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Revision as of 21:07, 6 September 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{chembox}} (no changed fields - added verified revid - updated 'ChemSpiderID_Ref', 'DrugBank_Ref', 'UNII_Ref', 'ChEMBL_Ref', 'ChEBI_Ref', 'KEGG_Ref', 'StdInChI_Ref', 'StdInChIKey_Ref', 'ChEBI_Ref') per [[WP:CHEMVALID|Chem/Drugbox validation← Previous edit		Latest revision as of 21:01, 6 November 2024 edit undoBvos9 (talk | contribs)2 editsm →Function in protein synthesis: spelling mistakeTag: Visual edit
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	{{DISPLAYTITLE:''N''-Formylmethionine}}		{{DISPLAYTITLE:''N''-Formylmethionine}}
	{{chembox		{{chembox
	| verifiedrevid = 431462664		| verifiedrevid = 448813033
	| Name = ''N''-Formylmethionine		| Name = ''N''-Formylmethionine
	| ImageFile = (S)-N-Formylmethionine V.1.svg		| ImageFile = (S)-N-Formylmethionine V.1.svg
	| ImageSize = 250px		| ImageSize = 200px
	| IUPACName = (''S'')-2-Formylamino-4-methylsulfanylbutanoic acid		| IUPACName = ''N''-Formylmethionine
			|SystematicName=(''S'')-2-Formylamino-4-methylsulfanylbutanoic acid
	| OtherNames = 2-Formylamino-4-methylsulfanyl-butyric acid<br>Formylmethionine<br>N-Formyl(methyl)homocysteine		| OtherNames = 2-Formylamino-4-methylsulfanyl-butyric acid; Formylmethionine; ''N''-Formyl(methyl)homocysteine
	| Section1 = {{Chembox Identifiers		|Section1={{Chembox Identifiers
	| abbreviations=fMet		| Abbreviations=fMet
			| CASNo_Ref = {{cascite|correct|??}}
	| CASNo = 4289-98-9		| CASNo = 4289-98-9
			| ChEBI = 182822
			| UNII_Ref = {{fdacite|correct|FDA}}
			| UNII = PS9357B4XH
	| EINECS = 224-322-8		| EINECS = 224-322-8
	| PubChem = 911		| PubChem = 911
			| ChemSpiderID=887
⚫	| SMILES = CSCCC(NC=O)C(O)=O
			| StdInChI=1S/C6H11NO3S/c1-11-3-2-5(6(9)10)7-4-8/h4-5H,2-3H2,1H3,(H,7,8)(H,9,10)
			| StdInChIKey = PYUSHNKNPOHWEZ-UHFFFAOYSA-N
		⚫	| SMILES = CSCC(NC=O)C(O)=O
	}}		}}
	| Section2 = {{Chembox Properties		|Section2={{Chembox Properties
	| C=6 | H=11 | N=1 | O=3 | S=1		| C=6 | H=11 | N=1 | O=3 | S=1
	| MolarMass = 177.22 g/mol		| MolarMass = 177.22 g/mol
	| Appearance =		| Appearance =
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	| BoilingPt =		| BoilingPt =
	| Solubility = }}		| Solubility = }}
	| Section3 = {{Chembox Hazards		|Section3={{Chembox Hazards
	| MainHazards =		| MainHazards =
	| FlashPt =		| FlashPt =
			| AutoignitionPt =
	| Autoignition = }}
			}}
			|Section7 = {{Chembox Hazards
			| GHS_ref=<ref>{{cite web |title=N-Formyl-DL-methionine |url=https://pubchem.ncbi.nlm.nih.gov/compound/911#section=Safety-and-Hazards |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref>
			| GHSPictograms = {{GHS07}}
			| GHSSignalWord = Warning
			| HPhrases = {{H-phrases|319}}
			| PPhrases = {{P-phrases|264+265|280|305+351+338|337+317}}
			}}
	}}		}}
	'''''N''-Formylmethionine''' (fMet) is a ] ] found in ] and related ] ]. It is a derivative of the ] ] in which a ] group has been added to the ] group. It is specifically used for initiation of ], and may be removed after.		'''''N''-Formylmethionine''' (fMet,<ref>{{Cite web|last=PubChem|title=N-Formyl-DL-methionine|url=https://pubchem.ncbi.nlm.nih.gov/compound/911|access-date=2020-10-24|website=pubchem.ncbi.nlm.nih.gov|language=en}}</ref> HCO-Met,<ref name="iupacaa"></ref> For-Met<ref name="iupacaa" />) is a derivative of the ] ] in which a ] group has been added to the ] group. It is specifically used for initiation of ] from ]l and ] genes, and may be removed ].
	fMet plays a crucial part in the protein synthesis of bacteria, ] and ]s. It is not used in ]ic protein synthesis of ]s, where eukaryotic ]s are ]. It is also not used by ]. In the human body, fMet is recognized by the immune system as foreign material and stimulates the body to fight against potential infection.		fMet plays a crucial part in the protein synthesis of bacteria, ] and ]s. It is not used in ]ic protein synthesis of ]s, where eukaryotic ]s are ]. It is also not used by ]. 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==		==Function in protein synthesis==
	fMet is a starting residue in the synthesis of ] in bacteria, and, consequently, is located at the N-terminus of the growing ]. fMet is delivered to the ] (30S) - mRNA complex by a specialized ] (tRNA<sup>fMet</sup>) which has a 3'-UAC-5' ] that is capable of binding with the 5'-AUG-3' start ] located on the ].
