Peptide bond

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]

It can also be called a eupeptide bond^[1] to distinguish it from an isopeptide bond, which is another type of amide bond between two amino acids.

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Let's talk about the peptide bond. Now, proteins are formed from the folding of polypeptide chains. And polypeptide chains are formed by linking amino acids together. And these links are called peptide bonds. So before we can work our way up to the fully-formed and functional protein, we have to start at the very beginning by forming a peptide bond between the first two amino acids. So let's review the structure of an amino acid really quickly. Here we have our backbone. We have our amino group, our carboxylic acid group. Here is our alpha carbon. And then, the r represents our side chain. Now, peptide bonds are formed by the nucleophilic addition-elimination reaction between the carboxyl group of one amino acid and the amino group of another amino acid. So let me show you what that looks like here. Let's have another amino acid drawn right here. So the electron pair on the amino group of the second amino acid comes over to form a bond with the carbonyl carbon of the first amino acid. You give off a water molecule in the process, and then you get your newly-formed dipeptide. And here is our newly-formed peptide bond. Now, remember that a peptide bond is just an amide bond that is formed between two amino acids. And you should also make note of the fact that this bond is a rigid and planar bond that is stabilized by resonance delocalization of this nitrogen's electrons to this carbonyl oxygen. So we can draw that out here. Remember that there is a lone pair of electrons on this nitrogen that can move here. And then, these electrons will move to this oxygen atom, which also has its own two lone pairs of electrons. So it can also be represented like this. And we'll have the formation of a double bond here and then an extra lone pair on the oxygen atom. So as you can see, the peptide bond with this resonance delocalization of electrons has a lot of double bond character. And because of this double-bond-like character, the peptide bond is a very rigid and planar one. But don't confuse this with thinking that an entire polypeptide chain would be a rigid-like structure because-- even though there isn't much rotation about the peptide bond-- you do still have for free rotation about these alpha carbon atoms here. So now, here we can see we have a dipeptide. And if we kept adding amino acids along in a chain here, we would have a polypeptide. Now, if we take a closer look at the backbone of this chain, we can see that there is a pattern formed by the atoms that form this backbone. And here, you have a nitrogen atom, the alpha carbon, and a carbonyl carbon. And then, it repeats with the nitrogen atom, the alpha carbon, and a carbonyl carbon. And you get a pattern that looks like this. And each time you add a new amino acid, the pattern just repeats. So that, whatever length of your polypeptide chain, you always start out with a nitrogen atom and you always end with the carbonyl carbon. And so this end of the backbone of the polypeptide chain is called the amino or N terminal. And then, this end of a polypeptide chain is called the C terminal. And then once, within a polypeptide chain, each amino acid is called a residue. So that's the formation of a peptide bond and a polypeptide chain. So now how do we go about breaking this peptide bond to get two amino acids again? Let's give ourselves just a little bit more room here to work, and we'll redraw a bond between two amino acids as a peptide bond here. And remember that here is our peptide bond-- just to highlight it for you. And we can break this peptide bond in a process called hydrolysis. So if we have hydrolysis of this peptide bond, then we go back to forming two free amino acids. The hydrolysis of a peptide bond is helped along by two common means, and those two means are with the help of strong acids or with proteolytic enzymes. So when we use strong acids, we call this acid hydrolysis. And acid hydrolysis, when combined with heat, is a nonspecific way of cleaving peptide bonds. So say you have a long polypeptide chain. And then, you throw this polypeptide into a pot with some strong acid, and then turn up the stove to add a little heat. Then, you would just end up with a jumbled up mix of amino acids as each of the peptide bonds gets cleaved. So the other way of cleaving a peptide bond is with proteolysis. And proteolysis is a specific cleavage of the peptide bond with the help of a special protein, an enzyme called a protease. So unlike acid hydrolysis, proteolytic cleavage is a specific process. And you can choose which peptide bonds you cleave because proteases are pretty picky about where they will cut, and many of them will only cleave peptide bonds between certain specific amino acids. One example of this is with the protease trypsin. Trypsin only cleaves on the carboxyl side of basic amino acids, like arginine and lysine. And interestingly, this is the same enzyme that is produced by our pancreas to help us digest food. So now say we have the following polypeptide chain-- and it can be any old, arbitrary polypeptide chain-- and say we add trypsin to the environment that this polypeptide chain is in. And here I'm just representing the amino acids as their abbreviated form. Now with the addition of trypsin, where would this polypeptide chain be cleaved? Well, remember that trypsin cleaves on the C terminus of arginine and lysine. Here we have an arginine, and this would be considered the C terminal of arginine, since it's closest to the C terminal of the polypeptide chain. So we would get cleavage here. And then, likewise, we would have cleavage on the C terminal of this lysine residue here. And so with this particular polypeptide chain, you would end up with three different fragments after the addition of trypsin since it cleaves in these very specific places. And there are many other examples of specific proteases that cleave in at certain parts of polypeptide chains. And you probably don't really need to memorize which proteases cleave after which amino acids, but you should probably remember that they are just specific means of breaking a peptide bond-- unlike acid hydrolysis over here, which is a very nonspecific way of cleaving a peptide bond.

