Proline

Lore & Background

The following year, Emil Fischer isolated proline from casein and published a synthesis from phthalimide propylmalonic ester. The name proline derives from pyrrolidine, one of its constituents. In biosynthesis, proline is derived from L-glutamate through a series of enzymatic steps involving glutamate 5-kinase and glutamate-5-semialdehyde dehydrogenase, leading to 1-pyrroline-5-carboxylic acid, which is reduced to proline. Alternatively, ornithine can be converted to proline via ornithine cyclodeaminase. Proline is charged onto tRNA by the enzyme EPRS1, which also acts as a proviral factor in mammarenavirus infections; inhibition of EPRS1 with halofuginon completely abolishes viral infection. Proline's cyclic side chain gives it exceptional conformational rigidity, locking the backbone dihedral angle φ at approximately −65°. This rigidity affects protein secondary structure, making proline a structural disruptor in alpha helices and beta sheets, though it is commonly found at the start of helices and in turns. Proline is also notable for its slow peptide bond formation and its ability to adopt both cis and trans isomers, with cis fractions typically 3-10% for X-Pro bonds.

Reader's Guide

Proline is significant for its unique structural and biochemical properties. As the only proteinogenic secondary amine, its cyclic side chain imposes conformational rigidity that influences protein folding, stability, and secondary structure. This rigidity is exploited in thermophilic organisms and is critical for collagen structure, where hydroxylation of proline stabilizes the triple helix. Defects in this hydroxylation, due to mutations or vitamin C deficiency, lead to scurvy. Proline's slow cis-trans isomerization can impede protein folding, and organisms possess prolyl isomerases to catalyze this process. Beyond structural roles, proline acts as a weak agonist of glycine and glutamate receptors and has been proposed as a potential endogenous excitotoxin. In plants, it accumulates under stress and in generative tissues. Its use in asymmetric catalysis (e.g., proline organocatalysis) and as an osmoprotectant in pharmaceuticals highlights its versatility. Proline's distinct ninhydrin reaction (orange-yellow instead of purple) aids in chromatographic identification.

Did You Know?

• Proline is the only proteinogenic amino acid that is a secondary amine.
• Peptide bonds to proline can adopt both cis and trans isomers, with cis fractions up to 40% for aromatic–proline bonds.
• Proline produces an orange-yellow colour when developed with ninhydrin, unlike the typical red-purple of other amino acids.
• Inhibition of the enzyme EPRS1 by halofuginon completely abolishes mammarenavirus infection by interrupting viral assembly and budding.