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Post Translational Modification
Post-translational modification of insulin. At the top, the ribosome translates a mRNA sequence into a protein, insulin, and passes the protein through the endoplasmic reticulum, where it is cut, folded and held in shape by disulfide (-S-S-) bonds. Then the protein passes through the golgi apparatus, where it is packaged into a vesicle. In the vesicle, more parts are cut off, and it turns into mature insulin.
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 hormoneinsulin 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.
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.
Other proteins or peptides
ISGylation, the covalent linkage to the ISG15 protein (Interferon-Stimulated Gene 15)
In 2011, statistics of each post-translational modification experimentally and putatively detected have been compiled using proteome-wide information from the Swiss-Prot database. The 10 most common experimentally found modifications were as follows:
Flowchart of the process and the data sources to predict PTMs.
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.
List of resources
PhosphoSitePlus - A database of comprehensive information and tools for the study of mammalian protein post-translational modification
ProteomeScout - A database of proteins and post-translational modifications experimentally
Human Protein Reference Database - A database for different modifications and understand different proteins, their class, and function/process related to disease causing proteins
PROSITE - A database of Consensus patterns for many types of PTM's including sites
Cleavage of polypeptide chains as crucial for lectin specificity
A major feature of addiction is its persistence. The addictive phenotype can be lifelong, with drug craving and relapse occurring even after decades of abstinence. Post-translational modifications consisting of epigenetic alterations of histone protein tails in specific regions of the brain appear to be crucial to the molecular basis of addictions. Once particular post-translational epigenetic modifications occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.
About 7% of the US population is addicted to alcohol. In rats exposed to alcohol for up to 5 days, there was an increase in the post-translational modification of histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol.
Cocaine addiction occurs in about 0.5% of the US population. Repeated cocaine administration in mice induces post-translational modifications including hyperacetylation of histone 3 (H3) or histone 4 (H4) at 1,696 genes in one brain reward region [the nucleus accumbens] and deacetylation at 206 genes. At least 45 genes, shown in previous studies to be upregulated in the nucleus accumbens of mice after chronic cocaine exposure, were found to be associated with post-translational hyperacetylation of histone H3 or histone H4. Many of these individual genes are directly related to aspects of addiction associated with cocaine exposure.
In 2013, 22.7 million persons aged 12 or older in the United States needed treatment for an illicit drug or alcohol use problem (8.6 percent of persons aged 12 or older).
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^ abSubstance Abuse and Mental Health Services Administration, Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2014
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^D'Addario C, Caputi FF, Ekström TJ, Di Benedetto M, Maccarrone M, Romualdi P, Candeletti S (February 2013). "Ethanol induces epigenetic modulation of prodynorphin and pronociceptin gene expression in the rat amygdala complex". Journal of Molecular Neuroscience. 49 (2): 312-9. doi:10.1007/s12031-012-9829-y. PMID22684622.