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{{split|Formylation|Formylation in biology|date=February 2023}}
[[File:FunktionelleGruppen Aldehyde.svg|thumbnail|Formyl functional group is shown in blue.]]

'''Formylation''' refers to any chemical processes in which a compound is functionalized with a formyl group (-CH=O). In organic chemistry, the term is most commonly used with regards to [[aromatic compound]]s (for example the conversion of [[benzene]] to [[benzaldehyde]] in the [[Gattermann–Koch reaction]]). In biochemistry the reaction is catalysed by enzymes such as [[formyltransferase]]s.

Formylation generally involves the use of formylation agents, reagents that give rise to the CHO group. Among the many formylation reagents, particularly important are [[formic acid]] and [[carbon monoxide]].<ref>{{cite journal |doi=10.1021/cr00080a001|title=Formylating agents |year=1987 |last1=Olah |first1=George A. |last2=Ohannesian |first2=Lena. |last3=Arvanaghi |first3=Massoud. |journal=Chemical Reviews |volume=87 |issue=4 |pages=671–686 }}</ref> A formylation reaction in [[organic chemistry]] refers to [[organic reaction]]s in which an [[organic compound]] is functionalized with a [[formyl]] group (-CH=O). The reaction is a route to [[aldehyde]]s (''C''-CH=O), [[formamide]]s (''N''-CH=O), and [[formate#Formate esters|formate esters]] (''O''-CH=O).

==Formylation agents==
A reagent that delivers the formyl group is called a '''formylating agent'''.<ref>{{cite journal|author1=[[George Olah|Olah, G. A.]] |author2=Ohannesian, L. |author3=Arvanaghi, M. |title=Formylating agents|journal=Chem. Rev.|year=1987|volume=87|issue=4 |pages=671–686|doi=10.1021/cr00080a001}}</ref> 
* [[Formic acid]]
* [[Dimethylformamide]] and [[phosphorus oxychloride]] in the [[Vilsmeier-Haack reaction]].<ref>{{cite journal|author1=Ding, S. |author2=Jiao, N. |title=''N,N''-Dimethylformamide: A Multipurpose Building Block|journal=Angew. Chem. Int. Ed.|year=2012|volume=51|issue=37 |pages=9226–9237|doi=10.1002/anie.201200859|pmid=22930476 }}</ref>
* [[Hexamethylenetetramine]] in the [[Duff reaction]] and the [[Sommelet reaction]]
* [[Carbon monoxide]] and [[hydrochloric acid]] in the [[Gattermann-Koch reaction]]
* [[Cyanide]]s in the [[Gattermann reaction]]. This method synthesizes aromatic aldehydes using [[hydrogen chloride]] and [[hydrogen cyanide]] (or another metallic cyanide as such [[zinc cyanide]]) in the presence of Lewis acid catalysts:
* [[Chloroform]] in the [[Reimer-Tiemann reaction]]
* [[Dichloromethyl methyl ether]] in [[Rieche formylation]]
A particularly important formylation process is [[hydroformylation]], which converts alkenes to the homologated aldehyde.

==Aromatic formylation==
[[File:Gattermann Koch Synthese 1 Überblick.svg|center]]
Formylation reactions are a form of [[electrophilic aromatic substitution]] and therefore work best with electron-rich starting materials. [[Phenol]]s are a common substrate, as they readily deprotonate to excellent [[phenoxide]] nucleophiles.  Other electron-rich substrates, such as [[mesitylene]], [[pyrrole]], or fused aromatic rings can also be expected to react. [[Benzene]] will react under aggressive conditions but deactivated rings such as [[pyridine]] are difficult to formylate effectively.

