Proline
Proteinogenic amino acid with a unique cyclic structure.
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid used in the biosynthesis of proteins. It is the only proteinogenic amino acid that is a secondary amine, with a distinctive cyclic side chain that forms a pyrrolidine loop. Proline is non-essential in humans, as the body can synthesize it from L-glutamate, and it is encoded by all codons starting with CC (CCU, CCC, CCA, and CCG).
First isolated in 1900 by Richard Willstätter during work on N-methylproline, proline was synthesized using the sodium salt of diethyl malonate and 1,3-dibromopropane. The following year, Emil Fischer independently isolated it from casein and from decomposition products of γ-phthalimido-propylmalonic ester, also publishing a synthesis from phthalimide propylmalonic ester. The name derives from pyrrolidine, one of its constituents. Under biological conditions, the secondary amine nitrogen exists in a protonated form (NH₂⁺), while the carboxyl group is deprotonated (−COO⁻). The side chain, which connects the α-carbon to the nitrogen, creates a five-membered pyrrolidine ring, classifying proline as an aliphatic amino acid. This cyclic structure confers exceptional conformational rigidity, locking the backbone dihedral angle φ at approximately −65°. Consequently, proline acts as a structural disruptor in the middle of alpha helices and beta sheets, though it is commonly found at the start of alpha helices, in beta turns, and on the edge strands of beta sheets. Despite its fully aliphatic side chain, proline is usually solvent-exposed. Peptide bond formation involving proline is notably slower than with other amino acids, especially for proline-proline bonds. The X-Pro peptide bond can adopt both cis and trans isomers, unlike most peptide bonds which overwhelmingly favor the trans form. Multiple consecutive prolines or hydroxyprolines can form a polyproline helix, the dominant structure in collagen. Hydroxylation of proline by prolyl hydroxylase, requiring ascorbate, is critical for connective tissue stability; defects in this process can lead to severe diseases like scurvy.
- classification
- Proteinogenic amino acid, secondary amine, aliphatic
- function
- Used in protein biosynthesis; weak agonist of glycine and glutamate receptors
- encoding
- Codons CCU, CCC, CCA, CCG
- biosynthesis
- Derived from L-glutamate via glutamate-5-semialdehyde
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.
Frequently Asked Questions
What is Proline?
Proline is a proteinogenic amino acid that serves as a standard building block in protein biosynthesis. It is classified as an aliphatic amino acid and is one of the twenty residues routinely incorporated into cellular proteins.
What makes Proline structurally unique among the amino acids?
Proline is the only proteinogenic amino acid whose backbone nitrogen is part of a secondary amine rather than a primary amine. Its side chain folds back to form a rigid pyrrolidine ring, which constrains the phi angle of the polypeptide backbone and introduces characteristic kinks into protein structures.
Which codons encode Proline?
Proline is specified by the entire CC codon family: CCU, CCC, CCA, and CCG. Any mRNA triplet that begins with the dinucleotide CC directs the ribosome to insert a proline residue.
Is Proline an essential amino acid in humans?
No, because the human body can synthesize proline endogenously from L-glutamate via the intermediate glutamate-5-semialdehyde. This internal biosynthetic route means dietary proline is not strictly required for survival.
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