Synthesis

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)

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.

References

^ ^a ^b ^c "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.

Chemical bonds

Intramolecular
(strong)

Covalent	Electron deficiency 3c–2e 4c–2e 8c–2e Hypervalence 3c–4e Agostic Bent Coordinate (dipolar) Pi backbond Metal–ligand multiple bond Charge-shift Hapticity Conjugation Hyperconjugation Aromaticity homo bicyclo
Metallic	Metal aromaticity
Ionic

Intermolecular
(weak)

Van der Waals forces	London dispersion
Hydrogen	Low-barrier Resonance-assisted Symmetric Dihydrogen bonds C–H···O interaction
Noncovalent other	Mechanical Halogen Chalcogen Metallophilic (aurophilic) Intercalation Stacking Cation–pi Anion–pi Salt bridge

Bond cleavage

Electron counting rules

Protein primary structure and posttranslational modifications

General

N terminus

C terminus

Single specific AAs

Serine/Threonine	Phosphorylation Dephosphorylation Glycosylation O-GlcNAc ADP-ribosylation
Tyrosine	Phosphorylation Dephosphorylation ADP-ribosylation Sulfation Porphyrin ring linkage Adenylylation Flavin linkage Topaquinone (TPQ) formation Detyrosination
Cysteine	Palmitoylation Prenylation
Aspartate	Succinimide formation ADP-ribosylation
Glutamate	Carboxylation ADP-ribosylation Methylation Polyglutamylation Polyglycylation
Asparagine	Deamidation Glycosylation
Glutamine	Transglutamination
Lysine	Methylation Acetylation Acylation Adenylylation Hydroxylation Ubiquitination Sumoylation ADP-ribosylation Deamination Oxidative deamination to aldehyde O-glycosylation Imine formation Glycation Carbamylation Succinylation Lactylation Propionylation Butyrylation
Arginine	Citrullination Methylation ADP-ribosylation
Proline	Hydroxylation
Histidine	Diphthamide formation Adenylylation
Tryptophan	C-mannosylation

Crosslinks between two AAs

Cysteine–Cysteine	Disulfide bond ADP-ribosylation
Methionine–Hydroxylysine	Sulfilimine bond
Lysine–Tyrosine	Lysine tyrosylquinone (LTQ) formation
Tryptophan–Tryptophan	Tryptophan tryptophylquinone (TTQ) formation

Crosslinks between three AAs

Serine–Tyrosine–Glycine	p-Hydroxybenzylidene-imidazolinone (HBI) formation (chromophore)
Histidine–Tyrosine–Glycine	4-(p-hydroxybenzylidene)-5-imidazolinone (HBI) formation (chromophore)
Alanine–Serine–Glycine	Methylidene-imidazolone (MIO) formation

Crosslinks between four AAs

Allysine–Allysine–Allysine–Lysine	Desmosine

This page was last edited on 27 April 2024, at 05:15

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