TY - JOUR
T1 - A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases
AU - Zhou, Bingsen
AU - Shao, Jimin
AU - Su, Leila
AU - Yuan, Yate Ching
AU - Qi, Christina
AU - Shih, Jennifer
AU - Xi, Bixin
AU - Chu, Bernard
AU - Yen, Yun
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-05-0273
DO - 10.1158/1535-7163.MCT-05-0273
M3 - Article
C2 - 16373698
AN - SCOPUS:30344471090
SN - 1535-7163
VL - 4
SP - 1830
EP - 1836
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 12
ER -