Razlika između verzija stranice "FAH (gen)"

'''Fumarilacetoacetaza''' je [[enzim]] koji je kod [[ljudi]] [[kodon|kodiran]] [[gen]]om '''FAH''' lociranom na [[Hromosom 15|hromosomu 15]]. Smatra se da je kod ljudi FAH uključen u [[katabolizam]] [[aminokiseline]] [[fenilalanin]]a.<ref name="pmid1998338">{{cite journal | vauthors = Phaneuf D, Labelle Y, Bérubé D, Arden K, Cavenee W, Gagné R, Tanguay RM | title = Cloning and expression of the cDNA encoding human fumarylacetoacetate hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome 15 | journal = American Journal of Human Genetics | volume = 48 | issue = 3 | pages = 525–35 | date = Marchmart 1991 | pmid = 1998338 | pmc = 1682993 }}</ref><ref name="pmid2336361">{{cite journal | vauthors = Agsteribbe E, van Faassen H, Hartog MV, Reversma T, Taanman JW, Pannekoek H, Evers RF, Welling GM, Berger R | title = Nucleotide sequence of cDNA encoding human fumarylacetoacetase | journal = Nucleic Acids Research | volume = 18 | issue = 7 | pages = 1887 | date = Aprilapril 1990 | pmid = 2336361 | pmc = 330610 | doi = 10.1093/nar/18.7.1887 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: FAH fumarylacetoacetate hydrolase (fumarylacetoacetase)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2184}}</ref>

Dužina [[polipeptid]]nog lanca je 419 [[aminokiselina]], a [[molekularna masa|molekulska težina]] 46.374 [[dalton (jedinica)|Da]].<ref name="UniProt">{{cite web|url=http://www.uniprot.org/uniprot/P16930#sequences |title=UniProt, P16930 |accessdateaccess-date=13. 7. 2021-07-13}}</ref>.

Fumarilacetoacetat-[[hidrolaza]] (FAH) je proteinski homodimer koji cijepa fumarilacetoacetat na njegovoj vezi ugljik-ugljik, tokom reakcije [[hidroliza|hidrolize]].<ref name=":0">{{cite journal | vauthors = Timm DE, Mueller HA, Bhanumoorthy P, Harp JM, Bunick GJ | title = Crystal structure and mechanism of a carbon-carbon bond hydrolase | journal = Structure | volume = 7 | issue = 9 | pages = 1023–33 | date = Septemberseptembar 1999 | pmid = 10508789 | doi = 10.1016/s0969-2126(99)80170-1 | doi-access = free }}</ref> Kao kritični enzim u metabolizmu [[fenilalanin]]a i [[tirozin]]a, 4-fumarilacetoacetat-hidrolaza katalizira završni korak u katabolizmu 4-fumarilacetoacetata i vode u acetoacetat, fumarat i H⁺.<ref name=":10">{{UniProt Full|P16930|FAH - Fumarylacetoacetase - Homo sapiens (Human) - FAH gene & protein}}</ref> These hydrolytic reactions are essential during aromatic amino acid human metabolism. Furthermore, FAH does not share known protein sequence homologs with other nucleotides or amino acids.<ref name=":0" />

