Proline, the only proteinogenic secondary
amino acid, is metabolized by its own family of
enzymes responding to metabolic stress and participating in metabolic signaling.
Collagen in extracellular matrix, connective tissue, and bone is an abundant reservoir for
proline.
Matrix metalloproteinases degrading
collagen are activated during stress to make
proline available, and
proline oxidase, the first
enzyme in
proline degradation, is induced by p53,
peroxisome proliferator-activated receptor gamma (
PPARgamma) and its
ligands, and by
AMP-activated protein kinase downregulating mTOR. Metabolism of
proline generates electrons to produce ROS and initiates a variety of downstream effects, including blockade of the cell cycle, autophagy, and apoptosis. The electrons can also enter the electron transport chain to produce
adenosine triphosphate for survival under nutrient stress.
Pyrroline-5-carboxylate, the product of
proline oxidation, is recycled back to
proline with redox transfers or is sequentially converted to
glutamate and
alpha-ketoglutarate. The latter augments the prolyl hydroxylation of
hypoxia-inducible factor-1alpha and its proteasomal degradation. These effects of
proline oxidase, as well as its decreased levels in
tumors, support its role as a
tumor suppressor. The mechanism for its decrease is mediated by a specific
microRNA. The metabolic signaling by
proline oxidase between oxidized
low-density lipoproteins and autophagy provides a functional link between
obesity and increased
cancer risk.