-N-Formylmethionine_V.1.svg) | |
| Names | |
|---|---|
| IUPAC name N-Formylmethionine | |
| Systematic IUPAC name 2-Formamido-4-methylsulfanylbutanoic acid | |
| Other names 2-Formylamino-4-methylsulfanyl-butyric acid; Formylmethionine;N-Formyl(methyl)homocysteine | |
| Identifiers | |
3D model (JSmol) | |
| Abbreviations | fMet |
| ChEBI | |
| ChemSpider | |
| EC Number |
|
| UNII | |
| |
| |
| Properties | |
| C6H11NO3S | |
| Molar mass | 177.22 g/mol |
| Hazards | |
| GHS labelling:[1] | |
 | |
| Warning | |
| H319 | |
| P264+P265,P280,P305+P351+P338,P337+P317 | |
| Supplementary data page | |
| N-Formylmethionine (data page) | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
N-Formylmethionine (fMet,[2] HCO-Met,[3] For-Met[3]) is a derivative of theamino acidmethionine in which aformyl group has been added to theamino group. It is specifically used for initiation ofprotein synthesis frombacterial andorganellar genes, and may be removedpost-translationally.
fMet plays a crucial part in the protein synthesis of bacteria,mitochondria andchloroplasts. It is not used incytosolic protein synthesis ofeukaryotes, where eukaryoticnuclear genes aretranslated. It is also not used byArchaea. In the human body, fMet is recognized by the immune system as foreign material, or as an alarm signal released by damaged cells, and stimulates the body to fight against potential infection.
fMet is required for efficient initiation of protein synthesis in most groups of bacteria. The 30S ribosome–mRNA complex specifically recruits tRNAs with a formylated amino acid – tRNAfMet attached to fMet in the natural case.[4]
Because the fMet directs initiation,proteins in bacteria start (N-terminus) with a fMet residue instead of a methionine. Further occurrences of the "AUG" codon will result in a normal methionine, because a normal "elongating" tRNAMet is used.[4]
The addition of the formyl group to methionine is catalyzed by theenzymemethionyl-tRNA formyltransferase. This modification is done after methionine has been loaded onto tRNAfMet byaminoacyl-tRNA synthetase. Methionine itself can be loaded either onto tRNAfMet or tRNAMet. However, formyltransferase will catalyze the addition of the formyl group to methionine only if methionine has been loaded onto tRNAfMet, not onto tRNAMet. This is because the formyltransferase recognizes specific features of tRNAfMet.[4]
Themitochondria ofeukaryotic cells, including those of humans, and thechloroplasts ofplant cells also initiate protein synthesis with fMet. Given that mitochondria and chloroplasts have this initial protein synthesis with fMet in common with bacteria, this has been cited as evidence for theendosymbiotic theory.[5]
Unexpectedly, formyltransferase can also act upon eukaryotic initiator tRNA in living yeast cells. Even under normal conditions, the nuclear-encoded formyltransferase is not completely imported into mitochondria; even more is left in the cytosol under stress. These cytosolic formyltransferase produce fMet-tRNAi, which can be used by cytosolic ribosomes to produce proteins with a N-terminal fMet. These proteins are targeted for degradation by specific processes in the cell.[6]
TheN-terminal fMet is removed from majority of proteins, both host and recombinant, by a sequence of two enzymatic reactions. First,peptide deformylase (PDF) deformylates it, converting the residue back to a normal methionine. Thenmethionine aminopeptidase (MetAP) removes the residue from the chain.[7] MetAP only acts on proteins with second-position residues that are less bulky than valine.[8]
TheN-terminal fMet, if not removed by PDF, seems to act as adegron, a signal for protein degradation.[8]
The formyl group is not strictly required for initiation. Bacteria with their formyltransferase knocked out, which prevents Met-tRNAfMet (i.e. methionine loaded onto tRNAfMet) from turning into fMet-tRNAfMet, can have varying degrees of residual ability to start protein synthesis.E. coli,S. pneumoniae andB. subtilis show almost no remaining translation ability, whileP. aeruginosa,S. aureus, H. influenzae, and possiblyS. faecalis still churn out plenty of protein. InP. aeruginosa, this ability is facilitated bybacterial initiation factor 2, which can carry both Met-tRNAfMet and fMet-tRNAfMet to the ribosome.[9]
Because fMet is present in proteins made by bacteria but not in those made byeukaryotes (other than in bacterially derived organelles), theimmune system might use it to help distinguish self from non-self.Polymorphonuclear cells can bind proteins starting with fMet, and use them to initiate the attraction of circulating bloodleukocytes and then stimulate microbicidal activities such asphagocytosis.[10][11][12]
Since fMet is present in proteins made by mitochondria and chloroplasts, more recent theories do not see it as a molecule that the immune system can use to distinguish self from non-self.[13] Instead, fMet-containingoligopeptides and proteins appear to be released by the mitochondria of damaged tissues as well as by damaged bacteria, and can thus qualify as an "alarm" signal, as discussed in theDanger model of immunity. The prototypical fMet-containing oligopeptide isN-formylmethionine-leucyl-phenylalanine (FMLP) which activates leukocytes and other cell types by binding with these cells'formyl peptide receptor 1 (FPR1) andformyl peptide receptor 2 (FPR2)G protein coupled receptors (see alsoformyl peptide receptor 3). Acting through these receptors, the fMet-containing oligopeptides and proteins are part of theinnate immune system; they function to initiate acuteinflammation responses but under other conditions function to inhibit and resolve these responses. fMet-containing oligopeptides and proteins also function in other physiological and pathological responses.
{{cite book}}: CS1 maint: location missing publisher (link)