Many formylation reactions will select only the ''ortho'' product (e.g. [[salicylaldehyde]]), attributed to attraction between the phenoxide and the formylating reagent. Ionic interactions have been invoked for the cationic nitrogen centres in the [[Vilsmeier–Haack reaction]] and [[Duff reaction]], and the electron-deficient [[carbene]] in the [[Reimer–Tiemann reaction|Reimer-Tiemann reaction]]; coordination to high oxidation metals has been invoked in the [[Casiraghi formylation|Casiraghi]] and [[Rieche formylation]]s (cf. [[Kolbe–Schmitt reaction]]).

The direct reaction between phenol and [[paraformaldehyde]] is possible via the Casiraghi formylation,<ref>{{cite journal|last1=Casiraghi|first1=Giovanni|last2=Casnati|first2=Giuseppe|last3=Puglia|first3=Giuseppe|last4=Sartori|first4=Giovanni|last5=Terenghi|first5=Giuliana|title=Selective reactions between phenols and formaldehyde. A novel route to salicylaldehydes|journal=Journal of the Chemical Society, Perkin Transactions 1|date=1980|pages=1862|doi=10.1039/P19800001862}}</ref> but other methods apply masked forms of formaldehyde, in part to limit the formation of [[phenol formaldehyde resin]]s. Aldehydes are strongly deactivating and as such phenols typically only react once.  However certain reactions, such as the [[Duff reaction]], can give double addition.<ref>{{cite journal|last1=Lindoy|first1=Leonard F.|title=Mono- and Diformylation of 4-Substituted Phenols: A New Application of the Duff Reaction|journal=Synthesis|date=July 1998|volume=1998|issue=7|pages=1029–1032|doi=10.1055/s-1998-2110}}</ref>

Formylation can be applied to other aromatic rings. As it generally begins with nucleophilic attack by the aromatic group, the electron density of the ring is an important factor. Some aromatic compounds, such as pyrrole, are known to formylate regioselectively.<ref>{{cite journal |last1=Warashina |first1=Takuya |last2=Matsuura |first2=Daisuke |last3=Sengoku |first3=Tetsuya |last4=Takahashi |first4=Masaki |last5=Yoda |first5=Hidemi |last6=Kimura |first6=Yoshikazu |title=Regioselective Formylation of Pyrrole-2-Carboxylate: Crystalline Vilsmeier Reagent vs Dichloromethyl Alkyl Ether |journal=Organic Process Research & Development |date=16 October 2018 |volume=23 |issue=4 |pages=614–618 |doi=10.1021/acs.oprd.8b00233|s2cid=106209464 }}</ref>

Formylation of benzene rings can be achieved via the [[Gattermann reaction]] and [[Gattermann-Koch reaction]]. These involve strong acid catalysis and proceed in a manner similar to the [[Friedel–Crafts reaction]].<!--not really a formylation:Formylation of arenes rings could be accomplished by [[Blanc chloromethylation]] and a further oxidation of the chloromethyl group. Highly activated substrates such as phenols and [[aniline|anilines]] are not suitable substrates, since they undergo further electrophilic attack by Friedel-Crafts alkylation. Deactivated substrates are suitable for this reaction, although the production of small amounts of highly carcinogenic [[bis(chloromethyl) ether]] is a disadvantage for industrial applications.-->

== Aliphatic formylation ==
[[Hydroformylation]] of alkenes is the most important method for obtaining aliphatic formyls (i.e., aldehydes). The reaction is largely restricted to industrial settings. Several specialty methods exist for laboratory-scale synthesis, including the [[Sommelet reaction]], [[Bouveault aldehyde synthesis]] or [[Bodroux–Chichibabin aldehyde synthesis]].

== Formylation reactions in biology ==
In biochemistry, the addition of a [[formyl functional group]] is termed "formylation". A formyl functional group consists of a carbonyl bonded to hydrogen. When attached to an [[Side chain|R group]], a formyl group is called an [[aldehyde]].

