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| {{infobox enzyme | | {{LPR |
| | Name = Protein farnesyltransferase | | | article = Camino |
| | EC_number = 2.5.1.58 | | | latest_release_version = none |
| | CAS_number = 131384-38-8 | | | latest_release_date = <!-- {{Start date and age|YYYY|MM|DD}} --> |
| | IUBMB_EC_number = 2/5/1/58
| | }}<noinclude> |
| | GO_code = 0004660
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| '''Farnesyltransferase''' ({{EC number|2.5.1.58}}) is one of the three [[enzyme]]s in the [[prenyltransferase]] group. Farnesyltransferase (FTase) adds a 15-carbon [[isoprenoid]] called a [[farnesol|farnesyl group]] to [[protein]]s bearing a CaaX [[Sequence motif|motif]]: a four-[[amino acid]] sequence at the [[carboxyl terminus]] of a protein. Farnesyltransferase's targets include members of the Ras superfamily of [[GTPase|small GTP-binding proteins]] critical to [[cell cycle]] progression. For this reason, several [[Farnesyltransferase inhibitor|FTase inhibitors]] are undergoing testing as anti-cancer agents. FTase inhibitors have shown efficacy as anti-parasitic agents, as well. FTase is also believed to play an important role in development of [[progeria]] and various forms of [[cancer]]s.
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| Farnesyltransferase [[catalysis|catalyzes]] the [[chemical reaction]]
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| :farnesyl diphosphate + protein-cysteine <math>\rightleftharpoons</math> S-farnesyl protein + [[diphosphate]]
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| Thus, the two [[substrate (biochemistry)|substrates]] of this enzyme are [[farnesyl diphosphate]] and [[protein-cysteine]], whereas its two [[product (chemistry)|products]] are [[S-farnesyl protein]] and [[diphosphate]].
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| ==Overview==
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| Farnesyltransferase [[Posttranslational modification|posttranslationally-modifies]] proteins by adding an isoprenoid [[lipid]] called a [[farnesol|farnesyl group]] to the -SH of the cysteine near the end of target proteins to form a [[thioether]] linkage. This process, called farnesylation (which is a type of [[prenylation]]), causes farnesylated proteins to become [[cell membrane|membrane]]-associated due to the [[hydrophobic]] nature of the farnesyl group. Most farnesylated proteins are involved in [[cell signaling|cellular signaling]] wherein membrane association is critical for function.
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| ==Farnesyltransferase structure and function==
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| Farnesyltransferase has two [[Protein subunit|subunit]]s: a 48kDa alpha subunit and a 46kDa [[FNTB|beta subunit]]. Both subunits are primarily composed of [[alpha helix|alpha helices]]. The α subunit is made of a double layer of paired alpha helices stacked in parallel, which wraps partly around the beta subunit like a blanket. The alpha helices of the β subunit form a barrel. The active site is formed by the center of the β subunit flanked by part of the α subunit. Farnesyltransferase coordinates a [[zinc]] [[cation]] on its β subunit at the lip of the active site. Farnesyltransferase has a hydrophobic binding pocket for [[farnesyl diphosphate]], the lipid donor molecule. All farnesyltransferase substrates have a [[cysteine]] as their fourth-to-last residue. This cysteine engages in an [[SN2]] type attack, coordinated by the zinc and a transient stabilizing [[magnesium]] ion on the farnesyl diphosphate, displacing the diphosphate. The product remains bound to farnesyltransferase until displaced by new substrates. The last three amino acids of the CaaX motif are removed later.
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| ===Specificity===
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| There are four binding pockets in FTase, which accommodate the last four amino acids on the carboxyl-terminus of a protein. Only those with a suitable CaaX motif can bind ('C' is Cysteine, 'a' is an [[aliphatic]] amino acid, and 'X' is variable). The carboxyl-terminal amino acid (X) discriminates FTase’s targets from those of the other prenyltransferases, allowing only six different amino acids to bind with any affinity. It has been shown that [[geranylgeranyltransferase]] can prenylate some of the substrates of Farnesyltransferase and vice versa.
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| ==Structural studies==
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| As of late 2007, 15 [[tertiary structure|structures]] have been solved for this class of enzymes, with [[Protein Data Bank|PDB]] accession codes {{PDB link|1S63}}, {{PDB link|1S64}}, {{PDB link|1SA4}}, {{PDB link|1SA5}}, {{PDB link|1TN6}}, {{PDB link|1TN7}}, {{PDB link|1TN8}}, {{PDB link|1X81}}, {{PDB link|2BED}}, {{PDB link|2F0Y}}, {{PDB link|2H6F}}, {{PDB link|2H6G}}, {{PDB link|2H6H}}, {{PDB link|2H6I}}, and {{PDB link|2IEJ}}.