[[Aktivno mjesto]] FAH-a sadrži Ca +²⁺ koji djeluje na vezanje supstrata i katalitska trijada ][[glutmin|Glu]]-[[histidin|His]]-[[voda]] funkcionira gdje imidaksolni prsten His133 aktivira [[nukleofil]]nu molekulu vode za napad na vezu ugljik-ugljik fumarilaktoacetata, stvarajući tako [[fumarat]] i [[acetoacetat]].<ref>{{cite journal | vauthors = Bateman RL, Bhanumoorthy P, Witte JF, McClard RW, Grompe M, Timm DE | title = Mechanistic inferences from the crystal structure of fumarylacetoacetate hydrolase with a bound phosphorus-based inhibitor | journal = The Journal of Biological Chemistry | volume = 276 | issue = 18 | pages = 15284–91 | date = Maymaj 2001 | pmid = 11154690 | doi = 10.1074/jbc.M007621200 | doi-access = free }}</ref> Slično putevima povezanim sa fenilalaninom, reakciona molekulska osnova je presudna u metabolizmu sisara, što dokazuje i opažena aktivnost enzima jetre u nedostatku FAH-a, tokom nasljednog tipa tirozinemije 1.<ref>{{Cite journal|date=1981-09-24. 9. 1981|title=Assay of fumarylacetoacetate fumarylhydrolase in human liver — deficient activity in a case of hereditary tyrosinemia |journal=Clinica Chimica Acta|language=en|volume=115|issue=3|pages=311–319|doi=10.1016/0009-8981(81)90244-8 |pmid=7296877 |last1=Kvittingen |first1=E.A. |last2=Jellum |first2=E. |last3=Stokke |first3=O. }}</ref><ref>{{Cite journal|date=1981-09-24. 9. 1981|title=Assay of fumarylacetoacetate fumarylhydrolase in human liver — deficient activity in a case of hereditary tyrosinemia |journal=Clinica Chimica Acta|language=en|volume=115|issue=3|pages=311–319|doi=10.1016/0009-8981(81)90244-8|pmid=7296877 |issn=0009-8981|last1=Kvittingen |first1=E.A. |last2=Jellum |first2=E. |last3=Stokke |first3=O. }}</ref> U ljudi se ovaj enzim uglavnom eksprimira u jetri. FAH je među aminokiselinskim hidroksilazama.<ref name=":1">{{cite journal | vauthors = Tanguay RM, Valet JP, Lescault A, Duband JL, Laberge C, Lettre F, Plante M | title = Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I) | journal = American Journal of Human Genetics | volume = 47 | issue = 2 | pages = 308–16 | date = Augustaugust 1990 | pmid = 2378356 | pmc = 1683717 }}</ref> Tirozin-aminotransferaza ([[tirozin aminotransferaza|TAT]]), 4-hidroksifenilpiruvat-dioksigenaza ([[4-hidroksifenilpiruvat-dioksigenaza|HPD]], homogentizat 1,2-dioksigenaza ([[Homogentizatna 1,2-dioksigenaza|HGD]] , tirozin-aminotransferaza ([[tirozin-aminotransferaza|TAT]]), 4-hidroksifenilpiruvat-dioksigenaza ([[4-hidroksifenilpiruvat-dioksigenaza| HPD]], homogentizat 1,2-dioksigenaza ([[Homogentizat 1,2-dioksigenaza| HGD]] , fenilalanin-4-hidroksilaza ([[fenilalanin-hidroksilaza|PAH]]), maleleketoacetat-izomeraza ([[GSTZ1]]) i druge aminokiselinske kataboličke hidroksilaze takođe su povezane u biološkom procesu [[hidroksilaza]].<ref name="entrez" /><ref name=":4">{{cite book | vauthors = Sniderman King L, Trahms C, Scott CR | chapter = Tyrosinemia Type I|date=Julyjuli 2006 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1515/| title = GeneReviews |publisher=University of Washington | location = Seattle | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A | pmid = 20301688 }}</ref> FAH potput je dio glavne razgradnje aminokiselina L-fenilalanina. Za promet unesenog fenilalanina za sintezu proteina, FAH je izravno povezan sa metodima zasnovanim na liječenju.

