Detoxification of environmental mutagens and carcinogens: structure, mechanism, and evolution of liver epoxide hydrolase.
Proc Natl Acad Sci U S A
; 96(19): 10637-42, 1999 Sep 14.
Article
en En
| MEDLINE
| ID: mdl-10485878
ABSTRACT
The crystal structure of recombinant murine liver cytosolic epoxide hydrolase (EC 3.3.2.3) has been determined at 2.8-A resolution. The binding of a nanomolar affinity inhibitor confirms the active site location in the C-terminal domain; this domain is similar to that of haloalkane dehalogenase and shares the alpha/beta hydrolase fold. A structure-based mechanism is proposed that illuminates the unique chemical strategy for the activation of endogenous and man-made epoxide substrates for hydrolysis and detoxification. Surprisingly, a vestigial active site is found in the N-terminal domain similar to that of another enzyme of halocarbon metabolism, haloacid dehalogenase. Although the vestigial active site does not participate in epoxide hydrolysis, the vestigial domain plays a critical structural role by stabilizing the dimer in a distinctive domain-swapped architecture. Given the genetic and structural relationships among these enzymes of xenobiotic metabolism, a structure-based evolutionary sequence is postulated.
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1
Base de datos:
MEDLINE
Asunto principal:
Carcinógenos
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Inactivación Metabólica
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Epóxido Hidrolasas
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Hígado
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Mutágenos
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
1999
Tipo del documento:
Article