Glutamine (Gln, Q)
Glutamine is a polar, uncharged amino acid with a side-chain amide. It deamidates more slowly than asparagine, but at the N-terminus it readily cyclises to pyroglutamate.
Structure and properties
Glutamine has a side chain of two methylene groups ending in a carboxamide. The amide is polar and uncharged, donates and accepts hydrogen bonds, and makes glutamine hydrophilic and common on protein surfaces. Its longer chain gives it more flexibility than asparagine and a stronger preference for helical structure. Glutamine side chains can form networks of hydrogen bonds with each other, which is why long polyglutamine tracts tend to aggregate into amyloid-like structures. In biochemistry, glutamine side chains are also substrates for transglutaminases, which crosslink them to lysine.
Role in peptides
Glutamine appears throughout hormone and antimicrobial sequences, often in helical regions where it contributes hydrogen bonding and solubility. Many natural peptide hormones begin with pyroglutamate formed from an N-terminal glutamine, including thyrotropin-releasing hormone and gonadotropin-releasing hormone, and the cyclised terminus protects them from aminopeptidases. Native GLP-1 contains glutamine in its sequence, and LL-37 includes glutamine in its amphipathic helix. Designers may replace glutamine with glutamate or other residues to reduce chemical heterogeneity, or deliberately start a sequence with pyroglutamate to give a uniform, protected N-terminus.
Stability and analysis
An N-terminal glutamine cyclises spontaneously to pyroglutamate with loss of ammonia, a reaction favoured by heat and mildly acidic or neutral conditions. The product loses a positive charge, shifts HPLC retention and blocks Edman sequencing. Internal glutamine deamidates to glutamate through a six-membered glutarimide, but far more slowly than asparagine. In synthesis, trityl side-chain protection improves solubility and prevents nitrile formation. Mass spectrometry should be checked for the characteristic small mass loss of pyroglutamate.
In PeptideWiki compounds
Compounds whose sequence contains glutamine, with the number of occurrences.
- Tesamorelin (5)
- CJC-1295 (3)
- Thymosin β4 (3)
- Abaloparatide (2)
- Calcitonin (salmon) (2)
- IGF-1 LR3 (2)
- Sermorelin (2)
- Teriparatide (2)
- AOD-9604 (1)
- ARA-290 (cibinetide) (1)
- Argireline (acetyl hexapeptide-8) (1)
- Exenatide (1)
- LL-37 (1)
- Larazotide (1)
- MOTS-c (1)
- Oxytocin (1)
- Pramlintide (1)
- Snap-8 (1)
- TB-500 (1)
- VIP (vasoactive intestinal peptide) (1)
Frequently asked questions
What is pyroglutamate?
Pyroglutamate (pGlu) is a cyclic lactam formed when the free amine of an N-terminal glutamine or glutamate attacks its own side chain. From glutamine the reaction releases ammonia; from glutamate it releases water. The cyclised residue has no free N-terminal amine, so it resists aminopeptidases and does not react in Edman sequencing. It can be deliberate, as in several natural hormones, or an unwanted impurity in synthetic peptides.
Does glutamine deamidate like asparagine?
Yes, but much more slowly. Asparagine deamidates through a five-membered succinimide, which forms readily. Glutamine must form a six-membered glutarimide, which is less favoured, so internal glutamine deamidation is usually minor over typical laboratory timescales. The more relevant glutamine-specific reaction in synthetic peptides is pyroglutamate formation when glutamine sits at the N-terminus.
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