A functional transsulfuration pathway in the brain links to glutathione homeostasis

Victor Vitvitsky, Mark Thomas, Anuja Ghorpade, Howard Eliot Gendelman, Ruma Banerjee

Research output: Contribution to journalArticle

153 Citations (Scopus)

Abstract

Oxidative stress and diminished glutathione pools play critical roles in the pathogenesis of neurodegenerative diseases, including Alzheimer and Parkinson disease. Synthesis of glutathione, the most abundant mammalian antioxidant, is regulated at the substrate level by cysteine, which is synthesized from homocysteine via the transsulfuration pathway. Elevated homocysteine and diminished glutathione levels, seen in Alzheimer and Parkinson disease patients suggest impairments in the transsulfuration pathway that connects these metabolites. However, the very existence of this metabolic pathway in the brain is a subject of controversy. The product of the first of two enzymes in this pathway, cystathionine, is present at higher levels in brain as compared with other organs. This, together with the reported absence of the second enzyme, γ-cystathionase, has led to the suggestion that the transsulfuration pathway is incomplete in the brain. In this study, we incubated mouse and human neurons and astrocytes and murine brain slices in medium with [35S]methionine and detected radiolabel incorporation into glutathione. This label transfer was sensitive to inhibition of γ-cystathionase. In adult brain slices, ∼40% of the glutathione was depleted within 10 h following γ-cystathionase inhibition. In cultured human astrocytes, flux through the transsulfuration pathway increased under oxidative stress conditions, and blockade of this pathway led to reduced cell viability under oxidizing conditions. This study establishes the presence of an intact transsulfuration pathway and demonstrates its contribution to glutathione-dependent redox-buffering capacity under ex vivo conditions in brain cells and slices.

Original languageEnglish (US)
Pages (from-to)35785-35793
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number47
DOIs
StatePublished - Nov 24 2006

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Glutathione
Brain
Homeostasis
Cystathionine gamma-Lyase
Oxidative stress
Homocysteine
Astrocytes
Parkinson Disease
Alzheimer Disease
Oxidative Stress
Cystathionine
Neurodegenerative diseases
Enzymes
Metabolites
Metabolic Networks and Pathways
Neurodegenerative Diseases
Methionine
Neurons
Oxidation-Reduction
Cysteine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A functional transsulfuration pathway in the brain links to glutathione homeostasis. / Vitvitsky, Victor; Thomas, Mark; Ghorpade, Anuja; Gendelman, Howard Eliot; Banerjee, Ruma.

In: Journal of Biological Chemistry, Vol. 281, No. 47, 24.11.2006, p. 35785-35793.

Research output: Contribution to journalArticle

Vitvitsky, Victor ; Thomas, Mark ; Ghorpade, Anuja ; Gendelman, Howard Eliot ; Banerjee, Ruma. / A functional transsulfuration pathway in the brain links to glutathione homeostasis. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 47. pp. 35785-35793.
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