Aktivnost fumarilacetoacetatne fumarilhidrolazeljudske jetre određena je fumarilacetoacetatom kao supstratom.<ref name=":6">{{cite journal | vauthors = Labelle Y, Phaneuf D, Leclerc B, Tanguay RM | title = Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense mutation abolishing enzymatic activity | journal = Human Molecular Genetics | volume = 2 | issue = 7 | pages = 941–6 | date = Julyjuli 1993 | pmid = 8364576 | doi = 10.1093/hmg/2.7.941 }}</ref> Kao urođena greška metabolizma, [[tirozinemija tip I]] proizlazi iz nedostatka enzimskog kataboličkog puta fumarilacetoacetat-hidrolaze (FAH). Do sada prijavljene mutacije uključuju tihe mutacije, zamjene aminokiselina unutar jednobaznih supstitucija, besmislene [[kodon]]e i nedostatke prerade.<ref name=":6"/><ref name=":7">{{cite journal | vauthors = Rootwelt H, Berger R, Gray G, Kelly DA, Coşkun T, Kvittingen EA | title = Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1 | journal = American Journal of Human Genetics | volume = 55 | issue = 4 | pages = 653–8 | date = Octoberoktobar 1994 | pmid = 7942842 | pmc = 1918286 }}</ref><ref name=":8">{{Cite journal|last1=St-Louis|first1=Maryse|last2=Tanguay|first2=Robert M.|date=1997|title=Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: Overview |journal=Human Mutation|volume=9|issue=4|pages=291–299|doi=10.1002/(sici)1098-1004(1997)9:4<291::aid-humu1>3.0.co;2-9|issn=1059-7794|pmid=9101289}}</ref> Mutacije širom gena FAH stvaraju nakupine aminokiselinskih ostataka kao što su ostaci alanina i asparaginske kiseline. Nasljedna tirozinemija tip 1 je metabolički poremećaj s autosomno recesivnim načinom nasljeđivanja. Bolest je uzrokovana nedostatkom fumarilacetoacetat-hidrolaze (FAH), posljednjeg enzima na putu razgradnje [[tirozin]]a. Očituje se u akutnom ili hroničnom obliku.<ref name=":5">{{cite journal|vauthors=Ploos van Amstel JK, Bergman AJ, van Beurden EA, Roijers JF, Peelen T, van den Berg IE, Poll-The BT, Kvittingen EA, Berger R|date=Januaryjanuar 1996|title=Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship|journal=Human Genetics|volume=97|issue=1|pages=51–9|doi=10.1007/BF00218833|pmid=8557261}}</ref> Međutim, simptomi se mogu pojaviti kod mutiranih [[heterozigot]]a u genu FAH, kao što je dokumentirano u slučaju 12-godišnjeg američkog dječaka s hroničnom tirozinemijom tipa 1.<ref>{{cite journal | vauthors = Hahn SH, Krasnewich D, Brantly M, Kvittingen EA, Gahl WA | title = Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1 | journal = Human Mutation | volume = 6 | issue = 1 | pages = 66–73 | date = 1995 | pmid = 7550234 | doi = 10.1002/humu.1380060113 | url = https://zenodo.org/record/1229190 }}</ref> Konkretno, majčinski [[alel]]i za kodon 234 pokazuju ovu mutaciju koja mijenja triptofan u glicin. To vjerovatno sugerira [[misens mutacije]] HT1, koje također inhibiraju enzimsku aktivnost. To se također pripisuje primijećenom klasterizmu između aktivnih mjesta ostataka aminokiselina 230 i 250, među stotinama drugih mutacija u genu FAH. [[Korelacija]] gena FAH sa HT1 ne povezuje klinički [[fenotip]] s [[genotip]]om.

Mogući simptom bolesti je razvoj nasljedne tirozinemije tipa 1 (HT1). Uzrokovan je nedostatkom fumarilacetoacetat hidrolaze (FAH), posljednjeg enzima u kataboličkom putu tirozina, HT 1 se nasljeđuje kao rijetka [[autosomno nasljeđivanje|autosomno recesivna]] bolest s prevalencijom u Evropi od 1/50.000. Međutim, u izoliranim dijelovima provincija [[Quebec]]a učestalost može biti tako visoka kao ½.000 sa frekvencijom nositelja od 1:20, moguće zbog mutacije [[efekt osnivača|jednog osnivača]]. Nedostatak FAH dovodi do nakupljanja alkilafing-metabolita koji uzrokuju oštećenje jetre. Poremećaj se predstavlja kao akutni, hronični ili srednje blagi fenotip. Akutni oblik manifestira se u prvoj polovini godine, a karakterizira ga zatajenje jetre, oštećenje bubrega i moguće smrt u prvoj godini života.<ref>{{cite journal | vauthors = Phaneuf D, Lambert M, Laframboise R, Mitchell G, Lettre F, Tanguay RM | title = Type 1 hereditary tyrosinemia. Evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient | journal = The Journal of Clinical Investigation | volume = 90 | issue = 4 | pages = 1185–92 | date = Octoberoktobar 1992 | pmid = 1401056 | pmc = 443158 | doi = 10.1172/JCI115979 }}</ref> Hronični oblik javlja se u dobi početka više od godinu dana nakon rođenja;<ref name=":3">{{cite journal | vauthors = Mohamed S, Kambal MA, Al Jurayyan NA, Al-Nemri A, Babiker A, Hasanato R, Al-Jarallah AS | title = Tyrosinemia type 1: a rare and forgotten cause of reversible hypertrophic cardiomyopathy in infancy | journal = BMC Research Notes | volume = 6 | pages = 362 | date = Septemberseptembar 2013 | pmid = 24016420 | pmc = 3846631 | doi = 10.1186/1756-0500-6-362 }}</ref> [[rahitis]] i progresivna bolest jetre često dovode do razvoja hepatoćelijskog [[karcinom]]a. Ostali simptomi mogu uključivati ozljedu bubrežnih tubula, nekrozu jetre, epizodnu slabost, napadae. Bibrežni [[Fanconijev sindrom]] i porfirinska kriza se također navode, uz oštećenje jetre i bubrega.<ref name=":5"/>

