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Chemical changes in proteins following their translation from mRNA

In molecular biology, post translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones. Post translational modifications can occur on the amino acid side chains or at the protein's C or N termini. They can expand the chemical set of the 22 amino acids by changing an existing functional group or adding a new one such as phosphate. Phosphorylation is highly effective for controlling the enzyme activity and is the most common change after translation. Many eukaryotic and prokaryotic proteins also have carbohydrate molecules attached to them in a process called glycosylation, which can promote protein folding and improve stability as well as serving regulatory functions. Attachment of lipid molecules, known as lipidation, often targets a protein or part of a protein attached to the cell membrane. Other forms of post translational modification consist of cleaving peptide bonds, as in processing a propeptide to a mature form or removing the initiator methionine residue. The formation of disulfide bonds from cysteine residues may also be referred to as a post translational modification. For instance, the peptide hormone insulin is cut twice after disulfide bonds are formed, and a propeptide is removed from the middle of the chain; the resulting protein consists of two polypeptide chains connected by disulfide bonds. Some types of post translational modification are consequences of oxidative stress. Carbonylation is one example that targets the modified protein for degradation and can result in the formation of protein aggregates. Specific amino acid modifications can be used as biomarkers indicating oxidative damage. Sites that often undergo post translational modification are those that have a functional group that can serve as a nucleophile in the reaction: the hydroxyl groups of serine, threonine, and tyrosine; the amine forms of lysine, arginine, and histidine; the thiolate anion of cysteine; the carboxylates of aspartate and glutamate; and the N and C termini. In addition, although the amide of asparagine is a weak nucleophile, it can serve as an attachment point for glycans. Rarer modifications can occur at oxidized methionines and at some methylene groups in side chains. Post translational modification of proteins can be experimentally detected by a variety of techniques, including mass spectrometry, Eastern blotting, and Western blotting. Additional methods are provided in the #External links section.

biotinylation: covalent attachment of a biotin moiety using a biotinylation reagent, typically for the purpose of labeling a protein. carbamylation: the addition of Isocyanic acid to a protein's N terminus or the side chain of Lys or Cys residues, typically resulting from exposure to urea solutions. oxidation: addition of one or more Oxygen atoms to a susceptible side chain, principally of Met, Trp, His or Cys residues. Formation of disulfide bonds between Cys residues. pegylation: covalent attachment of polyethylene glycol (PEG) using a pegylation reagent, typically to the N terminus or the side chains of Lys residues. Pegylation is used to improve the efficacy of protein pharmaceuticals.

Some common post translational modifications to specific amino acid residues are shown below. Modifications occur on the side chain unless indicated otherwise. Amino Acid Abbrev. Modification Alanine Ala or A N acetylation (N terminus) Arginine Arg or R deimination to citrulline, methylation Asparagine Asn or N deamidation to Asp or iso(Asp), N linked glycosylation, spontaneous isopeptide bond formation Aspartic acid Asp or D isomerization to isoaspartic acid, spontaneous isopeptide bond formation Cysteine Cys or C disulfide bond formation, oxidation to sulfenic, sulfinic or sulfonic acid, palmitoylation, N acetylation (N terminus), S nitrosylation Glutamine Gln or Q cyclization to pyroglutamic acid (N terminus), deamidation to Glutamic acid or isopeptide bond formation to a lysine by a transglutaminase Glutamic acid Glu or E cyclization to Pyroglutamic acid (N terminus), gamma carboxylation Glycine Gly or G N Myristoylation (N terminus), N acetylation (N terminus) Histidine His or H Phosphorylation Isoleucine Ile or I Leucine Leu or L Lysine Lys or K acetylation, ubiquitylation, SUMOylation, methylation, hydroxylation leading to allysine, spontaneous isopeptide bond formation Methionine Met or M N acetylation (N terminus), N linked Ubiquitination, oxidation to sulfoxide or sulfone Phenylalanine Phe or F Proline Pro or P hydroxylation Serine Ser or S Phosphorylation, O linked glycosylation, N acetylation (N terminus) Threonine Thr or T Phosphorylation, O linked glycosylation, N acetylation (N terminus) Tryptophan Trp or W mono or di oxidation, formation of kynurenine, tryptophan tryptophylquinone Tyrosine Tyr or Y sulfation, phosphorylation Valine Val or V N acetylation (N terminus)

Protein sequences contain sequence motifs that are recognized by modifying enzymes, and which can be documented or predicted in PTM databases. With the large number of different modifications being discovered, there is a need to document this sort of information in databases. PTM information can be collected through experimental means or predicted from high quality, manually curated data. Numerous databases have been created, often with a focus on certain taxonomic groups (e. g. human proteins) or other features.