What does 1-pyrroline-5-carboxylate do to ME?

ME patients had increased plasma levels of 1-pyrroline-5-carboxylic acid (P5C) and arginine. Females had increased OH-proline (1).

P5C is found at a crossroad, which exchanges metabolites from:

• proline degradation from collagen
• proline synthesis
• urea cycle
• TCA cycle

Research in tumor growth has shown(quote from ref 2):

"The metabolism of the nonessential amino acid proline contributes to tumor metabolic reprogramming. Previously we showed that MYC increases proline biosynthesis (PB) from glutamine. Here we show MYC increases the expression of the enzymes in PB at both protein and mRNA levels. Blockade of PB decreases tumor cell growth and energy production. Addition of Δ1- pyrroline-5-carboxylate (P5C) or proline reverses the effects of P5C synthase knockdown but not P5C reductases knockdown. Importantly, the reversal effect of proline was blocked by concomitant proline dehydrogenase/oxidase (PRODH/POX) knockdown. These findings suggest that the important regulatory contribution of PB to tumor growth derives from metabolic cycling between proline and P5C rather than product proline or intermediate P5C. We further document the critical role of PB in maintaining pyridine nucleotide levels by connecting the proline cycle to glycolysis and to the oxidative arm of the pentose phosphate pathway. These findings establish a novel function of PB in tumorigenesis, linking the reprogramming of glucose, glutamine and pyridine nucleotides, and may provide a novel target for antitumor therapy."

From page 9: "The proline cycle transfers reducing and oxidizing potentials to maintain redox homeostasis between cytosol and mitochondria through interconversion of proline and P5C catalyzed by PRODH/POX and PYCRs, respectively. In mitochondria, PRODH/POX oxidizes proline to P5C and donates electrons through its flavine adenine dinucleotide into the electron transport chain (ETC) to generate ATP or reactive oxygen species (ROS) for apoptosis or cell growth depending on the metabolic context of tumor environment (10,19). P5C can be converted to proline intra-mitochondrially or in the cytosol by PYCRs using NADPH or NADH as cofactor. Therefore, the interconversion of P5C and proline results in the recycling of cellular NAD(P)H to NAD(P)+. During the 1970s and early 1980s, researchers in proline metabolism documented the metabolic interlock between proline cycle and the oxPPP through the cycling of NADPH and NADP+ in various cells and reconstituted cell systems (26–28). They showed that P5C is a potent stimulator of oxPPP in cultured fibroblasts (26). Together with these early studies, our current findings seen with PB knockdown, i.e. marked decrease in oxPPP activity and decreased levels of both total NAD and NADP, suggest the PYCR-catalyzed conversion of P5C to proline provides a metabolic linkage to oxidize NAD(P)H as well as to generate total NAD and NADP (Fig. 8)". (Ref 2 and references herein).




Figure 8. Proposed scheme of interactions of proline biosynthesis with glucose and glutamine metabolism. Proline biosynthesis from glutamine in cancer cells promotes cell growth through interacting with glycolysis and oxidative arm of pentose phosphate pathway. P5C, Δ1 -pyrroline-5-carboxylate; GSA, glutamic-gamma-semialdehyde; GLS, glutaminase; GS, glutaminesynthase; P5CS, pyrroline-5- carboxylatesynthase; P5CDH, pyrroline-5-carboxylatedehydrogenase; PRODH/POX, proline dehydrogenase/ oxidase; PYCR1/2, pyrroline-5-carboxylatereductase1, and 2; PYCRL, pyrroline-5-carboxylatereductase L. oxPPP, oxidative arm of pentose phosphate pathway. Ref: Liu, W. et al. Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides. Sci. Rep. 5, 17206; doi: 10.1038/srep17206 (2015).

Is P5C used to control redox (NADP/NADPH) in ME?

Is P5C used to stimulate phosphoribosyl pyrophosphate and purine nucleotide production in ME (as shown in ref 3)?

Is P5C used as an intermediate to replenish the TCA cycle in ME?


References:

1) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113 

2) Liu, W. et al. Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides. Sci. Rep. 5, 17206; doi: 10.1038/srep17206 (2015).
https://www.nature.com/articles/srep17206.pdf

3) J Biol Chem. 1988 Sep 15;263(26):13083-9. Stimulation of phosphoribosyl pyrophosphate and purine nucleotide production by pyrroline 5-carboxylate in human erythrocytes.
Yeh GC1, Phang JM. https://www.ncbi.nlm.nih.gov/pubmed/2458343