N-Formylmethionine-leucyl-phenylalanine: Difference between revisions

{{DISPLAYTITLE:''N''-Formylmethionine-leucyl-phenylalanine}}

| verifiedrevid = 428867069

| Name = ''N''-Formylmethionine leucyl-phenylalanine

| ImageFile = Chemotactic peptide.png

| ImageSize = 200px

| SystematicName = (2''S'')-2-{(2''S'')-2-[(2''S'')-2-Formamido-4-(methylsulfanyl)butanamido]-4-methylpentanamido}-3-phenylpropanoic acid

| OtherNames = Chemotactic peptide<br>F-Met-Leu-Phe<br><small>L</small>-Phenylalanine, ''N''-(''N''-(''N''-formyl-<small>L</small>-methionyl)-<small>L</small>-leucyl)-<ref>[http://cancerweb.ncl.ac.uk/cgi-bin/omd?n-formylmethionine+leucyl-phenylalanine n-formylmethionine leucyl-phenylalanine], Cancerweb</ref>

<br>fMLP

| Section1 = {{Chembox Identifiers

| IUPHAR_ligand = 1022

| InChI1 = 1/C15H22N2O3.C6H11NO3S/c1-10(2)8-12(16)14(18)17-13(15(19)20)9-11-6-4-3-5-7-11;1-11-3-2-5(6(9)10)7-4-8/h3-7,10,12-13H,8-9,16H2,1-2H3,(H,17,18)(H,19,20);4-5H,2-3H2,1H3,(H,7,8)(H,9,10)

| CASNo_Ref = {{cascite|correct|??}}

| PubChem=443295

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = LO6AVJ8RCE

| ChEBI = 53490

| SMILES = OC(=O)C(NC=O)CCSC.CC(C)CC(N)C(=O)NC(Cc1ccccc1)C(O)=O

| MeSHName=N-Formylmethionine+Leucyl-Phenylalanine

| Section2 = {{Chembox Properties

| C=21|H=31|N=3|O=5|S=1

| Appearance=

| Density=

| MeltingPt=

| BoilingPt=

| Solubility=

| Section3 = {{Chembox Hazards

| MainHazards=

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'''''N''-Formylmethionyl-leucyl-phenylalanine''' ('''fMLF''', '''fMLP''' or '''''N''-formyl-met-leu-phe''') is an ''N''-[[formylation|formylated]] [[tripeptide]] and sometimes simply referred to as '''chemotactic peptide''' is a potent [[polymorphonuclear leukocyte]] (PMN) [[chemotactic factor]] and is also a [[macrophage]] activator.<ref name="pmid10466071">{{cite journal | vauthors = Panaro MA, Mitolo V | title = Cellular responses to fMLF challenging: a mini-review | journal = Immunopharmacology and Immunotoxicology | volume = 21 | issue = 3 | pages = 397–419 | date = Aug 1999 | pmid = 10466071 | doi = 10.3109/08923979909007117 }}</ref>

fMLF is the prototypical representative of the ''N''-formylated [[oligopeptide]] family of chemotactic factors. These oligopeptides are known to be, or mimic the actions of, the ''N''-formyl oligopeptides that are (a) released by tissue bacteria, (b) attract and activate circulating blood leukocytes by binding to specific [[G protein coupled receptor]]s on these cells, and (c) thereby direct the inflammatory response to sites of bacterial invasion. fMLF is involved in the [[innate immunity]] mechanism for host defense against [[pathogen]]s.

fMLF led to the first discovery of a leukocyte receptor for a chemotactic factor, defined three different types of fMLF receptors that have complementary and/or opposing effects on inflammatory responses as well as many other activities, and helped define the stimulus-response coupling mechanisms by which diverse chemotactic factors and their G protein coupled receptors induce cellular function.

