electron paramagnetic resonance spectroscopy and enzyme activity assays. Three-dimensional structural analysis reveals for the first time that these two tyrosines are located at opposite sides of the diiron cluster. We conclude that both tyrosines are necessary in maintaining the diiron cluster of the enzymes, suggesting that the assembly of a dityrosyl-diiron radical cofactor center in human ribonucleotide reductases is essential for enzyme catalytic activity. These results should provide insights to design better ribonucleotide reductase inhibitors for cancer therapy.

Original languageEnglish
Pages (from-to)1830-1836
Number of pages7
JournalMolecular Cancer Therapeutics
Issue number12
Publication statusPublished - Dec 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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