Formylation has been identified in several critical biological processes. Methionine was first discovered to be formylated in ''E. coli'' by Marcker and Sanger in 1964<ref name="Sanger1964">{{cite journal|last=Marcker|first=K|author2=Sanger, F.|title=N-formyl-methionyl-S-RNA|journal=J. Mol. Biol.|year=1964|volume=8|pages=835–840|pmid=14187409|doi=10.1016/S0022-2836(64)80164-9|issue=6}}<!--|access-date=24 February 2013--></ref> and was later identified to be involved in the initiation of protein synthesis in bacteria and organelles.<ref name="Adams 1966">{{cite journal|last=Adams|first=J.M.|author2=Capecchi, M.R.|title=N-Formylmethionyl-sRNA as the initiator of protein synthesis|journal=PNAS|year=1966|volume=55|pages=147–155|pmid=5328638|pmc=285768|issue=1|doi=10.1073/pnas.55.1.147|bibcode=1966PNAS...55..147A|doi-access=free}}</ref> The formation of [[N-formylmethionine|''N''-formylmethionine]] is catalyzed by the enzyme [[Methionyl-tRNA formyltransferase|methionyl-tRNA{{sup|Met}} transformylase]].<ref name="Kozak1983">{{cite journal|last=Kozak|first=M|title=Comparison of Initiation of Protein synthesis in Procaryotes, Eucaryotes, and Organelles|journal=Microbiological Reviews|year=1983|pages=1–45|pmid=6343825|pmc=281560|volume=47|issue=1|doi=10.1128/MMBR.47.1.1-45.1983}}</ref> Additionally, two formylation reactions occur in the [[Purine biosynthesis|de novo biosynthesis of purines]]. These reactions are catalyzed by the enzymes [[GAR transformylase|glycinamide ribonucleotide (GAR) transformylase]] and [[AICAR transformylase|5-aminoimidazole-4-carboxyamide ribotide (AICAR) transformylase]].<ref name="Voet">{{cite book|last=Voet and Voet|title=Fundamentals of Biochemistry 3rd edition|year=2008|publisher=Wiley|location=New York}}</ref> More recently, formylation has been discovered to be a [[histone]] modification, which may modulate gene expression.

===Methanogenesis===
[[File:Methanogenesis cycle.png|thumb|320px|Cycle for [[methanogenesis]], showing initial formylation of methanofuran<ref name=RT>{{cite journal|author=Thauer, R. K.|title=Biochemistry of Methanogenesis: a Tribute to Marjory Stephenson|journal=Microbiology|year=1998|volume=144|pages=2377–2406|doi=10.1099/00221287-144-9-2377|pmid=9782487|doi-access=free}}</ref>]]

Formylation of [[methanofuran]] initiates the [[methanogenesis]] cycle. The formyl group is derived from [[carbon dioxide]] and is converted to [[methane]].

===Formylation in protein synthesis===
[[File:Methionyl tRNAfMet transformylase complexed with initiator formylmethionyl tRNAfMet.png|thumbnail|Methionyl tRNAfMet transformylase complexed with initiator formylmethionyl tRNA<sup>fMet</sup>. Rendered from PDB 2FMT.]]

In bacteria and organelles, the initiation of protein synthesis is signaled by the formation of [[formyl-methionyl-tRNA]] (tRNA<sup>fMet</sup>). This reaction is dependent on [[10-formyltetrahydrofolate]], and the enzyme methionyl-tRNA formyltransferase.<ref name=Kozak1983 />
This reaction is not used by eukaryotes or Archaea, as the presence of tRNA<sup>fMet</sup> in non bacterial cells is dubbed as intrusive material and quickly eliminated. After its production, tRNA<sup>fMet</sup> is delivered to the [[30S ribosomal subunit|30S subunit of the ribosome]] in order to start protein synthesis. fMet possesses the same codon sequence as methionine. However, fMet is only used for the initiation of protein synthesis and is thus found only at the N terminus of the protein. Methionine is used during the rest translation. In ''E. coli'', tRNA<sup>fMet</sup> is specifically recognized by [[Initiation factor|initiation factor IF-2]], as the formyl group blocks peptide bond formation at the N-terminus of methionine.<ref name=Kozak1983 />

Once protein synthesis is accomplished, the formyl group on methionine can be removed by [[peptide deformylase]]. The methionine residue can be further removed by the enzyme [[methionine aminopeptidase]].