== Discovery ==

In 1887, [[Élie Metchnikoff]] observed that [[leukocytes]] isolated from the blood of various animals were attracted towards certain bacteria.<ref>{{cite journal | vauthors = Metchnikoff E | title = Sur la lutte des cellules de l'organisme contre l'invasion des microbes | journal = Ann. Inst. Pasteur | year = 1887 | volume = 1 | pages = 321 }}</ref> This attraction was soon proposed to be due to soluble elements released by the bacteria <ref>{{cite journal | vauthors = Grawitz P | title = unknown| journal = Virchows Adz. IIO | volume = I | year = 1887}}</ref> (see Harris<ref>{{cite journal | vauthors = Harris H | title = Role of chemotaxis in inflammation | journal = Physiological Reviews | volume = 34 | issue = 3 | pages = 529–62 | date = Jul 1954 | pmid = 13185754 | doi = 10.1152/physrev.1954.34.3.529 }}</ref> for a review of this area up to 1953). Peter Ward, Elmer Becker, Henry Showell, and colleagues showed that these elements were made by a variety of growing [[gram positive bacteria]] and [[gram negative bacteria]] and were of low [[molecular weight]], i.e. below 3600 [[Dalton (unit)]]s.<ref>{{cite journal | vauthors = Ward PA, Lepow IH, Newman LJ | title = Bacterial factors chemotactic for polymorphonuclear leukocytes | journal = The American Journal of Pathology | volume = 52 | issue = 4 | pages = 725–36 | date = Apr 1968 | pmid = 4384494 | pmc=2013377}}</ref><ref name="pmid1262785">{{cite journal | vauthors = Showell HJ, Freer RJ, Zigmond SH, Schiffmann E, Aswanikumar S, Corcoran B, Becker EL | title = The structure-activity relations of synthetic peptides as chemotactic factors and inducers of lysosomal secretion for neutrophils | journal = The Journal of Experimental Medicine | volume = 143 | issue = 5 | pages = 1154–69 | date = May 1976 | pmid = 1262785 | pmc = 2190180 | doi = 10.1084/jem.143.5.1154}}</ref><ref name="pmid4825785">{{cite journal | vauthors = Becker EL, Showell HJ | title = The ability of chemotactic factors to induce lysosomal enzyme release. II. The mechanism of release | journal = Journal of Immunology | volume = 112 | issue = 6 | pages = 2055–62 | date = Jun 1974 | doi = 10.4049/jimmunol.112.6.2055 | pmid = 4825785 | doi-access = free }}</ref> Further studies by Schiffmann and colleges found that cultures of growing [[Escherichia coli]] released oligopeptides of between 150 and 1500 daltons that appeared to have a free [[Carboxylic acid]] group but not a free [[Amine]] group.<ref>{{cite journal | vauthors = Schiffmann E, Showell HV, Corcoran BA, Ward PA, Smith E, Becker EL | title = The isolation and partial characterization of neutrophil chemotactic factors from Escherichia coli | journal = Journal of Immunology | volume = 114 | issue = 6 | pages = 1831–7 | date = Jun 1975 | doi = 10.4049/jimmunol.114.6.1831 | pmid = 165239 | s2cid = 22663271 | doi-access = free }}</ref>