			=== Translation ===
	fMet is coded by the same ] as methionine, AUG. However, AUG is also the ] initiation codon. When the codon is used for initiation, fMet is used instead of methionine, thereby forming the first amino acid of the nascent ] chain. When the same codon appears later in the ], normal methionine is used. Many organisms use variations of this basic mechanism.
			fMet is required for efficient initiation of protein synthesis in most groups of bacteria. The 30S ribosome&ndash;mRNA complex specifically recruits tRNAs with a formylated amino acid &ndash; tRNA<sup>fMet</sup> attached to fMet in the natural case.<ref name=p28204695>{{cite journal |last1=Shetty |first1=S |last2=Shah |first2=RA |last3=Chembazhi |first3=UV |last4=Sah |first4=S |last5=Varshney |first5=U |title=Two highly conserved features of bacterial initiator tRNAs license them to pass through distinct checkpoints in translation initiation. |journal=Nucleic Acids Research |date=28 February 2017 |volume=45 |issue=4 |pages=2040–2050 |doi=10.1093/nar/gkw854 |pmid=28204695 |pmc=5389676}}</ref>
			Because the fMet directs initiation, ]s in bacteria start (]) 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<sup>Met</sup> is used.<ref name=p28204695/>
	The addition of the formyl group to methionine is catalyzed by the ] ]. This modification is done after methionine has been loaded onto tRNA<sup>fMet</sup> by ].
	Note that methionine can be loaded either onto tRNA<sup>fMet</sup> or tRNA<sup>Met</sup>. However, transformylase will catalyze the addition of the formyl group to methionine only if methionine has been loaded onto tRNA<sup>fMet</sup> and NOT onto tRNA<sup>Met</sup>.		The addition of the formyl group to methionine is catalyzed by the ] ]. This modification is done after methionine has been loaded onto tRNA<sup>fMet</sup> by ]. Methionine itself can be loaded either onto tRNA<sup>fMet</sup> or tRNA<sup>Met</sup>. However, formyltransferase will catalyze the addition of the formyl group to methionine only if methionine has been loaded onto tRNA<sup>fMet</sup>, not onto tRNA<sup>Met</sup>. This is because the formyltransferase recognizes specific features of tRNA<sup>fMet</sup>.<ref name=p28204695/>
			The ] of ] cells, including those of humans, and the ] of ] 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 ].<ref>{{Cite book|last=Alberts, Bruce|url=https://www.worldcat.org/oclc/887605755|title=Molecular biology of the cell|date=18 November 2014|isbn=978-0-8153-4432-2|edition=Sixth|location=New York, NY|pages=800|oclc=887605755}}</ref>
⚫	This methionine is removed from majority of proteins (both host and recombinant) by methionine aminopeptidase (MAP).<ref name="pmid3024631">{{cite journal |author=Sherman F, Stewart JW, Tsunasawa S |title=Methionine or not methionine at the beginning of a protein |journal=] |volume=3 |issue=1 |pages=27–31 |year=1985 |month=July |pmid=3024631 |doi=10.1002/bies.950030108 |url=}}</ref>
			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<sub>i</sub>, 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.<ref name=degron>{{cite journal |last1=Varshavsky |first1=Alexander |title=N-degron and C-degron pathways of protein degradation |journal=Proceedings of the National Academy of Sciences |date=8 January 2019 |volume=116 |issue=2 |pages=358–366 |doi=10.1073/pnas.1816596116 |doi-access=free |pmid=30622213 |pmc=6329975|bibcode=2019PNAS..116..358V }}</ref>
			=== Further processing ===
		⚫	The ''N''-terminal fMet is removed from majority of proteins, both host and recombinant, by a sequence of two enzymatic reactions. First, ] (PDF) deformylates it, converting the residue back to a normal methionine. Then ] (MetAP) removes the residue from the chain.<ref name="pmid3024631">{{cite journal |vauthors=Sherman F, Stewart JW, Tsunasawa S |title=Methionine or not methionine at the beginning of a protein |journal=] |volume=3 |issue=1 |pages=27–31 |date=July 1985 |pmid=3024631 |doi=10.1002/bies.950030108 |s2cid=33735710 }}</ref> MetAP only acts on proteins with second-position residues that are less bulky than valine.<ref name=p26866044/>
