N-Formylmethionine-leucyl-phenylalanine

Last updated
N-Formylmethionine leucyl-phenylalanine
Chemotactic peptide.png
Names
Systematic IUPAC name
(2S)-2-{(2S)-2-[(2S)-2-Formamido-4-(methylsulfanyl)butanamido]-4-methylpentanamido}-3-phenylpropanoic acid
Other names
Chemotactic peptide
F-Met-Leu-Phe
L-Phenylalanine, N-(N-(N-formyl-L-methionyl)-L-leucyl)- [1]
fMLP
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
MeSH N-Formylmethionine+Leucyl-Phenylalanine
PubChem CID
UNII
  • InChI=1S/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) Yes check.svgY
    Key: HFSVAEOILMOWDY-UHFFFAOYSA-N Yes check.svgY
  • InChI=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)
    Key: HFSVAEOILMOWDY-UHFFFAOYAS
  • OC(=O)C(NC=O)CCSC.CC(C)CC(N)C(=O)NC(Cc1ccccc1)C(O)=O
Properties
C21H31N3O5S
Molar mass 437.56 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

N-Formylmethionyl-leucyl-phenylalanine (fMLF, fMLP or N-formyl-met-leu-phe) is an N-formylated tripeptide and sometimes simply referred to as chemotactic peptide is a potent polymorphonuclear leukocyte (PMN) chemotactic factor and is also a macrophage activator. [2]

Contents

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 receptors 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 pathogens.

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. [3] This attraction was soon proposed to be due to soluble elements released by the bacteria [4] (see Harris [5] 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. [6] [7] [8] 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. [9]

Given these clues and knowledge that bacteria transcribe (see Transcription (genetics)) proteins starting with 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. [10] In further studies of various N-formylated oligopeptides, fMLF proved the most potent in stimulating rabbit neutrophil chemotaxis. [7] 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 [11] 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); [12] 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. [7] [13] All of these responses are part of the innate immune systems 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 [14] 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. [15] Thus, fMLF can act as a find-me signal, released by dead or dying cells to attract phagocytes to those cells, so that the phagocytes phagocytose the dead or dying cells, thereby clearing up the damage. [14] fMLF and other N-formylated oligopeptides were found to be similarly active in human neutrophils. [16] [17] 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, [18] 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, [19] [20] 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 [21] [22] 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. [23]

Related Research Articles

<span class="mw-page-title-main">Chemotaxis</span> Movement of an organism or entity in response to a chemical stimulus

Chemotaxis is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming toward the highest concentration of food molecules, or to flee from poisons. In multicellular organisms, chemotaxis is critical to early development and development as well as in normal function and health. In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverted during cancer metastasis. The aberrant chemotaxis of leukocytes and lymphocytes also contribute to inflammatory diseases such as atherosclerosis, asthma, and arthritis. Sub-cellular components, such as the polarity patch generated by mating yeast, may also display chemotactic behavior.

<span class="mw-page-title-main">Monocyte</span> Subtype of leukocytes

Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also influence adaptive immune responses and exert tissue repair functions. There are at least three subclasses of monocytes in human blood based on their phenotypic receptors.

<span class="mw-page-title-main">Lipoxin</span> Acronym for lipoxygenase interaction product

A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">Interleukin 8</span> Mammalian protein found in Homo sapiens

Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel-Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.

<i>N</i>-Formylmethionine Chemical compound

N-Formylmethionine is a derivative of the amino acid methionine in which a formyl group has been added to the amino group. It is specifically used for initiation of protein synthesis from bacterial and organellar genes, and may be removed post-translationally.

<span class="mw-page-title-main">CCL7</span> Mammalian protein found in Homo sapiens

Chemokine ligand 7 (CCL7) is a small cytokine that was previously called monocyte-chemotactic protein 3 (MCP3). CCL7 is a small protein that belongs to the CC chemokine family and is most closely related to CCL2.

<span class="mw-page-title-main">CXCL5</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.

Cathelicidin antimicrobial peptide (CAMP) is an antimicrobial peptide encoded in the human by the CAMP gene. The active form is LL-37. In humans, CAMP encodes the peptide precursor CAP-18, which is processed by proteinase 3-mediated extracellular cleavage into the active form LL-37.

The formyl peptide receptors (FPR) belong to a class of G protein-coupled receptors involved in chemotaxis. In humans, there are three formyl peptide receptor isoforms, each encoded by a separate gene that are named FPR1, FPR2, and FPR3. These receptors were originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells. Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions. The close phylogenetic relation of signaling in chemotaxis and olfaction was recently proved by detection formyl peptide receptor like proteins as a distinct family of vomeronasal organ chemosensors in mice.

Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

<span class="mw-page-title-main">Formyl peptide receptor 2</span> Protein-coding gene in the species Homo sapiens

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 by binding any one of a wide variety of ligands including not only certain N-Formylmethionine-containing oligopeptides such as N-Formylmethionine-leucyl-phenylalanine (FMLP) but also the polyunsaturated fatty acid metabolite of arachidonic acid, lipoxin A4 (LXA4). Because of its interaction with lipoxin A4, FPR2 is also commonly named the ALX/FPR2 or just ALX receptor.

<span class="mw-page-title-main">Formyl peptide receptor 3</span> Protein-coding gene in the species Homo sapiens

N-formyl peptide receptor 3 (FPR3) is a receptor protein that in humans is encoded by the FPR3 gene.

<span class="mw-page-title-main">GPR32</span> Human biochemical receptor

G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors.

<span class="mw-page-title-main">5-Hydroxyeicosatetraenoic acid</span> Chemical compound

5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE).

<span class="mw-page-title-main">NR58-3.14.3</span> Chemical compound

NR58.3-14-3 is a cyclic peptide consisting of 11 D-amino acids. It is a broad-spectrum chemokine inhibitor and anti-inflammatory agent.

Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.

<span class="mw-page-title-main">Formyl peptide receptor 1</span> Protein-coding gene in the species Homo sapiens

Formyl peptide receptor 1 is a cell surface receptor protein that in humans is encoded by the formyl peptide receptor 1 (FPR1) gene. This gene encodes a G protein-coupled receptor cell surface protein that binds and is activated by N-Formylmethionine-containing oligopeptides, particularly N-Formylmethionine-leucyl-phenylalanine (FMLP). FPR1 is prominently expressed by mammalian phagocytic and blood leukocyte cells where it functions to mediate these cells' responses to the N-formylmethionine-containing oligopeptides which are released by invading microorganisms and injured tissues. FPR1 directs these cells to sites of invading pathogens or disrupted tissues and then stimulates these cells to kill the pathogens or to remove tissue debris; as such, it is an important component of the innate immune system that operates in host defense and damage control.

<span class="mw-page-title-main">HEBP1</span>

Heme binding protein 1 is a protein that in humans is encoded by the HEBP1 gene.

<span class="mw-page-title-main">5-Oxo-eicosatetraenoic acid</span> Chemical compound

5-Oxo-eicosatetraenoic acid is a nonclassic eicosanoid metabolite of arachidonic acid and the most potent naturally occurring member of the 5-HETE family of cell signaling agents. Like other cell signaling agents, 5-oxo-ETE is made by a cell and then feeds back to stimulate its parent cell and/or exits this cell to stimulate nearby cells. 5-Oxo-ETE can stimulate various cell types particularly human leukocytes but possesses its highest potency and power in stimulating the human eosinophil type of leukocyte. It is therefore suggested to be formed during and to be an important contributor to the formation and progression of eosinophil-based allergic reactions; it is also suggested that 5-oxo-ETE contributes to the development of inflammation, cancer cell growth, and other pathological and physiological events.

