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N-Formylmethionine Peptides (fMet Peptides)

fMet peptides are peptides that contain fragments of bacterial proteins. N-Formylmethionine (fMet) is a derivative of the amino acid methionine. In this case, a formyl group has been added to the amino group of the methionine.

Figure 1: Model of the formylated tripeptide fMLF.

N-Formylmethionyl-leucyl-phenylalanine (fMLF) or N-formyl-met-leu-phe is a formylated tripeptide. fMLP is known as a chemotactic peptide and a macrophage activator peptide.


fMet is used for initiation of protein synthesis from bacterial and organelle genes. Furthermore, fMet is known to play a crucial role in the protein synthesis of bacteria, mitochondria and chloroplasts. However, it is not used in cytosolic protein synthesis of eukaryotes and Archaea. The fMet group can be removed post-translationally.

Cells of the innate immune system are able to detect the presence of infection by binding bacterial peptides that contain N-formylmethionine, or fMet. The immune system of the human body recognizes fMet as foreign and stimulates the body to fight against potential infection. For example, it is known that peptides that bind to non-polymorphic class I molecules originating from M. tuberculosis can elicit immune reactivity directed towards M. tuberculosis.

N-formylated peptides were discovered and identified as low-molecular weight peptides with a blocked N-terminal end and were found to act as potent chemoattractants. The findings that N-formylated peptides could stimulate neutrophil chemotaxis and lysosomal enzyme release provided evidence for the presence of a functional receptor on target cells. Ultimately, studies conducted throughout the 1980s led to the identification of the formyl peptide receptor as a G protein coupled receptor (GPCR).

Since the discovery of the first formyl peptide receptor (FPR1) many more similar receptors have been identified leading to the expansion of the family of formyl peptide receptors as well as to the development of a nomenclature of this receptor family. fMet peptides are recognized by the fMet-Leu-Phe (fMLF) receptor. This receptor received its name from the tripeptide, fMLP, for which it has a high affinity. However, the receptor is not restricted to binding just this tripeptide. N-formylated peptides are agonistic ligands for the Formyl Receptor Family of Receptors (FPRs). Many agonists for FPRs have now been identified and purified from living organisms and a number of these were also synthesized based on the sequence of known proteins of microbes and host origins. However, more research is needed to determine the exact physiological functions of these peptides.

Agonists for FPRs can be groups into the following categories:

1. N-formyl peptides;
2. Microbe-derived nonformylated peptides;
3. Host-derived peptides;
4. Host-derived, non-peptide agonists;
5. Agonists from peptide libraries;
6. Agonists from non-peptide libraries.

Antagonists for the FPRs:

Replacing the formyl group of fMLF with a tertiary butyloxycarbonyl group (t-Boc) renders the peptide into an antagonist. Furthermore, among others, the N-ureido-substituted FdLFdLF was also found to have antagonistic activity. Through the years more FPR1 antagonists have been identified as well.


Reference

Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM.; International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev. 2009 Jun; 61(2):119-61. doi: 10.1124/pr.109.001578. Epub 2009 Jun 4.

Panaro MA, Mitolo V (Aug 1999). "Cellular responses to FMLP challenging: a mini-review". Immunopharmacology and Immunotoxicology. 21 (3): 397–419. doi:10.3109/08923979909007117. PMID 10466071.