Phenylalanine (Phe, F)
Phenylalanine is a hydrophobic, aromatic amino acid with a benzyl side chain. It provides aromatic packing and binding contacts, and its D-isomer is common in protease-resistant synthetic peptides.
Structure and properties
Phenylalanine carries a benzyl group, a phenyl ring joined to the backbone through a single methylene. The ring is non-polar and lacks hydrogen-bonding groups, making phenylalanine one of the most hydrophobic standard residues. It packs in protein cores and engages in aromatic stacking and cation-pi interactions with arginine and lysine. Phenylalanine absorbs ultraviolet light weakly compared with tryptophan and tyrosine, so it contributes little to standard UV-based peptide quantitation. It is the parent of tyrosine, which adds a hydroxyl group to the ring.
Role in peptides
Phenylalanine is a frequent receptor-contact residue. It sits in the His-Phe-Arg-Trp melanocortin core, and synthetic analogues such as Melanotan II and PT-141 use D-phenylalanine there. Ipamorelin and GHRP-6 also contain D-phenylalanine, which resists proteases and alters conformation. SS-31 ends with Phe-NH2, Kisspeptin-10 ends with a C-terminal Arg-Phe-NH2, and Semax contains phenylalanine. Aromatic Phe-Phe pairs also drive self-assembly in some peptide materials, and halogenated or extended aromatic analogues are used to probe receptor pockets.
Stability and analysis
Phenylalanine has few specific concerns. The ring is stable to oxidation under normal storage and does not cyclise or deamidate. Chiral purity is the main point for peptides that rely on D-phenylalanine, since L and D forms have the same mass; diastereomers usually separate by HPLC when other stereocentres are present. Phenylalanine-rich peptides can be poorly water-soluble and may aggregate, so dissolution conditions for analysis may need some organic solvent.
In PeptideWiki compounds
Compounds whose sequence contains phenylalanine, with the number of occurrences.
- IGF-1 LR3 (6)
- LL-37 (4)
- Exenatide (2)
- Kisspeptin-10 (2)
- Pramlintide (2)
- AOD-9604 (1)
- Afamelanotide (1)
- CJC-1295 (1)
- GHRP-2 (1)
- GHRP-6 (1)
- Humanin (1)
- Ipamorelin (1)
- MOTS-c (1)
- Melanotan II (1)
- PT-141 (bremelanotide) (1)
- SS-31 (elamipretide) (1)
- Semax (1)
- Sermorelin (1)
- Setmelanotide (1)
- Teriparatide (1)
- Tesamorelin (1)
- Thymosin β4 (1)
- VIP (vasoactive intestinal peptide) (1)
Frequently asked questions
Why do some peptides use D-phenylalanine?
Most proteases recognise L-amino acids, so a D-residue at or near a cleavage site slows degradation. D-phenylalanine also changes backbone geometry, which can lock a peptide into a shape that binds a receptor better or differently. Melanocortin analogues, several growth hormone secretagogues and many opioid peptide analogues use D-phenylalanine for these reasons. The D and L forms have the same mass, so chiral analysis is needed to confirm which is present.
Does phenylalanine absorb UV light?
Yes, but weakly. Its absorbance is much lower than that of tryptophan or tyrosine and falls at a shorter wavelength than the band normally used for protein quantitation. For peptides without tryptophan or tyrosine, UV quantitation at that band is unreliable, so concentration is usually based on the backbone absorbance at low wavelength, amino acid analysis or nitrogen content.
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