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| ==References==
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| {{refbegin}}
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| * {{cite journal | author = Reid TS, Terry KL, Casey PJ, Beese LS | title = Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity | journal = J. Mol. Biol. | volume = 343 | issue = 2 | pages = 417–33 |date=October 2004 | pmid = 15451670 | doi = 10.1016/j.jmb.2004.08.056 }}
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| * {{cite journal | author = Eastman RT, Buckner FS, Yokoyama K, Gelb MH, Van Voorhis WC | title = Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation | journal = J. Lipid Res. | volume = 47 | issue = 2 | pages = 233–40 |date=February 2006 | pmid = 16339110 | doi = 10.1194/jlr.R500016-JLR200 }}
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| * {{cite journal | author = Lane KT, Beese LS | title = Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I | journal = J. Lipid Res. | volume = 47 | issue = 4 | pages = 681–99 |date=April 2006 | pmid = 16477080 | doi = 10.1194/jlr.R600002-JLR200 }}
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| * {{cite journal | author = Long SB, Casey PJ, Beese LS | title = Reaction path of protein farnesyltransferase at atomic resolution | journal = Nature | volume = 419 | issue = 6907 | pages = 645–50 |date=October 2002 | pmid = 12374986 | doi = 10.1038/nature00986 }}
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| * {{cite journal | author = Agrawal AG, Somani RR | title = Farnesyltransferase inhibitor as anticancer agent | journal = Mini Rev Med Chem | volume = 9 | issue = 6 | pages = 638–52 |date=June 2009 | pmid = 19519490 | doi = 10.2174/138955709788452702| url = http://www.intechopen.com/articles/show/title/farnesyltransferase-inhibitor-in-cancer-treatment }}
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| * {{cite journal | author = Furfine ES, Leban JJ, Landavazo A, Moomaw JF, Casey PJ | date = 1995 | title = Protein farnesyltransferase: kinetics of farnesyl pyrophosphate binding and product release | journal = Biochemistry. | volume = 34 | pages = 6857–62 | pmid = 7756316 | doi = 10.1021/bi00020a032 | issue = 20 }}
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| * {{cite journal | author = Casey PJ, Seabra MC | date = 1996 | title = Protein prenyltransferases | journal = J. Biol. Chem. | volume = 271 | pages = 5289–92 | pmid = 8621375 | doi = 10.1074/jbc.271.10.5289 | issue = 10 }}
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| * {{cite journal | author = Long SB, Casey PJ, Beese LS | date = 1998 | title = Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate | journal = Biochemistry. | volume = 37 | pages = 9612–8 | pmid = 9657673 | doi = 10.1021/bi980708e | issue = 27 }}
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| * {{cite journal | author = Micali E, Chehade KA, Isaacs RJ, Andres DA, Spielmann HP | date = 2001 | title = Protein farnesyltransferase isoprenoid substrate discrimination is dependent on isoprene double bonds and branched methyl groups | journal = Biochemistry. | volume = 40 | pages = 12254–65 | pmid = 11591144 | doi = 10.1021/bi011133f | issue = 41 }}
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| * Sinnott, M. (Ed.), Comprehensive Biological Catalysis. A Mechanistic Reference, vol. 1, Academic Press, San Diego, CA, 1998, p. 31-118.
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| {{refend}}
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| ==See also==
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| * [[Prenylation]]
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| * [[Farnesyltransferase inhibitor]]
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| * [[Geranylgeranyltransferase type 1]] - also referred to as Geranylgeranyltranferase 1 or just Geranylgeranyltranferase
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| * [[Rab geranylgeranyltransferase]] - Geranylgeranyltransferase type 2
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| ==External links==
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| * [http://www.eurekalert.org/pub_releases/2005-08/uonc-nus082905.php EurekAlert: NIH, UNC scientists find anti-cancer drugs might work in treating deadly aging disease]
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| * {{MeshName|Farnesyltranstransferase}}
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| * {{EC number|2.5.1.29}}
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| {{Enzyme inhibition}}
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| {{Alkyl and aryl transferases}}
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| [[Category:EC 2.5.1]]
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