''N''-Formylmethionine (fMet, HCO-Met,
/ref> For-Met) is a derivative of the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...

in which a formyl group has been added to the

amino In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

group. It is specifically used for initiation of

protein synthesis Protein biosynthesis, or protein synthesis, is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critica ...

from

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

l and organellar genes, and may be removed post-translationally. fMet plays a crucial part in the protein synthesis of bacteria,

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

and

chloroplast A chloroplast () is a type of membrane-bound organelle, organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. Chloroplasts have a high concentration of chlorophyll pigments which captur ...

s. It is not used in

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

ic protein synthesis of

eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

s, where eukaryotic

nuclear gene A nuclear gene is a gene whose DNA sequence is located within the cell nucleus of a eukaryotic organism. These genes are distinguished from extranuclear genes, such as those found in the genomes of mitochondria and chloroplasts, which reside ou ...

s are

translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...

. It is also not used by

Archaea Archaea ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...

. 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.

Function in protein synthesis

Translation

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 – tRNA^fMet attached to fMet in the natural case. Because the fMet directs initiation,

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s 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" tRNA^Met is used. The addition of the formyl group to methionine is catalyzed by the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

methionyl-tRNA formyltransferase In enzymology, a methionyl-tRNA formyltransferase () is an enzyme that catalyzes the chemical reaction : 10-formyltetrahydrofolate + L-methionyl-tRNAfMet + H2O \rightleftharpoons tetrahydrofolate + ''N''-formylmethionyl-tRNAfMet This enzyme b ...

. This modification is done after methionine has been loaded onto tRNA^fMet by

aminoacyl-tRNA synthetase An aminoacyl-tRNA synthetase (aaRS or ARS), also called tRNA-ligase, is an enzyme that attaches the appropriate amino acid onto its corresponding tRNA. It does so by catalyzing the transesterification of a specific cognate amino acid or its pre ...

. Methionine itself can be loaded either onto tRNA^fMet or tRNA^Met. However, formyltransferase will catalyze the addition of the formyl group to methionine only if methionine has been loaded onto tRNA^fMet, not onto tRNA^Met. This is because the formyltransferase recognizes specific features of tRNA^fMet. The

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

cells, including those of humans, and the

chloroplasts A chloroplast () is a type of membrane-bound organelle, organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. Chloroplasts have a high concentration of chlorophyll pigments which captur ...

plant Plants are the eukaryotes that form the Kingdom (biology), kingdom Plantae; they are predominantly Photosynthesis, photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with c ...

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 the

endosymbiotic theory Symbiogenesis (endosymbiotic theory, or serial endosymbiotic theory) is the leading evolutionary theory of the origin of eukaryotic cells from prokaryotic organisms. The theory holds that mitochondria, plastids such as chloroplasts, and possibl ...

. 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-tRNA_i, 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.

Further processing

The ''N''-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. Then methionine aminopeptidase (MetAP) removes the residue from the chain. MetAP only acts on proteins with second-position residues that are less bulky than valine. The ''N''-terminal fMet, if not removed by PDF, seems to act as a

degron A degron is a portion of a protein that is important in regulation of protein degradation rates. Known degrons include short amino acid sequences, structural motifs and exposed amino acids (often lysine or arginine) located anywhere in the protei ...

, a signal for protein degradation.

Variation

The formyl group is not strictly required for initiation. Bacteria with their formyltransferase knocked out, which prevents Met-tRNA^fMet (i.e. methionine loaded onto tRNA^fMet) from turning into fMet-tRNA^fMet, can have varying degrees of residual ability to start protein synthesis. ''E. coli'', ''S. pneumoniae'' and ''B. subtilis'' show almost no remaining translation ability, while ''P. aeruginosa'', ''S. aureus'','' H. influenzae'', and possibly ''S. faecalis'' still churn out plenty of protein. In ''P. aeruginosa'', this ability is facilitated by

bacterial initiation factor 2 Bacterial initiation factor-2 is a bacterial initiation factor. IF2 binds to an initiator tRNA and controls the entry of tRNA onto the ribosome. IF2, bound to GTP, binds to the 30S P site. After associating with the 30S subunit, fMet-tRNAf bi ...

, which can carry both Met-tRNA^fMet and fMet-tRNA^fMet to the ribosome.

Relevance to immunology

Because fMet is present in proteins made by bacteria but not in those made by

eukaryotes The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of ...

(other than in bacterially derived organelles), the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

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 blood

leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

and then stimulate microbicidal activities such as

phagocytosis Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...

. 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. Instead, fMet-containing

oligopeptide An oligopeptide ('' oligo-'', "a few"), is a peptide consisting of two to twenty amino acids, including dipeptides, tripeptides, tetrapeptides, and other polypeptides. Some of the major classes of naturally occurring oligopeptides include aerugi ...

s 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 the Danger model of immunity. The prototypical fMet-containing oligopeptide is ''N''-formylmethionine-leucyl-phenylalanine (FMLP) which activates leukocytes and other cell types by binding with these cells'

formyl peptide receptor 1 Formyl peptide receptor 1 (FPR1, FPR1 receptor, fMet-Leu-Phe receptor 1, FMLP receptor 1, or N-formylmethionyl-leucyl-phenylalanine receptor 1) is a cell surface receptor protein that in humans is encoded by the ''formyl peptide receptor 1'' ('' ...

(FPR1) and

formyl peptide receptor 2 N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the ''FPR2'' gene and is activated to regulate cell function ...

(FPR2)

G protein coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

(see also

formyl peptide receptor 3 N-formyl peptide receptor 3 (FPR3) is a receptor protein that in humans is encoded by the ''FPR3'' gene. Nomenclature note Confusingly, there are two nomenclatures for FPR receptors and their genes, the first one used, FPR, FPR1, and FPR2 and ...

). Acting through these receptors, the fMet-containing oligopeptides and proteins are part of the

innate immune system The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...

; they function to initiate acute

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

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.

References

External links

* {{DEFAULTSORT:Formylmethionine, N- Alpha-Amino acids Amino acid derivatives Sulfur amino acids Formamides Dicarboxylic acids