References

  1. ↑ n-formylmethionine leucyl-phenylalanine, Cancerweb
  2. ↑ Panaro MA, Mitolo V (Aug 1999). "Cellular responses to fMLF challenging: a mini-review". Immunopharmacology and Immunotoxicology. 21 (3): 397–419. doi:10.3109/08923979909007117. PMID   10466071.
  3. ↑ Metchnikoff E (1887). "Sur la lutte des cellules de l'organisme contre l'invasion des microbes". Ann. Inst. Pasteur. 1: 321.
  4. ↑ Grawitz P (1887). "unknown". Virchows Adz. IIO. I.{{cite journal}}: Cite uses generic title (help)
  5. ↑ Harris H (Jul 1954). "Role of chemotaxis in inflammation". Physiological Reviews. 34 (3): 529–62. doi:10.1152/physrev.1954.34.3.529. PMID   13185754.
  6. ↑ Ward PA, Lepow IH, Newman LJ (Apr 1968). "Bacterial factors chemotactic for polymorphonuclear leukocytes". The American Journal of Pathology. 52 (4): 725–36. PMC   2013377 . PMID   4384494.
  7. 1 2 3 Showell HJ, Freer RJ, Zigmond SH, Schiffmann E, Aswanikumar S, Corcoran B, Becker EL (May 1976). "The structure-activity relations of synthetic peptides as chemotactic factors and inducers of lysosomal secretion for neutrophils". The Journal of Experimental Medicine. 143 (5): 1154–69. doi:10.1084/jem.143.5.1154. PMC   2190180 . PMID   1262785.
  8. ↑ Becker EL, Showell HJ (Jun 1974). "The ability of chemotactic factors to induce lysosomal enzyme release. II. The mechanism of release". Journal of Immunology. 112 (6): 2055–62. doi: 10.4049/jimmunol.112.6.2055 . PMID   4825785.
  9. ↑ Schiffmann E, Showell HV, Corcoran BA, Ward PA, Smith E, Becker EL (Jun 1975). "The isolation and partial characterization of neutrophil chemotactic factors from Escherichia coli". Journal of Immunology. 114 (6): 1831–7. doi: 10.4049/jimmunol.114.6.1831 . PMID   165239. S2CID   22663271.
  10. ↑ Schiffmann E, Corcoran BA, Wahl SM (Mar 1975). "N-formylmethionyl peptides as chemoattractants for leucocytes". Proceedings of the National Academy of Sciences of the United States of America. 72 (3): 1059–62. Bibcode:1975PNAS...72.1059S. doi: 10.1073/pnas.72.3.1059 . PMC   432465 . PMID   1093163.
  11. ↑ O'Flaherty JT, Kreutzer DL, Ward PA (Jul 1977). "Neutrophil aggregation and swelling induced by chemotactic agents". Journal of Immunology. 119 (1): 232–9. doi:10.4049/jimmunol.119.1.232. PMID   874320. S2CID   36465249.
  12. ↑ O'Flaherty JT, Showell HJ, Ward PA (May 1977). "Neutropenia induced by systemic infusion of chemotactic factors". Journal of Immunology. 118 (5): 1586–9. doi:10.4049/jimmunol.118.5.1586. PMID   858915. S2CID   32354288.
  13. ↑ Becker EL, Sigman M, Oliver JM (Apr 1979). "Superoxide production induced in rabbit polymorphonuclear leukocytes by synthetic chemotactic peptides and A23187". The American Journal of Pathology. 95 (1): 81–97. PMC   2042294 . PMID   219701.
  14. 1 2 Carp H (Jan 1982). "Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils". The Journal of Experimental Medicine. 155 (1): 264–75. doi:10.1084/jem.155.1.264. PMC   2186576 . PMID   6274994.
  15. ↑ Dorward DA, Lucas CD, Chapman GB, Haslett C, Dhaliwal K, Rossi AG (May 2015). "The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation". The American Journal of Pathology. 185 (5): 1172–84. doi:10.1016/j.ajpath.2015.01.020. PMC   4419282 . PMID   25791526.
  16. ↑ O'Flaherty JT, Kreutzer DL, Ward PA (Mar 1978). "Chemotactic factor influences on the aggregation, swelling, and foreign surface adhesiveness of human leukocytes". The American Journal of Pathology. 90 (3): 537–50. PMC   2018255 . PMID   564610.
  17. ↑ Lehmeyer JE, Snyderman R, Johnston RB (Jul 1979). "Stimulation of neutrophil oxidative metabolism by chemotactic peptides: influence of calcium ion concentration and cytochalasin B and comparison with stimulation by phorbol myristate acetate". Blood. 54 (1): 35–45. doi: 10.1182/blood.V54.1.35.35 . PMID   444673.
  18. ↑ Aswanikumar S, Corcoran B, Schiffmann E, Day AR, Freer RJ, Showell HJ, Becker EL (Jan 1977). "Demonstration of a receptor on rabbit neutrophils for chemotactic peptides". Biochemical and Biophysical Research Communications. 74 (2): 810–7. doi:10.1016/0006-291x(77)90375-8. PMID   836328.
  19. ↑ E. Schiffmann; B. A. Corcoran; A. Aswanikumar. (1978). "Molecular events in the response of neutrophils to synthetic N-formylmethionine chemotactic peptides.". In J. A. Gallin; P. G. Quie (eds.). Leukocyte chemotaxis: Methodology, physiology, clinical implications. New York.: Raven Press.
  20. ↑ O'Flaherty JT, Showell HJ, Kreutzer DL, Ward PA, Becker EL (Apr 1978). "Inhibition of in vivo and in vitro neutrophil responses to chemotactic factors by a competitive antagonist". Journal of Immunology. 120 (4): 1326–32. doi: 10.4049/jimmunol.120.4.1326 . PMID   641351. S2CID   42477532.
  21. ↑ O'Flaherty JT, Kreutzer DL, Showell HS, Becker EL, Ward PA (Dec 1978). "Desensitization of the neutrophil aggregation response to chemotactic factors". The American Journal of Pathology. 93 (3): 693–706. PMC   2018345 . PMID   717543.
  22. ↑ O'Flaherty JT, Kreutzer DL, Showell HJ, Vitkauskas G, Becker EL, Ward PA (Mar 1979). "Selective neutrophil desensitization to chemotactic factors". The Journal of Cell Biology. 80 (3): 564–72. doi:10.1083/jcb.80.3.564. PMC   2110355 . PMID   457760.
  23. ↑ Li Y, Ye D (Jul 2013). "Molecular biology for formyl peptide receptors in human diseases". Journal of Molecular Medicine. 91 (7): 781–9. doi:10.1007/s00109-013-1005-5. PMID   23404331. S2CID   150459.
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