MOLECULE

Proline

Proline or L-proline abbreviated Pro or is one of the twenty amino acids used in living organisms as the building blocks of proteins. Proline is sometimes called an imino acid, although the IUPAC definition of an imine requires a carbon-nitrogen double bond. Proline is a non-essential amino acid that is largely synthesized from glutamic acid. While proline biosynthetic pathways exist from eubacteria to eukaryotes, in the most prevalent pathway, proline is cyclized from glutamate. First glutamate is phosphorylated to gamma-glutamyl phosphate by gamma-glutamyl kinase, then second, reduced to gamma-glutamyl semialdehyde by gamma-glutamyl phosphate reductase, then third, cyclized spontaneously to delta(1)-pyrroline-5-carboxylate and fourth, reduced to proline by delta(1)-pyrroline-5-carboxylate reductase. In higher plants and animals, the first two steps are catalysed by a bi-functional delta(1) -pyrroline-5-carboxylate synthase. Alternative pathways of proline formation use the initial steps of the arginine biosynthetic pathway to ornithine, which can be converted to delta(1)-pyrroline-5-carboxylate by ornithine aminotransferase and then reduced to proline or converted directly to proline by ornithine cyclodeaminase (PMID: 25367752). Proline is an essential component of collagen and is important for proper functioning of joints and tendons. L-proline has acted as a weak agonist of the glycine receptor and of both NMDA and non-NMDA ionotropic glutamate receptors (PMID:1349155). It is a potential endogenous excitotoxin/neurotoxin, which causes damage to nerve cells and nerve tissues. Proline, when injected into the brains of rats, non-selectively destroyed pyramidal and granule cells (PMID: 3409032) suggesting that it can act as a neurotoxin. Proline can also be a metabotoxin which is an endogenously produced metabolite that causes adverse health effects at chronically high levels. At least five inborn errors of metabolism, including hyperprolinemia type I, hyperprolinemia type II, iminoglycinuria, prolinemia type II, and pyruvate carboxylase deficiency are associated with chronically high levels of proline (PMID: 18806117). While most people with hyperprolinemia type I often do not show any symptoms despite proline blood levels being between 3 and 10 times the normal level, some individuals have seizures, intellectual disability, or other neurological or psychiatric problems. Hyperprolinemia type II patients have proline blood levels between 10 and 15 times higher than normal, and high levels of a related compound called pyrroline-5-carboxylate. While Hyperprolinemia type II patients have signs and symptoms that vary in severity, they are more likely than type I patients to have seizures or intellectual disability. Hyperprolinemia I and II are caused by deficiencies in the enzymatic activities of proline dehydrogenase and Delta-1-pyrroline-5-carboxylate reductase, respectively. Proline is also found in Cannabis plants (PMID: 6991645).