The regulatory mechanisms of proline and hydroxyproline metabolism: Recent advances in perspective

Abstract

For diverse human tumors, growth and metastasis are dependent on proline synthesis, but the mechanisms underlying this association are not clear. Proline incorporated into collagen is primarily synthesized from glutamine. Thus, rates of collagen synthesis are modulated by the enzymes of proline synthesis. On the other hand, the hydroxylation of collagen proline requires αKG, ascorbate and ferrous iron, substrates necessary for the epigenetic demethylation of DNA and histones. The metabolic relationship of proline and hydroxyproline degradation are initiated by distinct dehydrogenases but the respective oxidized products, P5C and OH-P5C are substrates for P5C Reductase and P5C Dehydrogenase allowing for mutual competition. This provides a model by which proline synthesis in cancer plays a role in reprogramming gene expression. The metabolism of proline and hydroxyproline are also linked to the HIF response to hypoxia. Hypoxia increased the expression of ALDH18A1, which is the limiting step in proline and collagen synthesis. Hydroxyproline increases levels of HIF-1α presumably by inhibiting its degradation. These new findings allow the suggestion that there is a regulatory axis from glutamine to proline and collagen synthesis, and the release of free hydroxyproline can feed back on the HIF pathway.

The plasma metabolome of long COVID patients two years after infection

“…The glutamate/P5C synthase pathway in the intestine is responsible for most of the proline synthesis in the body. The increased levels of proline may arise from arginine or glutamine pathways, potentially in response to hypoxia 24 or tissue damage. Elevated blood levels of hydroxyproline have been proposed as a biomarker for diseases characterized by fibrosis, indicating an increased demand for proline in collagen synthesis.…”

The Urinary Metabolome of Newborns with Perinatal Complications

“…A significant increase in proline was found in BPD newborns. Proline plays a major role in arginine synthesis in human preterm infants [ 60 ] essential for ammonia disposal via urea synthesis and is associated with collagen synthesis for lung repair [ 61 ]. Organic acids and acylcarnitines were also found to be increased in BPD newborns, probably due to dysregulated energy metabolism and mitochondrial dysfunction in these very preterm infants.…”

Whole blood vs serum-derived exosomes for host and pathogen-specific tuberculosis biomarker identification: RNA-seq based machine learning approach

“…Under hypoxic conditions, HIF-1α activation help cells to adapt and survive by inducing the expression of genes that promote adaptation to low oxygen. However, down-regulation of this gene in the active stage under normoxic condition will enhance the bacterial killing during the early stage of TB infection (Phang 2023). These ndings suggest that modulating these pathways could be promising strategies to enhance the host's immune response and bacterial killing mechanisms, potentially serving as drug targets for active TB treatment.…”