Peptide bond

Last updated December 19, 2024

In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein chain.^[1]

Synthesis

Peptide bond formation via dehydration reaction Peptidformationball.svg — Peptide bond formation via dehydration reaction

When two amino acids form a dipeptide through a peptide bond,^[1] it is a type of condensation reaction.^[2] In this kind of condensation, two amino acids approach each other, with the non-side chain (C1) carboxylic acid moiety of one coming near the non-side chain (N2) amino moiety of the other. One loses a hydrogen and oxygen from its carboxyl group (COOH) and the other loses a hydrogen from its amino group (NH₂). This reaction produces a molecule of water (H₂O) and two amino acids joined by a peptide bond (−CO−NH−). The two joined amino acids are called a dipeptide.

The amide bond is synthesized when the carboxyl group of one amino acid molecule reacts with the amino group of the other amino acid molecule, causing the release of a molecule of water (H₂O), hence the process is a dehydration synthesis reaction.

The dehydration condensation of two amino acids to form a peptide bond (red) with expulsion of water (blue) AminoacidCondensation.svg — The dehydration condensation of two amino acids to form a peptide bond (red) with expulsion of water (blue)

The formation of the peptide bond consumes energy, which, in organisms, is derived from ATP.^[3] Peptides and proteins are chains of amino acids held together by peptide bonds (and sometimes by a few isopeptide bonds). Organisms use enzymes to produce nonribosomal peptides,^[4] and ribosomes to produce proteins via reactions that differ in details from dehydration synthesis.^[5]

Some peptides, like alpha-amanitin, are called ribosomal peptides as they are made by ribosomes,^[6] but many are nonribosomal peptides as they are synthesized by specialized enzymes rather than ribosomes. For example, the tripeptide glutathione is synthesized in two steps from free amino acids, by two enzymes: glutamate–cysteine ligase (forms an isopeptide bond, which is not a peptide bond) and glutathione synthetase (forms a peptide bond).^[7]^[8]

Degradation

A peptide bond can be broken by hydrolysis (the addition of water). The hydrolysis of peptide bonds in water releases 8–16 kJ/mol (2–4 kcal/mol) of Gibbs energy.^[9] This process is extremely slow, with the half life at 25 °C of between 350 and 600 years per bond.^[10]

In living organisms, the process is normally catalyzed by enzymes known as peptidases or proteases, although there are reports of peptide bond hydrolysis caused by conformational strain as the peptide/protein folds into the native structure.^[11] This non-enzymatic process is thus not accelerated by transition state stabilization, but rather by ground-state destabilization.

Spectra

The wavelength of absorption for a peptide bond is 190–230 nm,^[12] which makes it particularly susceptible to UV radiation.

Cis/trans isomers of the peptide group

Significant delocalisation of the lone pair of electrons on the nitrogen atom gives the group a partial double-bond character. The partial double bond renders the amide group planar, occurring in either the cis or trans isomers. In the unfolded state of proteins, the peptide groups are free to isomerize and adopt both isomers; however, in the folded state, only a single isomer is adopted at each position (with rare exceptions). The trans form is preferred overwhelmingly in most peptide bonds (roughly 1000:1 ratio in trans:cis populations). However, X-Pro peptide groups tend to have a roughly 30:1 ratio, presumably because the symmetry between the C^α and C^δ atoms of proline makes the cis and trans isomers nearly equal in energy, as shown in the figure below.

The dihedral angle associated with the peptide group (defined by the four atoms C^α–C'–N–C^α) is denoted $\omega$ ; $\omega =0^{\circ }$ for the cis isomer (synperiplanar conformation), and $\omega =180^{\circ }$ for the trans isomer (antiperiplanar conformation). Amide groups can isomerize about the C'–N bond between the cis and trans forms, albeit slowly ( $\tau \sim 20$ seconds at room temperature). The transition states $\omega =\pm 90^{\circ }$ requires that the partial double bond be broken, so that the activation energy is roughly 80 kJ/mol (20 kcal/mol). However, the activation energy can be lowered (and the isomerization catalyzed) by changes that favor the single-bonded form, such as placing the peptide group in a hydrophobic environment or donating a hydrogen bond to the nitrogen atom of an X-Pro peptide group. Both of these mechanisms for lowering the activation energy have been observed in peptidyl prolyl isomerases (PPIases), which are naturally occurring enzymes that catalyze the cis-trans isomerization of X-Pro peptide bonds.

