Analysis of the glutathione S -transferase ( GST ) gene family
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Analysis of the glutathione S-transferase (GST ) gene family Daniel W. Nebert1* and Vasilis Vasiliou2 1
Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267–0056, USA 2 Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA *Correspondence to: Tel: þ1 513 558 4347; Fax: þ1 513 558 3562; E-mail: [email protected] Date received (in revised form): 4th August 2004
Abstract
The glutathione S-transferase (GST) gene family encodes genes that are critical for certain life processes, as well as for detoxication and toxification mechanisms, via conjugation of reduced glutathione (GSH) with numerous substrates such as pharmaceuticals and environmental pollutants. The GST genes are upregulated in response to oxidative stress and are inexplicably overexpressed in many tumours, leading to problems during cancer chemotherapy. An analysis of the GST gene family in the Human Genome Organization-sponsored Human Gene Nomenclature Committee database showed 21 putatively functional genes. Upon closer examination, however, GST-kappa 1 (GSTK1), prostaglandin E synthase (PTGES) and three microsomal GSTs (MGST1, MGST2, MGST3) were determined as encoding membrane-bound enzymes having GST-like activity, but these genes are not evolutionarily related to the GST gene family. It is concluded that the complete GST gene family comprises 16 genes in six subfamilies — alpha (GSTA), mu (GSTM), omega (GSTO), pi (GSTP), theta (GSTT) and zeta (GSTZ). Keywords: human genome, glutathione S-transferase gene family, microsomal glutathione S-transferases, prostaglandin E synthase, MAPEG family, DsbA-like thioredoxin domain
Introduction One goal of this ‘Update on Genome Completion and Annotations’ series1,2 has been to select a gene, or gene family, check for accuracy in the databases, and then help to suggest ways to correct any nomenclature problems that might exist. The glutathione S-transferases (GSTs) represent an important group of enzymes which detoxify both endogenous compounds and foreign chemicals such as pharmaceuticals and environmental pollutants. Although a large number of reviews about this important enzyme family have appeared,3 – 11 there continues to be considerable confusion in the field with regard to the naming and classification of these genes and gene products. Homologous genes, having a common ancestral origin 2 billion years ago or more, can be identified more readily, if they are designated with a stem (or root) symbol. A root symbol is very much encouraged by the Human Gene Nomenclature Committee (HGNC) as the basis for a hierarchical series of genes (eg for the ABC family, subfamily A, ABCA1, ABCA2, ABCA3, ABCA4) that are either the result of evolutionary divergence of an ancient ancestral gene, or have conserved functions — via pathways, interactions or protein domains. Such a root symbol allows the easy
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