Given these clues and knowledge that bacteria transcribe (see [[Transcription (genetics)]]) proteins starting with [[N-Formylmethionine|''N''-formylmethionine]] whereas eukaryotic cells mostly initiate protein synthesis with non-formylated methionine, Schiffmann, Corcoran, and Wahl theorized and then showed that ''N''-formyl-methionine and a series ''N''-formyl-methionyl dipeptides and tripeptides stimulated the [[chemotaxis]] of [[neutrophils]] isolated from rabbit peritoneal exudates as well as of macrophages isolated from guinea pig peritoneal exudates.<ref>{{cite journal | vauthors = Schiffmann E, Corcoran BA, Wahl SM | title = N-formylmethionyl peptides as chemoattractants for leucocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 72 | issue = 3 | pages = 1059–62 | date = Mar 1975 | pmid = 1093163 | doi=10.1073/pnas.72.3.1059 | pmc=432465| bibcode = 1975PNAS...72.1059S | doi-access = free }}</ref> In further studies of various ''N''-formylated oligopeptides, fMLF proved the most potent in stimulating rabbit neutrophil chemotaxis.<ref name = "pmid1262785"/> fMLF and a sampling of other, less potent, ''N''-formyl oligopeptides were then found to stimulate a wide array of rabbit neutrophil functions such as: the transient auto-aggregation of these cells in suspension<ref>{{cite journal | vauthors = O'Flaherty JT, Kreutzer DL, Ward PA | title = Neutrophil aggregation and swelling induced by chemotactic agents | journal = Journal of Immunology | volume = 119 | issue = 1 | pages = 232–9 | date = Jul 1977 | doi = 10.4049/jimmunol.119.1.232 | pmid = 874320 | s2cid = 36465249 }}</ref> and equally transient fall in circulating neutrophils when injected into rabbit veins (these responses result from an increase in neutrophil adhesiveness to each other and/or vascular endothelium);<ref>{{cite journal | vauthors = O'Flaherty JT, Showell HJ, Ward PA | title = Neutropenia induced by systemic infusion of chemotactic factors | journal = Journal of Immunology | volume = 118 | issue = 5 | pages = 1586–9 | date = May 1977 | doi = 10.4049/jimmunol.118.5.1586 | pmid = 858915 | s2cid = 32354288 }}</ref> the release (see [[degranulation]]) of intracellular granule-bound enzymes and other [[antimicrobial]] [[cytotoxic]] molecules; and the production and release of cytotoxic [[reactive oxygen species]] such as [[Superoxide]] and [[hydrogen peroxide]].<ref name = "pmid1262785"/><ref>{{cite journal | vauthors = Becker EL, Sigman M, Oliver JM | title = Superoxide production induced in rabbit polymorphonuclear leukocytes by synthetic chemotactic peptides and A23187 | journal = The American Journal of Pathology | volume = 95 | issue = 1 | pages = 81–97 | date = Apr 1979 | pmid = 219701 | pmc=2042294}}</ref> All of these responses are part of the [[innate immune system]]s initial line of defense against bacterial invasions.