Conformational protein folding is usually much faster (typically 10–100 ms) than cis-trans isomerization (10–100 s). A nonnative isomer of some peptide groups can disrupt the conformational folding significantly, either slowing it or preventing it from even occurring until the native isomer is reached. However, not all peptide groups have the same effect on folding; nonnative isomers of other peptide groups may not affect folding at all.

Chemical reactions

Due to its resonance stabilization, the peptide bond is relatively unreactive under physiological conditions, even less than similar compounds such as esters. Nevertheless, peptide bonds can undergo chemical reactions, usually through an attack of an electronegative atom on the carbonyl carbon, breaking the carbonyl double bond and forming a tetrahedral intermediate. This is the pathway followed in proteolysis and, more generally, in N–O acyl exchange reactions such as those of inteins. When the functional group attacking the peptide bond is a thiol, hydroxyl or amine, the resulting molecule may be called a cyclol or, more specifically, a thiacyclol, an oxacyclol or an azacyclol, respectively.

Related Research Articles

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An alpha helix is a sequence of amino acids in a protein that are twisted into a coil.

<span class="mw-page-title-main">Beta sheet</span> Protein structural motif

The beta sheet is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet. A β-strand is a stretch of polypeptide chain typically 3 to 10 amino acids long with backbone in an extended conformation. The supramolecular association of β-sheets has been implicated in the formation of the fibrils and protein aggregates observed in amyloidosis, Alzheimer's disease and other proteinopathies.

<span class="mw-page-title-main">Chymotrypsin</span> Digestive enzyme

Chymotrypsin (EC 3.4.21.1, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme component of pancreatic juice acting in the duodenum, where it performs proteolysis, the breakdown of proteins and polypeptides. Chymotrypsin preferentially cleaves peptide amide bonds where the side chain of the amino acid N-terminal to the scissile amide bond (the P₁ position) is a large hydrophobic amino acid (tyrosine, tryptophan, and phenylalanine). These amino acids contain an aromatic ring in their side chain that fits into a hydrophobic pocket (the S₁ position) of the enzyme. It is activated in the presence of trypsin. The hydrophobic and shape complementarity between the peptide substrate P₁ side chain and the enzyme S₁ binding cavity accounts for the substrate specificity of this enzyme. Chymotrypsin also hydrolyzes other amide bonds in peptides at slower rates, particularly those containing leucine at the P₁ position.

Hydrolysis is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.

Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesis is most commonly performed by ribosomes in cells. Peptides can also be synthesized in the laboratory. Protein primary structures can be directly sequenced, or inferred from DNA sequences.

In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space. This contrasts with structural isomers, which share the same molecular formula, but the bond connections or their order differs. By definition, molecules that are stereoisomers of each other represent the same structural isomer.

Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group -NH^₂ but is rather a secondary amine. The secondary amine nitrogen is in the protonated form (NH₂⁺) under biological conditions, while the carboxyl group is in the deprotonated −COO⁻ form. The "side chain" from the α carbon connects to the nitrogen forming a pyrrolidine loop, classifying it as a aliphatic amino acid. It is non-essential in humans, meaning the body can synthesize it from the non-essential amino acid L-glutamate. It is encoded by all the codons starting with CC (CCU, CCC, CCA, and CCG).

In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the binding site, and residues that catalyse a reaction of that substrate, the catalytic site. Although the active site occupies only ~10–20% of the volume of an enzyme, it is the most important part as it directly catalyzes the chemical reaction. It usually consists of three to four amino acids, while other amino acids within the protein are required to maintain the tertiary structure of the enzymes.

Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms. While there exist a wide range of peptides that are not synthesized by ribosomes, the term nonribosomal peptide typically refers to a very specific set of these as discussed in this article.

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An isopeptide bond is a type of amide bond formed between a carboxyl group of one amino acid and an amino group of another. An isopeptide bond is the linkage between the side chain amino or carboxyl group of one amino acid to the α-carboxyl, α-amino group, or the side chain of another amino acid. In a typical peptide bond, also known as eupeptide bond, the amide bond always forms between the α-carboxyl group of one amino acid and the α-amino group of the second amino acid. Isopeptide bonds are rarer than regular peptide bonds. Isopeptide bonds lead to branching in the primary sequence of a protein. Proteins formed from normal peptide bonds typically have a linear primary sequence.

Carboxypeptidase A usually refers to the pancreatic exopeptidase that hydrolyzes peptide bonds of C-terminal residues with aromatic or aliphatic side-chains. Most scientists in the field now refer to this enzyme as CPA1, and to a related pancreatic carboxypeptidase as CPA2.

