Dipeptide

A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiologically important, and some are both physiologically and commercially significant. A well known dipeptide is aspartame, an artificial sweetener.[1]

Glycylglycine is the simplest dipeptide.

Dipeptides are white solids. Many are far more water-soluble than the parent amino acids.[1] For example, the dipeptide Ala-Gln has the solubility of 586 g/L more than 10x the solubility of Gln (35 g/L). Dipeptides also can exhibit different stabilities, e.g. with respect to hydrolysis. Gln does not withstand sterilization procedures, whereas this dipeptide does. Because dipeptides are prone to hydrolysis, the high solubility is exploited in infusions, i.e. to provide nutrition.[2]

Examples

Aspartame is produced commercially as an artificial sweetener.

Commercial value

About six dipeptides are of commercial interest.[1]

Aspartame (N-L-α-aspartyl-L-phenylalanine 1-methyl ester) is an artificial sweetener.
Carnosine (beta-alanyl-L-histidine) and Anserine (beta-alanyl-N-methyl histidine) are highly concentrated in muscle and brain tissues. They are used in sports medicines.
Acetylcarnosine, cataract prevention
Ala-Gln and Gly-Tyr, infusion[2]
Val-Tyr, antihypertensive

Other dipeptides

Homoanserine (N-(4-aminobutyryl)-L-histidine) is another dipeptide identified in the brain and muscles of mammals.
Diphenylalanine is the most studied building block in peptide nanotechnology
Kyotorphin (L-tyrosyl-L-arginine) is a neuroactive dipeptide which plays a role in pain regulation in the brain.
Balenine (or ophidine) (beta-alanyl-N tau-methyl histidine) has been identified in the muscles of several species of mammal (including man), and the chicken.
Glorin (N-propionyl-γ-L-glutamyl-L-ornithine-δ-lac ethyl ester) is a chemotactic dipeptide for the slime mold Polysphondylium violaceum.
Barettin (cyclo-[(6-bromo-8-en-tryptophan)-arginine]) is a cyclic dipeptide from the marine sponge Geodia barretti.
Pseudoproline
Dialanine is commonly used as a model in molecular dynamics.
Xenortides, isolated from the bacterium Xenorhabdus nematophila

Production

Synthetic dipeptides

Dipeptides are produced by coupling amino acids. The amino group on one amino acid is rendered non-nucleophilic (P in eq) and the carboxylic acid group in the second amino acid is deactivated as its methyl ester. The two modified amino acids are then combined in the presence of a coupling agent, which facilitates formation of the amide bond:

RCH(NHP)CO₂H + R'CH(NH₂)CO₂CH₃ → RCH(NHP)C(O)NH(CHR')CO₂CH₃ + H₂O

Subsequent to this coupling reaction, the amine protecting group P and the ester are converted to the free amine and carboxylic acid, respectively.[3]

For many amino acids, the ancillary functional groups are protected. The condensation of the amine and the carboxylic acid to form the peptide bond generally employs coupling agents to activate the carboxylic acid.[4]

The Bergmann azlactone peptide synthesis is a classic organic synthesis for the preparation of dipeptides.[1]

Biosynthesis

Dipeptides are produced from polypeptides by the action of the hydrolase enzyme dipeptidyl peptidase.[5] Dietary proteins are digested to dipeptides and amino acids, and the dipeptides are absorbed more rapidly than the amino acids, because their uptake involves a separate mechanism. Dipeptides activate G-cells found in the stomach to secrete gastrin.

Diketopiperazines (cyclic dipeptides)

Retosiban[6] is a cyclic dipeptide being investigated as an oral drug.

Diketopiperazines are a special class of dipeptides, which are cyclic. They form as side products in peptide synthesis. Many have been produced from non-canonical amino acids.[7]

References

Yagasaki M, Hashimoto S (November 2008). "Synthesis and application of dipeptides; current status and perspectives". Applied Microbiology and Biotechnology. 81 (1): 13–22. doi:10.1007/s00253-008-1590-3. PMID 18795289.
Fürst P, Pogan K, Stehle P (1997). "Glutamine dipeptides in clinical nutrition". Nutrition. 13 (7–8): 731–7. doi:10.1016/S0899-9007(97)83035-3. PMID 9263278.
Subirós-Funosas AE, Albericio F (2013). "Low-epimerization Peptide Bond Formation with Oxyma Pure: Preparation of Z-L-Phg-Val-OMe". Organic Syntheses. 90: 306. doi:10.15227/orgsyn.090.0306.
Suppo JS, de Figueiredo RM, Campagne JM (2015). "Dipeptide Syntheses via Activated α-Aminoesters". Organic Syntheses. 92: 296–308. doi:10.15227/orgsyn.092.0296.
Steane R. "Hydrolysis of a dipeptide". BioTopics. Retrieved 28 July 2014.
Borthwick AD, Liddle J (January 2013). "Retosiban and Epelsiban: Potent and Selective Orally available Oxytocin Antagonists". In Domling A (ed.). Methods and Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery. Weinheim: Wiley-VCH. pp. 225–256. ISBN 978-3-527-33107-9.
Borthwick AD (July 2012). "2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products". Chemical Reviews. 112 (7): 3641–716. doi:10.1021/cr200398y. PMID 22575049.

External links

An introduction to dipeptides at PeptideGuide.

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[Yagasaki-1] Yagasaki M, Hashimoto S (November 2008). "Synthesis and application of dipeptides; current status and perspectives". Applied Microbiology and Biotechnology. 81 (1): 13–22. doi:10.1007/s00253-008-1590-3. PMID 18795289.

[Gln-2] Fürst P, Pogan K, Stehle P (1997). "Glutamine dipeptides in clinical nutrition". Nutrition. 13 (7–8): 731–7. doi:10.1016/S0899-9007(97)83035-3. PMID 9263278.

[3] Subirós-Funosas AE, Albericio F (2013). "Low-epimerization Peptide Bond Formation with Oxyma Pure: Preparation of Z-L-Phg-Val-OMe". Organic Syntheses. 90: 306. doi:10.15227/orgsyn.090.0306.

[4] Suppo JS, de Figueiredo RM, Campagne JM (2015). "Dipeptide Syntheses via Activated α-Aminoesters". Organic Syntheses. 92: 296–308. doi:10.15227/orgsyn.092.0296.

[5] Steane R. "Hydrolysis of a dipeptide". BioTopics. Retrieved 28 July 2014.

[6] Borthwick AD, Liddle J (January 2013). "Retosiban and Epelsiban: Potent and Selective Orally available Oxytocin Antagonists". In Domling A (ed.). Methods and Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery. Weinheim: Wiley-VCH. pp. 225–256. ISBN 978-3-527-33107-9.

[7] Borthwick AD (July 2012). "2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products". Chemical Reviews. 112 (7): 3641–716. doi:10.1021/cr200398y. PMID 22575049.