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Nicolai E. Savaskan, Christoph Ufer, Hartmut Khn, Astrid Borchert

The molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

Keywords: Apoptosis, embryogenesis, excitotoxicity, glial cells, oxidative stress, phosphoinositides, selenium

Selenoproteins have been recognized as modulators of brain function and signaling. Phospholipid hydroperoxide glutathione peroxidase (GPx4/PHGPx) is a unique member of selenium-dependent glutathione peroxidases in mammals with a pivotal role for brain development and function. GPx4 exists as a cytosolic, mitochondrial, and nuclear isoform derived from a single gene. In mice, the GPx4 gene is located on chromosome 10 in close proximity to a functional retrotransposome, which is expressed under the control of captured regulatory elements. Elucidation of crystallographic data uncovered structural peculiarities of GPx4 providing the molecular basis to its unique enzymatic properties and substrate specificity. Monomeric GPx4 acts multifunctional, i.e. as a reducing enzyme of peroxidized phospholipids and thiols and as structural protein. Transcriptional regulation of the different GPx4 isoforms requires several isoforms-specific cis-regulatory sequences and trans-activating factors. Cytosolic and mitochondrial GPx4 are the major isoforms exclusively expressed by neurons in the developing brain. In stark contrast, following brain trauma, GPx4 is specifically upregulated in non-neuronal cells, i.e. reactive astrocytes. Molecular approaches to genetic modification in mice revealed an essential and isoform-specific function for GPx4 in development and disease. Here, we review recent findings on GPx4 with particular emphasis on its molecular structure and function and consider potential mechanisms that underlie neural development and neuropathological conditions.

Biological Chemistry, Walter de Gruyter

Print ISSN: 1431-6730
Volume: 2007
Pages: -

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