<span class="mw-page-title-main">Isomer</span> Chemical compounds with the same molecular formula but different atomic arrangements

In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism refers to the existence or possibility of isomers.

In epigenetics, proline isomerization is the effect that cis-trans isomerization of the amino acid proline has on the regulation of gene expression. Similar to aspartic acid, the amino acid proline has the rare property of being able to occupy both cis and trans isomers of its prolyl peptide bonds with ease. Peptidyl-prolyl isomerase, or PPIase, is an enzyme very commonly associated with proline isomerization due to their ability to catalyze the isomerization of prolines. PPIases are present in three types: cyclophilins, FK507-binding proteins, and the parvulins. PPIase enzymes catalyze the transition of proline between cis and trans isomers and are essential to the numerous biological functions controlled and affected by prolyl isomerization Without PPIases, prolyl peptide bonds will slowly switch between cis and trans isomers, a process that can lock proteins in a nonnative structure that can affect render the protein temporarily ineffective. Although this switch can occur on its own, PPIases are responsible for most isomerization of prolyl peptide bonds. The specific amino acid that precedes the prolyl peptide bond also can have an effect on which conformation the bond assumes. For instance, when an aromatic amino acid is bonded to a proline the bond is more favorable to the cis conformation. Cyclophilin A uses an "electrostatic handle" to pull proline into cis and trans formations. Most of these biological functions are affected by the isomerization of proline when one isomer interacts differently than the other, commonly causing an activation/deactivation relationship. As an amino acid, proline is present in many proteins. This aids in the multitude of effects that isomerization of proline can have in different biological mechanisms and functions.

References

1 2 3 "Nomenclature and Symbolism for Amino Acids and Peptides. Recommendations 1983". European Journal of Biochemistry. 138 (1): 9–37. 1984. doi: 10.1111/j.1432-1033.1984.tb07877.x . ISSN 0014-2956. PMID 6692818.
↑ Muller, P. (1994-01-01). "Glossary of terms used in physical organic chemistry (IUPAC Recommendations 1994)". Pure and Applied Chemistry. 66 (5): 1077–1184. doi: 10.1351/pac199466051077 . ISSN 1365-3075. S2CID 195819485.
↑ Watson, James; Hopkins, Nancy; Roberts, Jeffrey; Agetsinger Steitz, Joan; Weiner, Alan (1987) [1965]. Molecualar Biology of the Gene (hardcover) (Fourth ed.). Menlo Park, CA: The Benjamin/Cummings Publishing Company, Inc. p. 168. ISBN 978-0-8053-9614-0.
↑ Miller B. R.; Gulick A. M. (2016). "Structural Biology of Nonribosomal Peptide Synthetases". Nonribosomal Peptide and Polyketide Biosynthesis. Methods in Molecular Biology. Vol. 1401. pp. 3–29. doi:10.1007/978-1-4939-3375-4_1. ISBN 978-1-4939-3373-0. PMC 4760355 . PMID 26831698.
↑ Griffiths A. J.; Miller J. H.; Suzuki D. T.; Lewontin R. C.; Gelbart W. M. (2000). Protein synthesis (7th ed.). New York: W. H. Freeman. ISBN 978-0-7167-3520-5.{{cite book}}: |journal= ignored (help)
↑ Walton J. D.; Hallen-Adams H. E.; Luo H. (2010). "Ribosomal biosynthesis of the cyclic peptide toxins of Amanita mushrooms". Biopolymers. 94 (5): 659–664. doi:10.1002/bip.21416. PMC 4001729 . PMID 20564017.
↑ Wu G.; Fang Y. Z.; Yang S.; Lupton J. R.; Turner N. D. (March 2004). "Glutathione metabolism and its implications for health". The Journal of Nutrition. 134 (3): 489–492. doi: 10.1093/jn/134.3.489 . PMID 14988435.
↑ Meister A. (November 1988). "Glutathione metabolism and its selective modification". The Journal of Biological Chemistry. 263 (33): 17205–17208. doi: 10.1016/S0021-9258(19)77815-6 . PMID 3053703.
↑ Martin R. B. (December 1998). "Free energies and equilibria of peptide bond hydrolysis and formation". Biopolymers. 45 (5): 351–353. doi:10.1002/(SICI)1097-0282(19980415)45:5<351::AID-BIP3>3.0.CO;2-K.
↑ Radzicka, Anna; Wolfenden, Richard (1996-01-01). "Rates of Uncatalyzed Peptide Bond Hydrolysis in Neutral Solution and the Transition State Affinities of Proteases". Journal of the American Chemical Society. 118 (26): 6105–6109. doi:10.1021/ja954077c. ISSN 0002-7863.
↑ Sandberg A.; Johansson D. G.; Macao B.; Härd T. (April 2008). "SEA domain autoproteolysis accelerated by conformational strain: energetic aspects". Journal of Molecular Biology. 377 (4): 1117–1129. doi:10.1016/j.jmb.2008.01.051. PMID 18308334.
↑ Goldfarb A. R.; Saidel L. J.; Mosovich E. (November 1951). "The ultraviolet absorption spectra of proteins". The Journal of Biological Chemistry. 193 (1): 397–404. doi: 10.1016/S0021-9258(19)52465-6 . PMID 14907727.

