Lysine (Lys, K)
Lysine is a basic amino acid with a long side chain ending in a primary amine. It carries positive charge and is the most common attachment point for lipids, labels and linkers in peptides.
Structure and properties
Lysine has a flexible side chain of four methylene groups ending in an epsilon-amino group, which is protonated and positively charged at physiological pH. The long chain lets lysine reach across to form salt bridges and to interact with phosphates and carboxylates, while its methylene groups add some hydrophobic character. Lysine is highly solvent-exposed in folded proteins. The epsilon-amine is a good nucleophile once deprotonated, so it reacts with activated esters, aldehydes and other electrophiles. In cells, lysine side chains carry many post-translational modifications, including acetylation, methylation and ubiquitination. Trypsin cleaves after lysine and arginine.
Role in peptides
Lysine is the usual site for side-chain modification. In semaglutide and tirzepatide, a lysine side chain carries the fatty diacid that drives albumin binding. In PT-141 and Melanotan II, lysine forms a lactam bridge with aspartate to close the ring. Lysine is the C-terminal residue of GHK-Cu and the first residue of KPV, and appears in SS-31, ipamorelin and GHRP-6. Lysine-rich sequences contribute to the cationic character of LL-37. Lysine is also a frequent site for attaching fluorescent labels or biotin in research reagents.
Stability and analysis
Lysine is stable in storage but its amine is reactive. It can form adducts with reducing sugars, aldehydes or formaldehyde from excipients or solvents, and it can be acylated by reactive impurities. In synthesis, incomplete removal of the side-chain Boc group or unwanted acylation of a poorly protected lysine produces branched or adduct species detectable by mass spectrometry. Each lysine binds a counter-ion, so lysine-rich peptides carry more trifluoroacetate or acetate per unit weight.
In PeptideWiki compounds
Compounds whose sequence contains lysine, with the number of occurrences.
- Thymosin β4 (9)
- LL-37 (6)
- Abaloparatide (4)
- Thymosin α1 (4)
- IGF-1 LR3 (3)
- Teriparatide (3)
- VIP (vasoactive intestinal peptide) (3)
- CJC-1295 (2)
- Calcitonin (salmon) (2)
- Exenatide (2)
- Matrixyl (palmitoyl pentapeptide-4) (2)
- Sermorelin (2)
- TB-500 (2)
- Tesamorelin (2)
- Afamelanotide (1)
- BPC-157 (1)
- GHK-Cu (1)
- GHRP-2 (1)
- GHRP-6 (1)
- Humanin (1)
- Ipamorelin (1)
- KPV (1)
- MOTS-c (1)
- Melanotan II (1)
- PT-141 (bremelanotide) (1)
- Pramlintide (1)
- SS-31 (elamipretide) (1)
- Selank (1)
Frequently asked questions
Why is lysine used for lipidation?
The epsilon-amine sits at the end of a long, flexible side chain, so modifying it usually leaves the backbone and receptor-binding residues undisturbed. Orthogonal protecting groups let chemists unmask a single lysine on the resin and attach a fatty acid, spacer or label selectively. Semaglutide and tirzepatide both use this approach to attach a fatty diacid through a linker, giving reversible albumin binding.
What is a lactam bridge?
A lactam bridge is an amide bond formed between a side-chain amine, usually lysine, and a side-chain carboxyl, usually aspartate or glutamate. It cyclises a peptide or staples a helix without using a disulfide, so it is not sensitive to reduction. PT-141 and Melanotan II are cyclised through an Asp-Lys lactam bridge, which constrains the melanocortin pharmacophore.
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