Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress

Navasona Krishnan, Martin B. Dickman, Donald F. Becker

Research output: Contribution to journalArticlepeer-review

219 Scopus citations


The potential of proline to suppress reactive oxygen species (ROS) and apoptosis in mammalian cells was tested by manipulating intracellular proline levels exogenously and endogenously by overexpression of proline metabolic enzymes. Proline was observed to protect cells against H2O2, tert-butyl hydroperoxide, and a carcinogenic oxidative stress inducer but was not effective against superoxide generators such as menadione. Oxidative stress protection by proline requires the secondary amine of the pyrrolidine ring and involves preservation of the glutathione redox environment. Overexpression of proline dehydrogenase (PRODH), a mitochondrial flavoenzyme that oxidizes proline, resulted in 6-fold lower intracellular proline content and decreased cell survival relative to control cells. Cells overexpressing PRODH were rescued by pipecolate, an analog that mimics the antioxidant properties of proline, and by tetrahydro-2-furoic acid, a specific inhibitor of PRODH. In contrast, overexpression of the proline biosynthetic enzymes Δ1-pyrroline-5-carboxylate (P5C) synthetase (P5CS) and P5C reductase (P5CR) resulted in 2-fold higher proline content, significantly lower ROS levels, and increased cell survival relative to control cells. In different mammalian cell lines exposed to physiological H2O2 levels, increased endogenous P5CS and P5CR expression was observed, indicating that upregulation of proline biosynthesis is an oxidative stress response.

Original languageEnglish (US)
Pages (from-to)671-681
Number of pages11
JournalFree Radical Biology and Medicine
Issue number4
StatePublished - Feb 15 2008


  • Oxidative stress protection
  • Proline
  • Proline biosynthesis
  • Proline oxidation
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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