[[File:N-formylmethionine synthesis.png|thumb|675px|center|The chemical synthesis of ''N''-formylmethionine is catalyzed by the enzyme methionyl-tRNA formyltransferase.]]

===Formylation reactions in purine biosynthesis===
Two formylation reactions are required in the eleven step de novo synthesis of [[Inosine monophosphate|inosine monophosphate (IMP)]], the precursor of the purine ribonucleotides AMP and GMP. [[GAR transformylase|Glycinamide ribonucleotide (GAR) transformylase]] catalyzes the formylation of GAR to formylglycinamidine ribotide (FGAR) in the fourth reaction of the pathway. In the penultimate step of de novo purine biosynthesis, 5-aminoimidazole-4-carboxyamide ribotide (AICAR) is formylated to 5-formaminoimidazole-4-carboxamide ribotide (FAICAR) by [[AICAR transformylase]].<ref name=Voet />

====GAR transformylase====
PurN GAR transformylase is found in eukaryotes and prokaryotes. However, a second GAR transformylase, PurT GAR transformylase has been identified in ''E. coli''. While the two enzymes have no sequence conservation and require different formyl donors, the specific activity and Km for GAR are the same in both PurT and PurN GAR transformylase.

=====PurN GAR transformylase=====
PurN GAR transformylase 1CDE uses the coenzyme N10-formyltetrahydrofolate (N10-formyl-THF) as a formyl donor to formylate the α-amino group of GAR. In eukaryotes, PurN GAR transformylase is part of a large multifunctional protein, but is found as a single protein in prokaryotes.<ref name="Warren 1996">{{cite journal|last=Warren|first=M.S. |author2=K.M. Mattia |author3=A.E. Marolewski |author4=S.J. Benkovic|title=The transformylase enzymes of de novo purine biosynthesis|journal=Pure Appl. Chem.|year=1996|volume=68|issue=11 |pages=2029–2036|url=http://195.37.231.82/publications/pac/pdf/1996/pdf/6811x2029.pdf|access-date=24 February 2013|doi=10.1351/pac199668112029|s2cid=39555269 }}</ref>

=====Mechanism=====
[[File:GAR transformylase active site with folate based inhibitor.png|thumbnail|Active site of PurN GAR transformylased in a complex with the folate based inhibitor 5-deaza-5,6,7,8-tetrahydrofolate (5dTHF). The α-amino group of GAR (Pink) is located in a position which would attack a N10-formate group on the folate based inhibitor (yellow). Asn 106, His 108, and Asp 144 are colored green. Rendered from PDB 1CDE.]]
The formylation reaction is proposed to occur through a direct transfer reaction in which the amine group of GAR nucleophilically attacks N10-formyl-THF creating a tetrahedral intermediate.<ref name=Voet /> As the α-amino group of GAR is relatively reactive, deprotonation of the nucleophile is proposed to occur by solvent. In the active site, Asn 106, His 108, and Asp 144 are positioned to assist with formyl transfer.<ref name="Warren 1996" /> However, mutagenesis studies have indicated that these residues are not individually essential for catalysis, as only mutations of two or more residues inhibit the enzyme. Based on the structure the negatively charged Asp144 is believed to increase the pKa of His108, allowing the protonated imidazolium group of His108 to enhances the electrophillicity of the N10-formyl-THF formyl group. Additionally, His108 and Asn106 are believed to stabilize the oxyanion formed in the transition state.<ref name="Wolan 2002">{{cite journal|last=Wolan|first=D|author2=Greasley, S.E. |author3=Beardsley, P. |author4=Wilson, I.A. |title=Structural Insights into the Avian AICAR Transformylase Mechanism|journal=Biochemistry|year=2002|volume=41|pages=15505–15513|pmid=12501179|issue=52 |doi=10.1021/bi020505x}}</ref>
[[File:PurN GAR transformylase mechanism.png|thumb|675px|center|Mechanism of PurN GAR transformylase]]

