Structure−Function Modeling of the Interactions of N -Alkyl- N -hydroxyanilines with Rat Hepatic Aryl Sulfotransferase IV

Roberta S. King; Vyas Sharma; Lars C. Pedersen; Yoshimitsu Kakuta; Masahiko Negishi; Michael W. Duffel

doi:10.1021/tx990184z

Back

Structure−Function Modeling of the Interactions of N -Alkyl- N -hydroxyanilines with Rat Hepatic Aryl Sulfotransferase IV

Journal article

Open access

Peer reviewed

Structure−Function Modeling of the Interactions of N -Alkyl- N -hydroxyanilines with Rat Hepatic Aryl Sulfotransferase IV

Roberta S. King, Vyas Sharma, Lars C. Pedersen, Yoshimitsu Kakuta, Masahiko Negishi and Michael W. Duffel

Chemical research in toxicology, Vol.13(12), pp.1251-1258

12/01/2000

DOI: 10.1021/tx990184z

PMID: 11123966

Files and links (1)

url

https://digitalcommons.uri.edu/php_facpubs/1041View

Open Access

Abstract

Although previous investigations have clearly shown that N-hydroxy arylamines and N-hydroxy heterocyclic amines are substrates for sulfotransferases, relatively little is known about which structural features of the N-hydroxy arylamines are important for sulfation to occur. The purpose of this investigation was to determine the extent to which secondary N-alkyl-N-hydroxy arylamines interact with aryl sulfotransferase (AST) IV (also known as tyrosine-ester sulfotransferase or ST1A1) and to evaluate these interactions using molecular modeling techniques. AST IV is a major cytosolic sulfotransferase in the rat, and it catalyzes the sulfation of various phenols, benzylic alcohols, arylhydroxamic acids, oximes, and primary N-hydroxy arylamines. In this study, three secondary N-hydroxy arylamines, N-hydroxy-N-methylaniline, N-ethyl-N-hydroxyaniline, and N-hydroxy-N-n-propylaniline, were found to be substrates for the purified rat hepatic AST IV. However, when the N-alkyl substituent was an n-butyl group (i.e., N-n-butyl-N-hydroxyaniline), the interaction with the enzyme changed from that of a substrate to competitive inhibition. This change in specificity was further explored through the construction and use of a model for AST IV based on mouse estrogen sulfotransferase, an enzyme whose crystal structure has been previously determined to high resolution. Molecular modeling techniques were used to dock each of the above N-hydroxy arylamines into the active site of the homology model of AST IV and determine optimum ligand geometries. The results of these experiments indicated that steric constraints on the orientation of binding of secondary N-alkyl-N-hydroxy arylamines at the active site of AST IV play a significant role in determining the nature of the interaction of the enzyme with these compounds.

Details

Title: Subtitle: Structure−Function Modeling of the Interactions of N -Alkyl- N -hydroxyanilines with Rat Hepatic Aryl Sulfotransferase IV
Creators: Roberta S. King - University of Iowa
Vyas Sharma - University of Iowa
Lars C. Pedersen - National Institutes of Health
Yoshimitsu Kakuta - National Institutes of Health
Masahiko Negishi - National Institutes of Health
Michael W. Duffel - University of Iowa
Resource Type: Journal article
Publication Details: Chemical research in toxicology, Vol.13(12), pp.1251-1258
DOI: 10.1021/tx990184z
PMID: 11123966
NLM abbreviation: Chem Res Toxicol
ISSN: 0893-228X
eISSN: 1520-5010
Language: English
Date published: 12/01/2000
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984303285202771

Metrics

10 Record Views

7 Times Cited - Web of Science