当前位置： SCI文献检索 > CHEMICAL RESEARCH IN TOXICOLOGY期刊下所有文献 > Catalytic activities of human alpha class glutathione transferases toward carcinogenic dibenzo[a,l]pyrene diol epoxides.

Catalytic activities of human alpha class glutathione transferases toward carcinogenic dibenzo[a,l]pyrene diol epoxides.

Abstract：

:In this study, human glutathione transferases (GSTs) of alpha class have been assayed with the ultimate carcinogenic (-)-anti- and (+)-syn-diol epoxides (DEs) derived from the nonplanar dibenzo[a,l]pyrene (DBPDE) and the (+)-anti-diol epoxide of the planar benzo[a]pyrene [(+)-anti-BPDE] in the presence of glutathione (GSH). In all DEs, the benzylic oxirane carbon reacting with GSH, possess R-absolute configuration. GSTA1-1 demonstrated activity with all DEs tested whereas A2-2 and A3-3 only were active with the DBPDE enantiomers. With GSTA4-4, no detectable activity was observed. GSTA1-1 was found to be the most efficient enzyme and demonstrated a catalytic efficiency (k(cat)/K(m)) of 464 mM(-)(1) s(-)(1) with (+)-syn-DBPDE. This activity was about 7-fold higher than that observed with (-)-anti-DBPDE and more than 65-fold higher than previously observed with less complex fjord-region DEs. GSTA3-3 also demonstrated high k(cat)/K(m) with the DEs of DBP and a high preference for the (+)-syn-DBPDE enantiomer [190 vs 16.2 mM(-)(1) s(-)(1) for (-)-anti-DBPDE]. Lowest k(cat)/K(m) value of the active enzymes was observed with GSTA2-2. In this case, 30.4 mM(-)(1) s(-)(1) was estimated for (+)-syn-DBPDE and 3.4 mM(-)(1) s(-)(1) with (-)-anti-DBPDE. Comparing the activity of the alpha class GSTs with (-)-anti-DBPDE and (+)-anti-BPDE revealed that GSTA1-1 was considerable more active with the former substrate (about 25-fold). Molecular modeling studies showed that the H-site of GSTA1-1 is deeper and wider than that of GSTA4-4. This is mainly due to the changes of Ser212-->Tyr212 and Ala216-->Val216, which cause a shallower active site, which cannot accommodate large substrates such as DBPDE. The higher activity of GSTA1-1 with (+)-syn-DBPDE relative to (-)-anti-DBPDE is explained by the formation of more favorable interactions between the substrate and the enzyme-GSH complex. The presence of GSTA1-1 in significant amounts in human lung, a primary target tissue for PAH carcinogenesis, may be an important factor for the protection against the harmful action of this type of potent carcinogenic intermediates.

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Dreij K,Sundberg K,Johansson AS,Nordling E,Seidel A,Persson B,Mannervik B,Jernström B

doi

10.1021/tx025519i

subject

Has Abstract

pub_date

2002-06-01 00:00:00

pages

825-31

issue

eissn

0893-228X

issn

1520-5010

pii

tx025519i

journal_volume

pub_type

杂志文章

在线工具

Catalytic activities of human alpha class glutathione transferases toward carcinogenic dibenzo[a,l]pyrene diol epoxides.