Follow-up studies found that the genes of mitochondria and chloroplasts organelles of [[Eukaryote]] cells, including those of humans, which, unlike nuclear genes, code for ''N''-formyl-methionine proteins, release ''N''-formyl-methionyl containing peptides with chemotactic activities that exactly mimic those of fMLF chemotaxis<ref name=":0">{{cite journal | vauthors = Carp H | title = Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils | journal = The Journal of Experimental Medicine | volume = 155 | issue = 1 | pages = 264–75 | date = Jan 1982 | pmid = 6274994 | doi=10.1084/jem.155.1.264 | pmc=2186576}}</ref> These organelle-derived formylated peptides are true analogs of fMLF that operate through fMLF receptors to recruit circulating blood leukocytes to and thereby initiate inflammation responses at sites of cell damage and tissue destruction not caused by bacteria.<ref name="pmid25791526">{{cite journal | vauthors = Dorward DA, Lucas CD, Chapman GB, Haslett C, Dhaliwal K, Rossi AG | title = The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation | journal = The American Journal of Pathology | volume = 185 | issue = 5 | pages = 1172–84 | date = May 2015 | pmid = 25791526 | doi = 10.1016/j.ajpath.2015.01.020 | pmc=4419282}}</ref> Thus, fMLF can act as a [[Find-me signals|find-me signal]], released by dead or dying cells to attract [[Phagocyte|phagocytes]] to those cells, so that the phagocytes [[Phagocytosis|phagocytose]] the dead or dying cells, thereby clearing up the damage.<ref name=":0" /> fMLF and other ''N''-formylated oligopeptides were found to be similarly active in human neutrophils.<ref>{{cite journal | vauthors = O'Flaherty JT, Kreutzer DL, Ward PA | title = Chemotactic factor influences on the aggregation, swelling, and foreign surface adhesiveness of human leukocytes | journal = The American Journal of Pathology | volume = 90 | issue = 3 | pages = 537–50 | date = Mar 1978 | pmid = 564610 | pmc=2018255}}</ref><ref>{{cite journal | vauthors = Lehmeyer JE, Snyderman R, Johnston RB | title = Stimulation of neutrophil oxidative metabolism by chemotactic peptides: influence of calcium ion concentration and cytochalasin B and comparison with stimulation by phorbol myristate acetate | journal = Blood | volume = 54 | issue = 1 | pages = 35–45 | date = Jul 1979 | doi = 10.1182/blood.V54.1.35.35 | pmid = 444673 | doi-access = free }}</ref> The high degree of structural specificity of a broad series of formylated peptides in stimulating these neutrophil responses, the specific binding of ''N''-formylated oligopeptides to neutrophils with affinities that paralleled their stimulating potencies,<ref>{{cite journal | vauthors = Aswanikumar S, Corcoran B, Schiffmann E, Day AR, Freer RJ, Showell HJ, Becker EL | title = Demonstration of a receptor on rabbit neutrophils for chemotactic peptides | journal = Biochemical and Biophysical Research Communications | volume = 74 | issue = 2 | pages = 810–7 | date = Jan 1977 | pmid = 836328 | doi=10.1016/0006-291x(77)90375-8}}</ref> the ability of ''t''-carbobenzoxy-phenylalanyl-methionine to bind to but not stimulate neutrophils and thereby to block the neutrophil binding and stimulating activity of N-formylated oligopeptides,<ref>{{cite book | author1 = E. Schiffmann | author2 = B. A. Corcoran | author3 = A. Aswanikumar. | year = 1978 | chapter = Molecular events in the response of neutrophils to synthetic N-formylmethionine chemotactic peptides. | title = Leukocyte chemotaxis: Methodology, physiology, clinical implications |editor1=J. A. Gallin |editor2=P. G. Quie | publisher = Raven Press | location = New York.}}</ref><ref>{{cite journal | vauthors = O'Flaherty JT, Showell HJ, Kreutzer DL, Ward PA, Becker EL | title = Inhibition of in vivo and in vitro neutrophil responses to chemotactic factors by a competitive antagonist | journal = Journal of Immunology | volume = 120 | issue = 4 | pages = 1326–32 | date = Apr 1978 | doi = 10.4049/jimmunol.120.4.1326 | pmid = 641351 | s2cid = 42477532 | doi-access = free }}</ref> and the ability of the formylated oligopeptides to desensitize (i.e. render unresponsive) neutrophil functional responses to themselves but have no or a lesser ability to desensitize to a range of other chemotactic stimuli<ref>{{cite journal | vauthors = O'Flaherty JT, Kreutzer DL, Showell HS, Becker EL, Ward PA | title = Desensitization of the neutrophil aggregation response to chemotactic factors | journal = The American Journal of Pathology | volume = 93 | issue = 3 | pages = 693–706 | date = Dec 1978 | pmid = 717543 | pmc=2018345}}</ref><ref>{{cite journal | vauthors = O'Flaherty JT, Kreutzer DL, Showell HJ, Vitkauskas G, Becker EL, Ward PA | title = Selective neutrophil desensitization to chemotactic factors | journal = The Journal of Cell Biology | volume = 80 | issue = 3 | pages = 564–72 | date = Mar 1979 | pmid = 457760 | doi=10.1083/jcb.80.3.564 | pmc=2110355}}</ref> provided strong suggestive evidence that the formylated peptides acted on cells through a common, dedicated receptor system that differed from other chemotactic factor receptors.

== Receptors ==

The studies cited above lead to the eventual [[cloning]] of the human [[Formyl peptide receptor 1]], a [[G protein coupled receptor]] that binds fMLF and other formylated oligopeptides to mediate their stimulatory actions on human and rabbit neutrophils. Subsequently, [[Formyl peptide receptor 2]] and [[Formyl peptide receptor 3]] were also cloned based on the similarities in their amino acid sequence to that of formyl peptide receptor 1. Formyl peptide receptors 2 and 3 have very different abilities to bind and respond to formylated oligopeptides including fMLF compared to formyl peptide receptor 1 and compared to each other and have very different functions than those of formyl peptide receptor 1.<ref name="Li_2013">{{cite journal | vauthors = Li Y, Ye D | title = Molecular biology for formyl peptide receptors in human diseases | journal = Journal of Molecular Medicine | volume = 91 | issue = 7 | pages = 781–9 | date = Jul 2013 | pmid = 23404331 | doi = 10.1007/s00109-013-1005-5 | s2cid = 150459 }}</ref>

==References==

{{Reflist|33em}}

== External links ==

* {{MeSH name|N-Formylmethionine Leucyl-Phenylalanine}}

{{DEFAULTSORT:Formylmethionyl-leucyl-phenylalanine, N-}}

[[Category:Tripeptides]]

[[Category:Formamides]]