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

研究成果: 雜誌貢獻文章

12 引文 (Scopus)

摘要

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.

原文英語
頁(從 - 到)1830-1836
頁數7
期刊Molecular Cancer Therapeutics
4
發行號12
DOIs
出版狀態已發佈 - 十二月 1 2005
對外發佈Yes

指紋

Ribonucleotide Reductases
Tyrosine
Enzymes
Deoxyribonucleotides
Ribonucleotides
Electron Spin Resonance Spectroscopy
Enzyme Assays
Catalysis
Human Activities
Spectrum Analysis
Mutation
DNA
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

引用此文

A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases. / Zhou, Bingsen; Shao, Jimin; Su, Leila; Yuan, Yate Ching; Qi, Christina; Shih, Jennifer; Xi, Bixin; Chu, Bernard; Yen, Yun.

於: Molecular Cancer Therapeutics, 卷 4, 編號 12, 01.12.2005, p. 1830-1836.

研究成果: 雜誌貢獻文章

Zhou, Bingsen ; Shao, Jimin ; Su, Leila ; Yuan, Yate Ching ; Qi, Christina ; Shih, Jennifer ; Xi, Bixin ; Chu, Bernard ; Yen, Yun. / A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases. 於: Molecular Cancer Therapeutics. 2005 ; 卷 4, 編號 12. 頁 1830-1836.
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abstract = "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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AU - Su, Leila

AU - Yuan, Yate Ching

AU - Qi, Christina

AU - Shih, Jennifer

AU - Xi, Bixin

AU - Chu, Bernard

AU - Yen, Yun

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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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