''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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

methionine in which a formyl group has been added to the

amino In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...

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 critical ...

from

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

l and

organellar In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...

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

chloroplast A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it ...

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 Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...

s, where eukaryotic

nuclear gene A nuclear gene is a gene whose physical DNA nucleotide sequence is located in the cell nucleus of a eukaryote. The term is used to distinguish nuclear genes from genes found in mitochondria or chloroplasts. The vast majority of genes in eukaryot ...

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. 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

fMet is a starting residue in the synthesis of

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respondi ...

in bacteria, and, consequently, is located at the ''N''-terminus of the growing

polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides ...

. fMet is delivered to the ribosome (30S) - mRNA complex by a specialized

tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino a ...

(tRNA^fMet) which has a 3'-UAC-5'

anticodon Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino a ...

that is capable of binding with the 5'-AUG-3' start

codon The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...

located on the

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

. fMet is thus coded by the same

as methionine; however, AUG is also the

translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...

initiation codon. When the codon is used for initiation, fMet is used instead of methionine, thereby forming the first amino acid as the

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

chain is synthesized. When the same codon appears later in the mRNA, normal methionine is used. Many organisms use variations of this basic mechanism. The addition of the formyl group to methionine is catalyzed by the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

methionyl-tRNA formyltransferase. 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 ...

. Methionine itself can be loaded either onto tRNA^fMet or tRNA^Met. However, transformylase will catalyze the addition of the formyl group to methionine only if methionine has been loaded onto tRNA^fMet, not onto tRNA^Met. The ''N''-terminal fMet is removed from majority of proteins, both host and recombinant, by a sequence of two enzymatic reactions. First,

peptide deformylase In enzymology, a peptide deformylase () is an enzyme that catalyzes the chemical reaction :H2O + formyl-L-methionyl peptide \rightleftharpoons methionyl peptide + formate Thus, the two substrates of this enzyme are formyl-L-methionyl peptide ...

deformylates it, converting the residue back to a normal methionine. Then

methionine aminopeptidase Methionyl aminopeptidase (, ''methionine aminopeptidase'', ''peptidase M'', ''L-methionine aminopeptidase'', ''MAP'') is an enzyme. This enzyme catalyses the following chemical reaction : Release of N-terminal amino acids, preferentially methi ...

(MAP) removes the residue from the chain. The mitochondria of

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...

cells, including those of humans, and the

chloroplasts A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it i ...

plant Plants are predominantly Photosynthesis, photosynthetic eukaryotes of the Kingdom (biology), kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all curr ...

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 pos ...

Relevance to immunology

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

eukaryotes Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...

(other than in bacterially derived organelles), the

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

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, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mul ...

and then stimulate microbicidal activities such as

phagocytosis Phagocytosis () is the process by which a 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 phagocytosis i ...

. 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, often just called peptide ('' oligo-'', "a few"), consists of two to twenty amino acids and can include dipeptides, tripeptides, tetrapeptides, and pentapeptides. Some of the major classes of naturally occurring oligopeptides in ...

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 The danger model of the immune system proposes that it differentiates between components that are capable of causing damage, rather that distinguishing between self and non-self. History of immunologic models The first major immunologic model wa ...

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 p ...

(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 i ...

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

innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is th ...

; they function to initiate acute

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

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- Amino acid derivatives Sulfur amino acids Formamides

Function in protein synthesis

Relevance to immunology

See also

References

External links