			The ''N''-terminal fMet, if not removed by PDF, seems to act as a ], a signal for protein degradation.<ref name=p26866044>{{cite journal |last1=Piatkov |first1=KI |last2=Vu |first2=TT |last3=Hwang |first3=CS |last4=Varshavsky |first4=A |title=Formyl-methionine as a degradation signal at the N-termini of bacterial proteins. |journal=Microbial Cell (Graz, Austria) |date=2015 |volume=2 |issue=10 |pages=376–393 |doi=10.15698/mic2015.10.231 |pmid=26866044 |pmc=4745127}}</ref>
			=== Variation ===
			The formyl group is not strictly required for initiation. Bacteria with their formyltransferase knocked out, which prevents Met-tRNA<sup>fMet</sup> (i.e. methionine loaded onto tRNA<sup>fMet</sup>) from turning into fMet-tRNA<sup>fMet</sup>, 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 ], which can carry both Met-tRNA<sup>fMet</sup> and fMet-tRNA<sup>fMet</sup> to the ribosome.<ref>{{cite journal |last1=Piatkov |first1=KI |last2=Vu |first2=TT |last3=Hwang |first3=CS |last4=Varshavsky |first4=A |title=Formyl-methionine as a degradation signal at the N-termini of bacterial proteins. |journal=Microbial Cell (Graz, Austria) |date=2015 |volume=2 |issue=10 |pages=376–393 |doi=10.15698/mic2015.10.231 |pmid=26866044 |doi-access=free|pmc=4745127 }}</ref>
	==Relevance to immunology==		==Relevance to immunology==
	Because fMet is present in proteins made by ] but not in those made by ], the ] can use it to help distinguish self from non-self. ] can bind proteins starting with N-Formylmethionine, and use them to initiate ].<ref>{{GeorgiaImmunology|1/phagstep}}</ref><ref name="urlThe Innate Immune System">{{cite web |url=http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/prr.html |title=The Innate Immune System: Pattern-Recognition Receptors, Antigen-Nonspecific Antimicrobial Body Molecules, and Cytokines |format= |work= |accessdate=}}</ref><ref name="pmid2958480">{{cite journal |author=Detmers PA, Wright SD, Olsen E, Kimball B, Cohn ZA |title=Aggregation of complement receptors on human neutrophils in the absence of ligand |journal=] |volume=105 |issue=3 |pages=1137–45 |year=1987 |month=September |pmid=2958480 |pmc=2114803 |doi= |url=http://www.jcb.org/cgi/pmidlookup?view=long&pmid=2958480}}</ref>		Because fMet is present in proteins made by bacteria but not in those made by ] (other than in bacterially derived organelles), the ] might use it to help distinguish self from non-self. ] can bind proteins starting with fMet, and use them to initiate the attraction of circulating blood ] and then stimulate microbicidal activities such as ].<ref>{{GeorgiaImmunology|1/phagstep}}</ref><ref name="urlThe Innate Immune System">{{cite web |url=http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/prr.html |title=The Innate Immune System: Pattern-Recognition Receptors, Antigen-Nonspecific Antimicrobial Body Molecules, and Cytokines |url-status=dead |archive-url=https://web.archive.org/web/20100727061353/http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/prr.html |archive-date=2010-07-27 }}</ref><ref name="pmid2958480">{{cite journal |vauthors=Detmers PA, Wright SD, Olsen E, Kimball B, Cohn ZA |title=Aggregation of complement receptors on human neutrophils in the absence of ligand |journal=] |volume=105 |issue=3 |pages=1137–45 |date=September 1987 |pmid=2958480 |pmc=2114803 |doi= 10.1083/jcb.105.3.1137|url=http://www.jcb.org/cgi/pmidlookup?view=long&pmid=2958480}}</ref>
			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.<ref>{{cite journal | title = Circulating mitochondrial DAMPs cause inflammatory responses to injury | journal =Nature | date=Mar 4, 2010 | volume = 464 | issue = 7285 | pages = 104–107 | doi=10.1038/nature08780 | pmid=20203610 | pmc=2843437 | vauthors=Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ| bibcode =2010Natur.464..104Z }}</ref> Instead, fMet-containing ]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 ] of immunity. The prototypical fMet-containing oligopeptide is ] (FMLP) which activates leukocytes and other cell types by binding with these cells' ] (FPR1) and ] (FPR2) ] (see also ]). Acting through these receptors, the fMet-containing oligopeptides and proteins are part of the ]; they function to initiate acute ] 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.
			== See also ==
			* ]
			* ]
			* ]
	==References==		==References==
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	{{DEFAULTSORT:Formylmethionine, N-}}		{{DEFAULTSORT:Formylmethionine, N-}}
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