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 journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1830-1836
Number of pages7
JournalMolecular Cancer Therapeutics
Volume4
Issue number12
DOIs
Publication statusPublished - Dec 1 2005
Externally publishedYes

Fingerprint

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

Cite this

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.

In: Molecular Cancer Therapeutics, Vol. 4, No. 12, 01.12.2005, p. 1830-1836.

Research output: Contribution to journalArticle

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. In: Molecular Cancer Therapeutics. 2005 ; Vol. 4, No. 12. pp. 1830-1836.
@article{02dd2b3bbd314677bd3f6fb22594d6b0,
title = "A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases",
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.",
author = "Bingsen Zhou and Jimin Shao and Leila Su and Yuan, {Yate Ching} and Christina Qi and Jennifer Shih and Bixin Xi and Bernard Chu and Yun Yen",
year = "2005",
month = "12",
day = "1",
doi = "10.1158/1535-7163.MCT-05-0273",
language = "English",
volume = "4",
pages = "1830--1836",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

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

PY - 2005/12/1

Y1 - 2005/12/1

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.

UR - http://www.scopus.com/inward/record.url?scp=30344471090&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=30344471090&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-05-0273

DO - 10.1158/1535-7163.MCT-05-0273

M3 - Article

VL - 4

SP - 1830

EP - 1836

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 12

ER -