The effect of pyrroline-5-carboxylic acid on nucleotide metabolism in erythrocytes from normal and glucose-6-phosphate dehydrogenase-deficient subjects.

Yeh, Grace Chao; Röth, Elizabeth; Phang, James M.; Harris, Shirley; Nagel, Ronald L.; Rinaldi, A

doi:10.1016/s0021-9258(18)91032-x

Cited by 30 publications

(9 citation statements)

References 22 publications

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“…In a separate publication, we showed that in red cells with G6PD deficiency, the P5C-mediated increases in R-5-P and PRPP were mitigated. (Yeh et al 1984) PRPP is used in the salvage pathways for both purine and pyridine nucleotides three genes, the specific PYCRs were characterized for their differential preference for reduced pyridine nucleotides, their sensitivity to proline inhibition and their cellular localization (De Ingeniis et al 2012). Of the three isozymes, designated PYCR 1,2,3 (PYCR3 aka PYCRL), PYCR1 and 2 prefer NADH and are in mitochondria whereas PYCR3 prefers NADPH and is in the cytosol.…”

Section: Early Studies On Regulation Of Pycr Activitymentioning

confidence: 99%

Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

Phang

2021

Amino Acids

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In the 35 years since the introduction of the “proline cycle”, its relevance to human tumors has been widely established. These connections are based on a variety of mechanisms discovered by many laboratories and have stimulated the search for small molecule inhibitors to treat cancer or metastases. In addition, the multi-layered connections of the proline cycle and the role of proline and hydroxyproline in collagen provide an important regulatory link between the extracellular matrix and metabolism.

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Section: Early Studies On Regulation Of Pycr Activitymentioning

confidence: 99%

Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

Phang

2021

Amino Acids

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“…It is located in the cytosol and is involved in the conversion of P5C to proline; however, the source of P5C is ornithine [ 58 , 59 ]. The preferred co-factor for mitochondrial isoforms is NADH, while for cytosolic isoforms it is NADPH [ 58 ] in interlock to G6PD and 6PGD of the pentose phosphate pathway [ 9 ] which is important for purine nucleotide synthesis [ 42 , 60 ].…”

Section: Enzymes Of the P5c Metabolismmentioning

confidence: 99%

“…Using a method to produce 14 CO 2 from glucose-1- 14 C it was shown that P5C added to cell cultures markedly enhanced oxPPP activity [ 1 , 41 ]. Moreover, metabolic interlock withG6PDH of the PPP was demonstrated in experiments on human erythrocytes, which have high PYCR expression but are deprived of PRODH/POX activity [ 9 ]. Redox transfer significantly enhanced oxPPP and increased the formation of PRPP, a key compound for both de novo DNA synthesis and the salvage pathways of nucleic acid synthesis [ 42 , 60 ].…”

Section: Biological Role Of P5cmentioning

confidence: 99%

“…Redox transfer significantly enhanced oxPPP and increased the formation of PRPP, a key compound for both de novo DNA synthesis and the salvage pathways of nucleic acid synthesis [ 42 , 60 ]. In studies, it has been observed that treatment of human erythrocytes with P5C, increases the level of ribosyl-5-phosphate (R5P) and then incorporates the formed purines into nucleotides in the rescue pathway in the PPRP-dependent process [ 9 ], and the addition of P5C to red blood cells greatly increases the incorporation of labeled purines into the appropriate nucleotides [ 1 , 42 , 60 , 109 ]. Other research has shown that knockdown of P5CS has impaired oxPPP activity, and treatment of P5C compensated for this effect.…”

Section: Biological Role Of P5cmentioning

confidence: 99%

“…In this system particularly important is PRODH/POX converting proline to P5C, during which ATP or ROS are generated, depending on the metabolic context. It has also been highlighted that conversion of P5C back into proline, catalyzed by P5C reductase (PYCR), is coupled to the pentose phosphate pathway, regenerating NADPH and producing nucleotides for DNA biosynthesis [ 9 ]. Thus, P5C participates not only in the regulation of survival processes—autophagy, growth, and proliferation, via involvement in the synthesis of biomass components but also in the regulation of cell death by apoptosis, due to the modulation of ROS levels dependent on the activity of (PRODH/POX).…”

Section: Introductionmentioning

confidence: 99%

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

Chalecka

Kazberuk

Pałka

et al. 2021

IJMS

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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.

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Proline dehydrogenase (oxidase) in cancer

Liu

Phang

2012

BioFactors

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Proline dehydrogenase (oxidase, PRODH/POX), the first enzyme in the proline degradative pathway, plays a special role in tumorigenesis and tumor development. Proline metabolism catalyzed by PRODH/POX is closely linked with the tricarboxylic acid (TCA) cycle and urea cycle. The proline cycle formed by the interconversion of proline and Δ(1) -pyrroline-5-carboxylate (P5C) between mitochondria and cytosol interlocks with pentose phosphate pathway. Importantly, by catalyzing proline to P5C, PRODH/POX donates electrons into the electron transport chain to generate ROS or ATP. In earlier studies, we found that PRODH/POX functions as a tumor suppressor to initiate apoptosis, inhibit tumor growth, and block the cell cycle, all by ROS signaling. It also suppresses hypoxia inducible factor signaling by increasing α-ketoglutarate. During tumor progression, PRODH/POX is under the control of various tumor-associated factors, such as tumor suppressor p53, inflammatory factor peroxisome proliferator-activated receptor gamma (PPARγ), onco-miRNA miR-23b*, and oncogenic transcription factor c-MYC. Recent studies revealed the two-sided features of PRODH/POX-mediated regulation. Under metabolic stress such as oxygen and glucose deprivation, PRODH/POX can be induced to serve as a tumor survival factor through ATP production or ROS-induced autophagy. The paradoxical roles of PRODH/POX can be understood considering the temporal and spatial context of the tumor. Further studies will provide additional insights into this protein and on its metabolic effects in tumors, which may lead to new therapeutic strategies.

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The effect of pyrroline-5-carboxylic acid on nucleotide metabolism in erythrocytes from normal and glucose-6-phosphate dehydrogenase-deficient subjects.

Cited by 30 publications

References 22 publications

Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

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

Proline dehydrogenase (oxidase) in cancer

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