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Annual review of nutrition
Aug 21, 2010;30 441-63.

Proline metabolism and microenvironmental stress.

James M Phang, Wei Liu, Olga Zabirnyk
Author Information
  1. James M Phang: Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, NCI at Frederick, Frederick, Maryland 21702, USA. phangj@mail.nih.gov
PMID: 20415579 DOI: 10.1146/annurev.nutr.012809.104638

Abstract

Proline, the only proteinogenic secondary amino acid, is metabolized by its own family of enzymes responding to metabolic stress and participating in metabolic signaling. Collagen in extracellular matrix, connective tissue, and bone is an abundant reservoir for proline. Matrix metalloproteinases degrading collagen are activated during stress to make proline available, and proline oxidase, the first enzyme in proline degradation, is induced by p53, peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands, and by AMP-activated protein kinase downregulating mTOR. Metabolism of proline generates electrons to produce ROS and initiates a variety of downstream effects, including blockade of the cell cycle, autophagy, and apoptosis. The electrons can also enter the electron transport chain to produce adenosine triphosphate for survival under nutrient stress. Pyrroline-5-carboxylate, the product of proline oxidation, is recycled back to proline with redox transfers or is sequentially converted to glutamate and alpha-ketoglutarate. The latter augments the prolyl hydroxylation of hypoxia-inducible factor-1alpha and its proteasomal degradation. These effects of proline oxidase, as well as its decreased levels in tumors, support its role as a tumor suppressor. The mechanism for its decrease is mediated by a specific microRNA. The metabolic signaling by proline oxidase between oxidized low-density lipoproteins and autophagy provides a functional link between obesity and increased cancer risk.

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Grants

  1. Z01 BC010743/Intramural NIH HHS
  2. ZIA BC010743/Intramural NIH HHS
  3. ZIA BC010744/Intramural NIH HHS
  4. HHSN27612080001/PHS HHS

MeSH Term

AMP-Activated Protein Kinases
Apoptosis
Autophagy
Collagen
Gene Expression Regulation, Enzymologic
Humans
Intracellular Signaling Peptides and Proteins
Matrix Metalloproteinases
PPAR gamma
Proline
Proline Oxidase
Protein Serine-Threonine Kinases
Reactive Oxygen Species
Signal Transduction
TOR Serine-Threonine Kinases
Tumor Suppressor Protein p53

Chemicals

Intracellular Signaling Peptides and Proteins
PPAR gamma
Reactive Oxygen Species
Tumor Suppressor Protein p53
Collagen
Proline
Proline Oxidase
MTOR protein, human
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
AMP-Activated Protein Kinases
Matrix Metalloproteinases
Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Review
Article has an altmetric score of 1

Word Cloud

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