The Multifaceted Roles of Proline in Cell Behavior

Abstract

Herein, we review the multifaceted roles of proline in cell biology. This peculiar cyclic imino acid is: (i) A main precursor of extracellular collagens (the most abundant human proteins), antimicrobial peptides (involved in innate immunity), salivary proteins (astringency, teeth health) and cornifins (skin permeability); (ii) an energy source for pathogenic bacteria, protozoan parasites, and metastatic cancer cells, which engage in extracellular-protein degradation to invade their host; (iii) an antistress molecule (an osmolyte and chemical chaperone) helpful against various potential harms (UV radiation, drought/salinity, heavy metals, reactive oxygen species); (iv) a neural metabotoxin associated with schizophrenia; (v) a modulator of cell signaling pathways such as the amino acid stress response and extracellular signal-related kinase pathway; (vi) an epigenetic modifier able to promote DNA and histone hypermethylation; (vii) an inducer of proliferation of stem and tumor cells; and (viii) a modulator of cell morphology and migration/invasiveness. We highlight how proline metabolism impacts beneficial tissue regeneration, but also contributes to the progression of devastating pathologies such as fibrosis and metastatic cancer.

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

“…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 function in generating proline, a donor of the main substrate for collagen biosynthesis [ 4 , 21 ]. Currently, it is recognized that P5C as a product of proline, glutamate, and ornithine interconversion is involved in the regulation of cell growth, redox balance, production of ATP, and immunomodulation [ 1 , 22 , 23 ].…”

“…One of the first reports confirming the involvement of P5C in the regulation of redox potential dates back to 1985 [ 1 ]. At that time, studies on rats provided evidence that food deprivation impaired rate of collagen biosynthesis in connective tissues independently of hydroxylation of proline but depended only on energy metabolism and the availability of proline—the main substrate for collagen production [ 21 , 25 ]. These observations became the basis for an attempt to understand the precise mechanisms that determine the contribution of proline-P5C to the regulation of the cellular redox potential and its metabolic implications.…”

“…In bacteria, proline plays a protective role against osmotic stress, allowing bacteria to grow in saline environments. On the other hand, in plants, increased proline levels are a response to water deprivation, salt stress, and low temperature [ 21 , 40 ]. The P5C-proline cycle, through regeneration of oxidative potential, directs glucose and glutamate carbons to produce cellular biomass that is essential for growth and proliferation.…”

Interactive Regulations of Dynamic Methylation and Transcriptional Responses to Recurring Environmental Stresses During Biological Invasions

“…PYCR1.2 is responsible for encoding pyrroline-5-carboxylate reductase 1, an enzyme catalyzing the rate-limiting step of proline synthesis from pyrroline-5-carboxylate (Xiao et al, 2020). Proline has been testified to play essential roles in various biological processes such as osmotic adjustment, redox homeostasis, radical scavenging, and cell signaling (Servet et al, 2012;Patriarca et al, 2021). As a compatible solute, proline enables living cells to adjust osmotic homeostasis and cell volume without overaccumulation of inorganic osmolytes, thus protecting organisms from fluctuations of osmotic pressure.…”

Circ_0000705 facilitates proline metabolism of esophageal squamous cell carcinoma cells by targeting miR-621/PYCR1 axis

“…Proline metabolism, which synthesizes and catabolizes proline to generate ATP, is a key feature of metabolic reprogramming in some cancers [ 13 – 15 ]. Although proline metabolism is less efficient in ATP production, it facilitates cell proliferation, restrains cell apoptosis, and produces metabolites to promote cancer cell survival under various stressful conditions [ 16 , 17 ].…”