=====PurT GAR transformylase=====
PurT GAR transformylase requires formate as the formyl donor and ATP for catalysis. It has been estimated that PurT GAR transformylase carries out 14-50% of GAR formylations in ''E. coli''. The enzyme is a member of the [[ATP-grasp]] superfamily of proteins.<ref name="Thoden 2000">{{cite journal|last=Thoden|first=J.B.|author2=Firestine, S. |author3=Nixon, A. |author4=Benkovic, S.J. |author5=Holden, H.M |title=Molecular Structure of Escherichia coli PurT-Encoded Glycinamide Ribonucleotide Transformylase|journal=Biochemistry|year=2000|volume=39|pages=8791–8802|pmid=10913290|issue=30 |doi=10.1021/bi000926j}}<!--|access-date=24 February 2013--></ref>

=====Mechanism=====
A sequential mechanism has been proposed for PurT GAR transformylase in which a short lived formyl phosphate intermediate is proposed to first form. This formyl phosphate intermediate then undergoes nucleophilic attack by the GAR amine for transfer of the formyl group. A formyl phosphate intermediate has been detected in mutagenesis experiments, in which the mutant PurT GAR transforymylase had a weak affinity for formate.<ref name="Warren 1996" /> Incubating PurT GAR transformylase with formyl phosphate, ADP, and GAR, yields both ATP and FGAR. This further indicating that formyl phosphate may be an intermediate, as it is kinetically and chemically competent to carry out the formylation reaction in the enzyme.<ref name="Marolewski 1997">{{cite journal|last=Marolewski|first=A.E.|author2=Mattia, K.M. |author3=Warren, M.S. |author4=Benkovic, S.J. |journal=Biochemistry|year=1997|volume=36|pages=6709–6716|pmid=9184151|doi=10.1021/bi962961p |issue=22 |title=Formyl phosphate: a proposed intermediate in the reaction catalyzed by Escherichia coli PurT GAR transformylase.}}</ref> An enzyme phosphate intermediate preceding the formylphosphate intermediate has also been proposed to form based on positional isotope exchange studies.<ref name="Marolewski 1997" /> However, structural data indicates that the formate may be positioned for a direct attack on the γ-phosphate of ATP in the enzyme's active site to form the formylphosphate intermediate.<ref name="Thoden 2000" />

[[File:PurT GAR Transformylase Reaction.png|thumb|675px|center|Reaction catalyzed by PurT GAR transformylase]]

====AICAR transformylase====
AICAR transformylase requires the coenzyme N10-formyltetrahydrofolate (N10-formyl-THF) as the formyl donor for the formylation of AICAR to FAICAR. However, AICAR transformylase and GAR transformylase do not share a high sequence similarity or structural homology.<ref name="Wolan 2002" />

=====Mechanism=====
[[File:AICAR transformylase active site.png|thumbnail|1M9N Active site of AICAR transformylase. Lys267 (cyan), His268 (purple), AICAR (green). Rendered from PDB 1M9N.]]
The amine on AICAR is much less nucleophillic than its counterpart on GAR due to delocalization of electrons in AICAR through conjugation. Therefore, the N5 nucleophile of AIRCAR must be activated for the formylation reaction to occur. Histidine 268 and Lysine 267 have been found to be essential for catalysis and are conserved in all AICAR transformylase. Histidine 268 is involved in deprotonation of the N5 nucleophile of AICAR, whereas Lysine 267 is proposed to stabilize the tetrahedral intermediate.<ref name="Wolan 2002" />

[[File:AICAR transformylase mechanism.png|thumb|675px|center|Mechanism catalyzed by AICAR transformylase]]

===Formylation in histone proteins===
[[File:Lysine and n-formyl lysine.png|thumbnail|left|Formylation is a post-translational modification which occurs on lysine residues.]]

