Proline metabolism and microenvironmental stress.
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.
Phang
James M
JM
Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, NCI at Frederick, Frederick, Maryland 21702, USA. phangj@mail.nih.gov
Liu
Wei
W
Zabirnyk
Olga
O
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D003094:Collagen / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D011392:Proline / Q000378:metabolism*; D011394:Proline Oxidase / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D003094:Collagen; D011392:Proline; D011394:Proline Oxidase; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020782:Matrix Metalloproteinases