Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the protonated form (NH2+) under biological conditions, while the carboxyl group is in the deprotonated −COO− form. The "side chain" from the α carbon connects to the nitrogen forming a pyrrolidine loop, classifying it as a aliphatic amino acid. It is non-essential in humans, meaning the body can synthesize it from the non-essential amino acid L-glutamate. It is encoded by all the codons starting with CC (CCU, CCC, CCA, and CCG). Proline is the only proteinogenic secondary amino acid which is a secondary amine, as the nitrogen atom is attached both to the α-carbon and to a chain of three carbons that together form a five-membered ring. History and etymology Proline was first isolated in 1900 by Richard Willstätter who obtained the amino acid while studying N-methylproline, and synthesized proline by the reaction of sodium salt of diethyl malonate with 1,3-dibromopropane. The next year, Emil Fischer isolated proline from casein and the decomposition products of γ-phthalimido-propylmalonic ester, and published the synthesis of proline from phthalimide propylmalonic ester. The name proline comes from pyrrolidine, one of its constituents. Biosynthesis Proline is biosynthetically derived from the amino acid L-glutamate. Glutamate-5-semialdehyde is first formed by glutamate 5-kinase (ATP-dependent) and glutamate-5-semialdehyde dehydrogenase (which requires NADH or NADPH). This can then either spontaneously cyclize to form 1-pyrroline-5-carboxylic acid, which is reduced to proline by pyrroline-5-carboxylate reductase (using NADH or NADPH), or turned into ornithine by ornithine aminotransferase, followed by cyclisation by ornithine cyclodeaminase to form proline. Biological activity L-Proline has been found to act as a weak agonist of the glycine receptor and of both NMDA and non-NMDA (AMPA/kainate) ionotropic glutamate receptors. It has been proposed to be a potential endogenous excitotoxin. In plants, proline accumulation is a common physiological response to various stresses but is also part of the developmental program in generative tissues (e.g. pollen). A diet rich in proline was linked to an increased risk of depression in humans in a study from 2022 that was tested on a limited pre-clinical trial on humans and primarily in other organisms. Results were significant in the other organisms. Properties in protein structure The distinctive cyclic structure of proline's side chain gives proline an