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.
Highlights
Recent studies on metabolism of cancer cells are focused on the role of proline, glutamate, and ornithine interconversions in regulation of redox potential for cell survival and death
It has been demonstrated that P5C transport is different from other amino acid transport and depends on adenosine triphosphate (ATP), sodium ions, and transporter that is in close relationship with PYCR [19,20]
That human P5CS undergoes alternative splicing to form two mature RNA transcripts which encode two isoforms, long (P5CS.long) and short (P5CS.short). These isoforms differ by two amino acids at the N-terminal of the active center in glutamate 5-kinase, which results in different sensitivity to their inhibition by ornithine [5,34] removal of ornithine from the environment, restores P5C synthase activity (P5CS)
Summary
Recent studies on metabolism of cancer cells are focused on the role of proline, glutamate, and ornithine interconversions in regulation of redox potential for cell survival and death. Initial studies on the role of P5C in cellular metabolism were focused on pathways that generate this intermediate in the conversion of proline, glutamate, and ornithine and their role in generating proline, a donor of the main substrate for collagen biosynthesis. In this system important is PRODH/POX converting proline to P5C, during which ATP or ROS are generated, depending on the metabolic context. P5C participates in the regulation of survival processes—autophagy, growth, and proliferation, via involvement in the synthesis of biomass components and in the regulation of cell death by apoptosis, due to the modulation of ROS levels dependent on the activity of (PRODH/POX)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
