P5C as an Interface of Proline Interconvertible Amino Acids and Its Role in Regulation of Cell Survival and Apoptosis

Abstract

Studies of cancer metabolism have focused on the production of energy and the interconversion of carbons between cell cycles. More recently, amino acid metabolism, especially non-essential amino acids (NEAAs), has been investigated, underlining their regulatory role. One of the important mediators in energy production and interconversion of carbons in the cell is Δ1-pyrroline-5-carboxylate (P5C)—the physiological intracellular intermediate of the interconversion of proline, ornithine, and glutamate. As a central component of these conversions, it links the tricarboxylic acid cycle (TCA), urea cycle (UC), and proline cycle (PC). P5C has a cyclic structure containing a tertiary nitrogen atom (N) and is in tautomeric equilibrium with the open-chain form of L-glutamate-γ-semialdehyde (GSAL). P5C is produced by P5C synthase (P5CS) from glutamate, and ornithine via ornithine δ-amino acid transferase (δOAT). It can also be converted to glutamate by P5C dehydrogenase (P5CDH). P5C is both a direct precursor of proline and a product of its degradation. The conversion of P5C to proline is catalyzed by P5C reductase (PYCR), while proline to P5C by proline dehydrogenase/oxidase (PRODH/POX). P5C-proline-P5C interconversion forms a functional redox couple. Their transformations are accompanied by the transfer of a reducing-oxidizing potential, that affect the NADP+/NADPH ratio and a wide variety of processes, e.g., the synthesis of phosphoribosyl pyrophosphate (PRPP), and purine ribonucleotides, which are crucial for DNA synthesis. This review focuses on the metabolism of P5C in the cell as an interconversion mediator of proline, glutamate, and ornithine and its role in the regulation of survival and death with particular emphasis on the metabolic context.

Cultivation of Cells in a Physiological Plasmax Medium Increases Mitochondrial Respiratory Capacity and Reduces Replication Levels of RNA Viruses

“…Another metabolite that could have contributed to enhanced respiration could be proline that is present in Plasmax at higher levels than in DMEM. Proline can be converted into glutamate via pyrrolidine-5-carboxylate [ 43 ]. However, this hypothesis requires verification by flux analysis using mass-spectrometry, which is beyond the scope of our study.…”

Intriguing Role of Proline in Redox Potential Conferring High Temperature Stress Tolerance

“…Proline is synthesized not only from glutamate but also from ornithine (derived from arginine) by OAT ( Chalecka et al, 2021 ). Shin et al (2016) have presented evidence that ornithine, rather than glutamate pathway is the major route for the synthesis of proline both during growth resumption and HTS in Prunus persica .…”

“…If the levels of P5C are higher, which are toxic to the cells, it may get converted to glutamate. So, P5C is at a central point to deal with the situation depending on cellular conditions ( Anwar et al, 2018 ; Chalecka et al, 2021 ). It has also been pointed out that proline regulates the function of mitochondria influencing the death of cells when biotrophic and necrotrophic pathogens invade and in cancer state ( Rizzi et al, 2016 ; Phang, 2019 ).…”

NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells

“…The mechanism of NSAID-induced apoptosis in MCF7 POX-KO cells can be explained by the interplay of the TCA cycle, urea cycle, and proline cycle. Removing PRODH/POX from MCF7 cells influenced the concentration of P5C, the intermediate in the interconversion of proline, glutamine, α-KG, and ornithine, affecting the interplay between the metabolites of those cycles and the energy metabolism in the cells [ 27 , 94 ]. PRODH/POX knockout contributed to an increase in intracellular proline because of the inhibition of its degradation and the increase in prolidase expression.…”