Proline Metabolism and Microenvironmental Stress

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.

Optimization of Light-Harvesting Pigment Improves Photosynthetic Efficiency

“…These results indicate that the turnover rate of carbohydrates in hpe1 mutants is comparable to that in wild-type plants, implying that the greater accumulation of carbohydrates is due to the more efficient carbon fixation in hpe1 mutants. More interestingly, the content of Pro, the only proteinogenic secondary amino acid that responds to metabolic stress and participates in metabolic signaling (Phang et al, 2010), was significantly higher in the hpe1 mutants than in the wild-type plants ( Fig. 2C; Supplemental Fig.…”

A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy

“…Interestingly, a role of mitochondrial ROS in neuronal oxidative stress is yet to be clearly defined. Therefore, we considered the contribution of POX in this response because POX is a mitochondrial inner membrane enzyme that is well established to generate ROS (10,73). This mitochondrial ROS generation by POX is dependent on its ability to generate electrons during proline catabolism (Fig.…”

MiRNA and Proline Metabolism in Cancer

“…Together with hydroxyproline, proline constitutes more t h a n 2 5 % o f r e s i d u e s i n c o l l a g e n , t h e predominant protein (80%) in the extracellular matrix (ECM) of the human body. Although proline can be obtained from the dietary proteins, an important source of proline is from the degradation of collagen in the ECM by sequential enzymatic catalysis of matrix metalloproteinases (MMPs) and prolidase [9,23]. The upregulation of MMPs in tumors has been considered a critical step for tumor progression and invasion [24][25][26].…”

“…These effects seem paradoxical with PRODH/POX-induced apoptosis, but they can be well understood considering the temporal and spatial development of the evolving tumor, like the "two faces" of tumor suppressor p53 [45]. A detailed description of this point can be found in our recent review [9].…”