Prolidase‐proline dehydrogenase/proline oxidase‐collagen biosynthesis axis as a potential interface of apoptosis/autophagy

Abstract

Prolidase is a cytosolic imidodipeptidase that specifically splits imidodipeptides with C-terminal proline or hydroxyproline. The enzyme plays an important role in the recycling of proline from imidodipeptides for resynthesis of collagen and other proline-containing proteins. The mechanism of prolidase-dependent regulation of collagen biosynthesis was found at both transcriptional and post-transcriptional level. The increase in the enzyme activity is due to its phosphorylation on serine/threonine residues. Prolidase-dependent transcriptional regulation of collagen biosynthesis was found at the level of NF-κB, known inhibitor of type I collagen gene expression. Proline dehydrogenase/proline oxidase (PRODH/POX) is flavin-dependent enzyme associated with the inner mitochondrial membrane. The enzyme catalyzes conversion of proline into Δ(1) -pyrroline-5-carboxylate (P5C), during which reactive oxygen species (ROS) are produced, inducing intrinsic and extrinsic apoptotic pathways. Alternatively, under low glucose stress, PRODH/POX activation produces ATP for energy supply and survival. Of special interest is that PRODH/POX gene is induced by P53 and peroxisome proliferator-activated gamma receptor (PPARγ). Among down-regulators of PRODH/POX is an oncogenic transcription factor c-MYC and miR-23b*. On the other hand, PRODH/POX suppresses HIF-1α transcriptional activity, the MAPK pathway, cyclooxygenase-2, epidermal growth factor receptor and Wnt/b-catenin signaling. PRODH/POX expression is often down-regulated in various tumors, limiting mitochondrial proline utilization to P5C. It is accompanied by increased cytoplasmic level of proline. Proline availability for PRODH/POX-dependent ATP or ROS generation depends on activity of prolidase and utilization of proline in process of collagen biosynthesis. Therefore, Prolidase-PRODH/POX-Collagen Biosynthesis axis may represent potential interface that regulate apoptosis and survival. © 2016 BioFactors, 42(4):341-348, 2016.

Hydroxyproline Attenuates Dextran Sulfate Sodium‐Induced Colitis in Mice: Involvment of the NF‐κB Signaling and Oxidative Stress

“…It has been proposed that free Hyp may help to inhibit the degradation of IκBα and the nuclear translocation of NF-κB, thus decreasing the expression of pro-inflammatory cytokines (e.g., IL-6). [45,46] More studies are needed to explore underlying mechanisms responsible for the inactivation of NF-κB signaling by Hyp, which is abundant in mammalian milk, extracellular matrix protein, feather meal, as well as meat and bone meal. [47] In conclusion, using DSS-induced colitic mice and in vitro macrophage RAW264.7, we demonstrated that Hyp administration attenuated DSS-induced colitis in mice as evidenced by reduced disease activity index scores, decreased MPO activity, histological damage, apoptosis, and reduced IL-6 and TNF-α levels in colonic tissues.…”

Development of an LC-MS Targeted Metabolomics Methodology to Study Proline Metabolism in Mammalian Cell Cultures

“…Despite that limitation, the present method exhibits numerous advantages, such as a short time of analysis, simple sample preparation, high specificity, accuracy, and precision. The importance of proline in cell regulation [ 23 , 24 , 53 ] encourages the development of different analytical approaches that offer high throughput and absolute quantitation of metabolites of interest. The present method meets the conditions mentioned above.…”

“…Among amino acids, proline seems to be unique, thus, exploring the role of proline in cellular metabolism is of an emerging interest as this amino acid affects many biological processes such as collagen biosynthesis, proline cycle, intracellular signaling, apoptosis, and autophagy [ 23 , 24 ]. Synthesis of proline involves the enzymatic conversion of pyrroline-5-carboxylic acid (P5C) derived from glutamate or ornithine [ 25 ].…”

FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells

“…PRODH is a flavin-dependent enzyme catalyzing the conversion of proline into Δ(1)-pyrroline-5-carboxylate (P5C). This PRODH-mediated enzymatic reaction produces reactive oxygen species (ROS), which induces intrinsic and extrinsic apoptotic pathways [28]. In addition, PRODH, a p53 target gene, is involved in negatively regulating multiple oncogenic factors and pathways such as HIF-1α transcriptional activity, the MAPK pathway, cyclooxygenase-2, epidermal growth factor receptor and Wnt/β-catenin signaling [28].…”