ε-Formylation is one of many [[post-translational modifications]] that occur on histone proteins, which been shown to modulate [[chromatin]] conformations and gene activation.
[[File:Formation n-formyl lysine and acetyl-lysine.png|thumbnail|right|Formylation of lysine can compete with acetylation as a post-translational modification.]]
Formylation has been identified on the Nε of lysine residues in histones and proteins. This modification has been observed in linker histones and [[high mobility group proteins]], it is highly abundant and it is believed to have a role in the epigenetics of chromatin function. Lysines that are formylated have been shown to play a role in DNA binding. Additionally, formylation has been detected on histone lysines that are also known to be acetylated and methylated. Thus, formylation may block other post-translational modifications.<ref name=Wisniewski>{{cite journal|last=Wisniewski|first=J.R.|author2=Zougman, A. |author3=Mann, M. |title=N-Formylation of lysine is a widespread post-translational modification of nuclear proteins occurring at residues involved in regulation of chromatin function.|journal=Nucleic Acids Research|year=2002|volume=36|pages=570–577|pmid=18056081|doi=10.1093/nar/gkm1057|pmc=2241850|issue=2}}</ref>
Formylation is detected most frequently on 19 different modification sites on Histone H1. The genetic expression of the cell is highly disrupted by formylation, which may cause diseases such as cancer. The development of these modifications may be due to oxidative stress.<ref name=Wisniewski />

In histone proteins, lysine is typically modified by Histone Acetyl-Transferases (HATs) and Histone Deacetylases (HDAC or KDAC).
The acetylation of lysine is fundamental to the regulation and expression of certain genes. Oxidative stress creates a significantly different environment in which acetyl-lysine can be quickly outcompeted by the formation of formyl-lysine due to the high reactivity of formylphosphate species. This situation is currently believed to be caused by oxidative DNA damage.
A mechanism for the formation of formylphosphate has been proposed, which it is highly dependent on oxidatively damaged DNA and mainly driven by radical chemistry within the cell.<ref name="Jiang 2007">{{cite journal|last=Jiang|first=T|author2=Zhou, X. |author3=Taghizadeh, K. |author4=Dong, M. |author5=Dedon, PC. |title=N-formylation of lysine in histone proteins as a secondary modification arising from oxidative DNA damage|journal=PNAS|year=2007|volume=104|pages=60–65|pmid=17190813|doi=10.1073/pnas.0606775103|pmc=1765477 |issue=1|bibcode=2007PNAS..104...60J|doi-access=free}}</ref> The formylphosphate produced can then be used to formylate lysine. Oxidative stress is believed to play a role in the availability of lysine residues in the surface of proteins and the possibility of being formylated.
[[File:Formation of formyl phosphate.png|thumb|400 px|center|Formyl phosphate is a proposed product of oxidative DNA damage.]]

==Formylation in medicine==

===Formylation reactions as a drug target===
[[File:Lometrexol.png|thumbnail|right|Chemical structure of lometrexol]]

Inhibition of enzymes involved in purine biosynthesis has been exploited as a potential drug target for chemotherapy. 