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[:0-1] 1 2 3 "Nomenclature and Symbolism for Amino Acids and Peptides. Recommendations 1983". European Journal of Biochemistry. 138 (1): 9–37. 1984. doi: 10.1111/j.1432-1033.1984.tb07877.x . ISSN 0014-2956. PMID 6692818.

[2] Muller, P. (1994-01-01). "Glossary of terms used in physical organic chemistry (IUPAC Recommendations 1994)". Pure and Applied Chemistry. 66 (5): 1077–1184. doi: 10.1351/pac199466051077 . ISSN 1365-3075. S2CID 195819485.

[3] Watson, James; Hopkins, Nancy; Roberts, Jeffrey; Agetsinger Steitz, Joan; Weiner, Alan (1987) [1965]. Molecualar Biology of the Gene (hardcover) (Fourth ed.). Menlo Park, CA: The Benjamin/Cummings Publishing Company, Inc. p. 168. ISBN 978-0-8053-9614-0.

[4] Miller B. R.; Gulick A. M. (2016). "Structural Biology of Nonribosomal Peptide Synthetases". Nonribosomal Peptide and Polyketide Biosynthesis. Methods in Molecular Biology. Vol. 1401. pp. 3–29. doi:10.1007/978-1-4939-3375-4_1. ISBN 978-1-4939-3373-0. PMC 4760355 . PMID 26831698.

[5] Griffiths A. J.; Miller J. H.; Suzuki D. T.; Lewontin R. C.; Gelbart W. M. (2000). Protein synthesis (7th ed.). New York: W. H. Freeman. ISBN 978-0-7167-3520-5.{{cite book}}: |journal= ignored (help)

[6] Walton J. D.; Hallen-Adams H. E.; Luo H. (2010). "Ribosomal biosynthesis of the cyclic peptide toxins of Amanita mushrooms". Biopolymers. 94 (5): 659–664. doi:10.1002/bip.21416. PMC 4001729 . PMID 20564017.

[7] Wu G.; Fang Y. Z.; Yang S.; Lupton J. R.; Turner N. D. (March 2004). "Glutathione metabolism and its implications for health". The Journal of Nutrition. 134 (3): 489–492. doi: 10.1093/jn/134.3.489 . PMID 14988435.

[8] Meister A. (November 1988). "Glutathione metabolism and its selective modification". The Journal of Biological Chemistry. 263 (33): 17205–17208. doi: 10.1016/S0021-9258(19)77815-6 . PMID 3053703.

[9] Martin R. B. (December 1998). "Free energies and equilibria of peptide bond hydrolysis and formation". Biopolymers. 45 (5): 351–353. doi:10.1002/(SICI)1097-0282(19980415)45:5<351::AID-BIP3>3.0.CO;2-K.

[10] Radzicka, Anna; Wolfenden, Richard (1996-01-01). "Rates of Uncatalyzed Peptide Bond Hydrolysis in Neutral Solution and the Transition State Affinities of Proteases". Journal of the American Chemical Society. 118 (26): 6105–6109. doi:10.1021/ja954077c. ISSN 0002-7863.

[pmid18308334-11] Sandberg A.; Johansson D. G.; Macao B.; Härd T. (April 2008). "SEA domain autoproteolysis accelerated by conformational strain: energetic aspects". Journal of Molecular Biology. 377 (4): 1117–1129. doi:10.1016/j.jmb.2008.01.051. PMID 18308334.

[pmid14907727-12] Goldfarb A. R.; Saidel L. J.; Mosovich E. (November 1951). "The ultraviolet absorption spectra of proteins". The Journal of Biological Chemistry. 193 (1): 397–404. doi: 10.1016/S0021-9258(19)52465-6 . PMID 14907727.

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