摘要
Cellular redox signaling is important in diverse physiological and pathological processes. The activity of rat phenol sulfotransferase (rSULT1A1), which is important for the metabolism of hormone and drug, is subjected to redox regulation. Two cysteines, Cys232 and Cys66, nanometer away from each other and from the enzyme active site were proposed to form disulfide bond to regulate the activity of rSULT1A1. A nano switch, composed of a flexible loop from amino acid residues 59-70, explained how this long distance interaction between two cysteines can be achieved. The enzyme properties were investigated through site-directed muatagnesis, circular dichroism, enzyme kinetics and homologous modeling of the rSULT1A1 structures. We proposed that the formation of disulfide bond between Cys232 and Cys66 induced conformational changes of sulfotransferase, then in turn affected its nucleotide binding and enzyme activity. This discovery was extended to understand the possible redox regulation of other sulfotransferases from different organisms. The redox switch can be created in other redox-insensitive sulfotransferases, such as human phenol sulfotransferase (hSULT1A1) and human alcohol sulfotransferase (hSULT2A1), to produce mutant enzymes with redox regulation capacity. This study strongly suggested that redox regulation of drug and hormone metabolism can be significantly varied even though the sequence and structure of SULT1A1 of human and rat have a high degree of homology.
| 原文 | 英語 |
|---|---|
| 頁（從 - 到） | 224-231 |
| 頁數 | 8 |
| 期刊 | Biochemical Pharmacology |
| 卷 | 84 |
| 發行號 | 2 |
| DOIs | |
| 出版狀態 | 已發佈 - 七月 15 2012 |
指紋
ASJC Scopus subject areas
- Pharmacology
- Biochemistry
引用此文
A nano switch mechanism for the redox-responsive sulfotransferase. / Lin, Chih Heng; Lin, En Shyh; Su, Tian Mu; Hung, Kuo Sheng; Yang, Yuh Shyong.
於: Biochemical Pharmacology, 卷 84, 編號 2, 15.07.2012, p. 224-231.研究成果: 雜誌貢獻 › 文章
}
TY - JOUR
T1 - A nano switch mechanism for the redox-responsive sulfotransferase
AU - Lin, Chih Heng
AU - Lin, En Shyh
AU - Su, Tian Mu
AU - Hung, Kuo Sheng
AU - Yang, Yuh Shyong
PY - 2012/7/15
Y1 - 2012/7/15
N2 - Cellular redox signaling is important in diverse physiological and pathological processes. The activity of rat phenol sulfotransferase (rSULT1A1), which is important for the metabolism of hormone and drug, is subjected to redox regulation. Two cysteines, Cys232 and Cys66, nanometer away from each other and from the enzyme active site were proposed to form disulfide bond to regulate the activity of rSULT1A1. A nano switch, composed of a flexible loop from amino acid residues 59-70, explained how this long distance interaction between two cysteines can be achieved. The enzyme properties were investigated through site-directed muatagnesis, circular dichroism, enzyme kinetics and homologous modeling of the rSULT1A1 structures. We proposed that the formation of disulfide bond between Cys232 and Cys66 induced conformational changes of sulfotransferase, then in turn affected its nucleotide binding and enzyme activity. This discovery was extended to understand the possible redox regulation of other sulfotransferases from different organisms. The redox switch can be created in other redox-insensitive sulfotransferases, such as human phenol sulfotransferase (hSULT1A1) and human alcohol sulfotransferase (hSULT2A1), to produce mutant enzymes with redox regulation capacity. This study strongly suggested that redox regulation of drug and hormone metabolism can be significantly varied even though the sequence and structure of SULT1A1 of human and rat have a high degree of homology.
AB - Cellular redox signaling is important in diverse physiological and pathological processes. The activity of rat phenol sulfotransferase (rSULT1A1), which is important for the metabolism of hormone and drug, is subjected to redox regulation. Two cysteines, Cys232 and Cys66, nanometer away from each other and from the enzyme active site were proposed to form disulfide bond to regulate the activity of rSULT1A1. A nano switch, composed of a flexible loop from amino acid residues 59-70, explained how this long distance interaction between two cysteines can be achieved. The enzyme properties were investigated through site-directed muatagnesis, circular dichroism, enzyme kinetics and homologous modeling of the rSULT1A1 structures. We proposed that the formation of disulfide bond between Cys232 and Cys66 induced conformational changes of sulfotransferase, then in turn affected its nucleotide binding and enzyme activity. This discovery was extended to understand the possible redox regulation of other sulfotransferases from different organisms. The redox switch can be created in other redox-insensitive sulfotransferases, such as human phenol sulfotransferase (hSULT1A1) and human alcohol sulfotransferase (hSULT2A1), to produce mutant enzymes with redox regulation capacity. This study strongly suggested that redox regulation of drug and hormone metabolism can be significantly varied even though the sequence and structure of SULT1A1 of human and rat have a high degree of homology.
KW - Drug metabolism
KW - Glutathione
KW - Redox regulation
KW - Sulfotransferase
KW - Xenobiotics
UR - http://www.scopus.com/inward/record.url?scp=84861229583&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861229583&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2012.04.003
DO - 10.1016/j.bcp.2012.04.003
M3 - Article
C2 - 22521946
AN - SCOPUS:84861229583
VL - 84
SP - 224
EP - 231
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 2
ER -