Glutamic acid (Glu, E)
Glutamic acid (glutamate) is an acidic amino acid with a carboxylate side chain one carbon longer than aspartate. It favours helices and is used as a linker element in lipidated GLP-1 analogues.
Structure and properties
Glutamic acid has a side chain of two methylene groups ending in a carboxylic acid, which is negatively charged at physiological pH. The longer, more flexible chain places the carboxylate further from the backbone than in aspartate, so glutamate is a good helix former and readily forms salt bridges with lysine or arginine spaced three or four residues away. It is strongly hydrophilic and typically solvent-exposed, and it can coordinate metal ions. Glutamate can link to other molecules through either its alpha or its side-chain (gamma) carboxyl, and gamma linkages occur in natural peptides and in engineered drug conjugates.
Role in peptides
Glutamate is common in designed helical peptides, where Glu-Lys pairs at i, i+4 spacing stabilise the helix. Glutathione is a gamma-glutamyl peptide, linked through the side-chain carboxyl, which makes it resistant to ordinary peptidases. A gamma-glutamate spacer joins the fatty diacid side chain to lysine in semaglutide and tirzepatide, supporting albumin binding. Glutamate is also present in Semax (Met-Glu-His-Phe-Pro-Gly-Pro), epitalon and pinealon, and contributes negative charge to BPC-157. Adding glutamate is a simple way to raise solubility or lower net charge.
Stability and analysis
Glutamate is relatively stable. An N-terminal glutamate can slowly cyclise to pyroglutamate, losing water, though much more slowly than N-terminal glutamine. Internal glutamate can form a six-membered glutarimide under some conditions, but this is far less common than aspartimide formation. In synthesis, side-chain tert-butyl esters must be fully removed during cleavage. Glutamate-rich peptides can be poorly soluble near their isoelectric point and may need mildly basic buffers to dissolve for analysis.
In PeptideWiki compounds
Compounds whose sequence contains glutamic acid, with the number of occurrences.
- Thymosin β4 (8)
- Thymosin α1 (6)
- Exenatide (5)
- Abaloparatide (3)
- IGF-1 LR3 (3)
- LL-37 (3)
- Teriparatide (3)
- ARA-290 (cibinetide) (2)
- Argireline (acetyl hexapeptide-8) (2)
- Snap-8 (2)
- Tesamorelin (2)
- AOD-9604 (1)
- Afamelanotide (1)
- BPC-157 (1)
- Calcitonin (salmon) (1)
- DSIP (1)
- Epitalon (1)
- Glutathione (1)
- Humanin (1)
- MOTS-c (1)
- Pinealon (1)
- Semax (1)
- TB-500 (1)
Frequently asked questions
What is the difference between glutamate and glutamine?
Glutamate has a side-chain carboxylic acid that is negatively charged at physiological pH. Glutamine has a side-chain amide instead and is uncharged. Glutamine can deamidate to glutamate, and an N-terminal glutamine cyclises far more readily to pyroglutamate than an N-terminal glutamate does. The two differ by about one dalton, so high-resolution mass spectrometry can distinguish them.
What does gamma-glutamyl mean?
A gamma-glutamyl bond is formed through glutamate's side-chain carboxyl rather than its alpha carboxyl. Because ordinary peptidases recognise alpha-linked bonds, gamma linkages resist many of them. Glutathione is the best-known natural example. In lipidated incretin analogues, a gamma-glutamate spacer connects the fatty acid chain to a lysine side chain, positioning it for albumin binding.
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