Cancer cells require high concentrations of purines to facilitate division<ref name="Warren 1996" /> and tend to rely on de novo synthesis rather than the [[Nucleotide salvage|nucleotide salvage pathway]].<ref name="Wolan 2002" /><ref name="DeMartino 2006">{{cite journal|last=DeMartino|first=J.K.|author2=Hwang, I. |author3=Xu, L. |author4=Wilson, I.A. |author5=Boger, D.L. |title=Discovery of a Potent, Nonpolyglutamatable Inhibitor of Glycinamide Ribonucleotide Transformylase.|journal=Journal of Medicinal Chemistry|year=2006|volume=49|pages=2998–3002|pmid=16686541|doi=10.1021/jm0601147|pmc=2531195 |issue=10}}</ref> Several folate based inhibitors have been developed to inhibit formylation reactions by GAR transformylase and AICAR transformylase.<ref name="Christopherson 2002">{{cite journal|last=Christopherson|first=R.I.|author2=Lyons, S.D. |author3=Wilson, P.K |title=Inhibitors of de Novo Nucleotide Biosynthesis as Drugs|journal=Acc. Chem. Res.|year=2002|volume=35|pages=961–971|pmid=12437321|issue=11|doi=10.1021/ar0000509}}<!--|access-date=24 February 2013--></ref> The first GAR transformylase inhibitor Lometrexol [(6R)5,10-dideazatetrahydrofolate] was developed in the 1980s through a collaboration between [[Eli Lilly]] and academic laboratories.<ref>{{cite journal|last=Wang|first=L |author2=Desmoulin, S.K. |author3=Cherian, C. |author4=Polin, L. |author5=White, K. |author6=Kushner, J. |author7=Fulterer, A. |author8=Chang, M. |author9=Mitchell, S. |author10=Stout, M. |author11=Romero, M.F. |author12=Hou, Z. |author13=Matherly, L.H. |author14=Gangjee, A|title=Synthesis, biological and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase.|journal=Journal of Medicinal Chemistry|year=2011|volume=54|pages=7150–7164|pmid=21879757|doi=10.1021/jm200739e|pmc=3209708|issue=20}}</ref>
Although similar in structure to N10-formyl-THF, lometrexol is incapable of carrying out one carbon transfer reactions.<ref name="Christopherson 2002" /> Additionally, several GAR based inhibitors of GAR transformylase have also been synthesized.<ref name="Christopherson 2002" />
Development of folate based inhibitors have been found to be particularly challenging as the inhibitors also down regulate the enzyme [[FPGS (gene)|folypolyglutamate synthase]], which adds additional γ-glutamates to monoglutamate folates and antifolates after entering the cell for increased enzyme affinity. This increased affinity can lead to antifolate resistance.<ref name="DeMartino 2006" />

===Leigh syndrome===
[[Leigh syndrome]] is a neurodegenerative disorder that has been linked to a defect in an enzymatic formylation reaction. Leigh syndrome is typically associated with defects in oxidative phosphorylation, which occurs in the mitochondria.<ref name=OMIM>{{cite web|title=Leigh Syndrome|url=http://omim.org/entry/256000|publisher=Online Mendelian Inheritance in Man|access-date=24 February 2013}}</ref> [[Exome sequencing]], has been used to identify a mutation in the gene coding for mitochondrial methionyl-tRNA formyltransferase (MTFMT) in patients with Leigh syndrome. The c.626C>T mutation identified in MTFMT yielding symptoms of Leigh Syndrome is believed to alter exon splicing leading to a frameshift mutation and a premature stop codon. Individuals with the MTFMT c.626C>T mutation were found to have reduced fMet-tRNAMet levels and changes in the formylation level of mitochondrically translated COX1. This link provides evidence for the necessity of formylated methionine in initiation of expression for certain mitochondrial genes.<ref name=Tucker>{{cite journal|vauthors=Tucker EJ, Hershman SG, Köhrer C, Belcher-Timme CA, Patel J, Goldberger OA, Christodoulou J, Silberstein JM, McKenzie M, Ryan MT, Compton AG, Jaffe JD, Carr SA, Calvo SE, RajBhandary UL, Thorburn DR, Mootha VK|title=Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation.|journal=Cell Metab.|year=2011|volume=14|pages=428–434|pmid=21907147|doi=10.1016/j.cmet.2011.07.010|pmc=3486727|issue=3}}</ref>

== See also ==

* [[Hydroformylation]]
* [[Hydroacylation]]

==References==
{{Reflist}}

==See also==
* [[N-Formylmethionine|''N''-Formylmethionine]]

{{Protein posttranslational modification}}

[[Category:Proteins]]
[[Category:Post-translational modification]]