Proline

Lore & Background

The following year, Emil Fischer isolated proline from casein and the decomposition products of γ-phthalimido-propylmalonic ester, and published its synthesis from phthalimide propylmalonic ester. The name proline derives from pyrrolidine, one of its constituents. In biosynthesis, proline is derived from L-glutamate. Glutamate-5-semialdehyde is formed by glutamate 5-kinase and glutamate-5-semialdehyde dehydrogenase, then either spontaneously cyclizes to 1-pyrroline-5-carboxylic acid (reduced to proline by pyrroline-5-carboxylate reductase) or is converted to ornithine and then cyclized to proline. L-Proline acts as a weak agonist of the glycine receptor and both NMDA and non-NMDA ionotropic glutamate receptors, and has been proposed as a potential endogenous excitotoxin. Proline's cyclic structure locks the backbone dihedral angle φ at approximately −65°, giving it exceptional rigidity. It is a structural disruptor in alpha helices and beta sheets but is commonly found at the start of helices, in beta turns, and in polyproline helices such as those in collagen. Hydroxylation of proline by prolyl hydroxylase is critical for collagen stability; defects can cause scurvy. Peptide bonds to proline can adopt cis or trans isomers, with cis fractions typically 3-10%, and isomerization is slow, often requiring prolyl isomerase enzymes for protein folding.

Reader's Guide

Proline is significant as the only proteinogenic amino acid that is a secondary amine, giving it unique structural and biochemical properties. Its cyclic side chain imposes conformational rigidity that influences protein secondary structure, making it a common component of turns and collagen helices. The slow rate of peptide bond formation involving proline affects protein synthesis and folding, and its ability to adopt cis isomers is crucial for proper folding in many proteins. Biologically, proline serves as an osmoprotectant in plants and is involved in stress responses. In humans, the enzyme EPRS1, which charges proline onto tRNA, acts as a proviral factor for mammarenaviruses, and its inhibition can block viral infection. Proline is also used in asymmetric organocatalysis, brewing (where it contributes to haze), and plant tissue culture. Its detection in chromatography yields an orange-yellow color with ninhydrin, unlike other amino acids.

Did You Know?

• Proline is the only proteinogenic amino acid that is a secondary amine.
• Proline produces an orange-yellow colour when developed with ninhydrin, not the typical red-purple.
• Peptide bonds to proline can adopt cis isomers at rates of 3-10%, much higher than other amino acids.
• Hydroxylation of proline is critical for collagen stability; defects can lead to scurvy.