Još ne postoji lijek za tirozinemiju tipa 1. Dijagnosticiranim osobama trebaju posebna prehrambena ograničenja tokom cijelog života za aminokiseline, fenilalanin i tirozin.<ref>{{OMIM|276700|Tyrosinemia, Type I; TYRSN1}}</ref><ref name=":9">{{cite journal | vauthors = Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CD, Grompe M, Mitchell G, Waisbren SE, Gucsavas-Calikoglu M, Wasserstein MP, Coakley K, Scott CR | title = Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations | journal = Genetics in Medicine | volume = 19 | issue = 12 | pages = 1380 | date = Decemberdecembar 2017 | pmid = 28771246 | pmc = 5729346 | doi = 10.1038/gim.2017.101 }}</ref> Pogođene osobe mogu se liječiti i lijekom odobrenim od strane FDA, nazvanim nitisinon. Preporučeni tretman treba započeti što je ranije moguće kada se dijagnosticira stanje. Analiza inhibicije [[bakterija]], poput ''Guthrie'' testa, može pored novonastale bolesti kod djece utvrditi i nedostatak FAH uz povećani nivo fenilalanina.<ref name=":9" /><ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/2658/tyrosinemia-type-1|title=Tyrosinemia type 1 {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|website=rarediseases.info.nih.gov|access-date=2018-12-13. 12. 2018}}</ref> Ostale dijagnostičke metode uključuju mjerenja s tandemskom fragmentacijom masene spektrometrije. Nekim osobama je potrebna transplantacija jetre ako bolest jetre napreduje u napredni razvoj prije nego što počne dijetalno liječenje.

* {{cite journal | vauthors = Phaneuf D, Lambert M, Laframboise R, Mitchell G, Lettre F, Tanguay RM | title = Type 1 hereditary tyrosinemia. Evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient | journal = The Journal of Clinical Investigation | volume = 90 | issue = 4 | pages = 1185–92 | date = Octoberoktobar 1992 | pmid = 1401056 | pmc = 443158 | doi = 10.1172/JCI115979 }}

* {{cite journal | vauthors = Tanguay RM, Valet JP, Lescault A, Duband JL, Laberge C, Lettre F, Plante M | title = Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I) | journal = American Journal of Human Genetics | volume = 47 | issue = 2 | pages = 308–16 | date = Augustaugust 1990 | pmid = 2378356 | pmc = 1683717 }}

* {{cite journal | vauthors = Laberge C, Grenier A, Valet JP, Morissette J | title = Fumarylacetoacetase measurement as a mass-screening procedure for hereditary tyrosinemia type I | journal = American Journal of Human Genetics | volume = 47 | issue = 2 | pages = 325–8 | date = Augustaugust 1990 | pmid = 2378358 | pmc = 1683713 }}

* {{cite journal | vauthors = Kvittingen EA, Halvorsen S, Jellum E | title = Deficient fumarylacetoacetate fumarylhydrolase activity in lymphocytes and fibroblasts from patients with hereditary tyrosinemia | journal = Pediatric Research | volume = 17 | issue = 7 | pages = 541–4 | date = Julyjuli 1983 | pmid = 6622096 | doi = 10.1203/00006450-198307000-00005 | doi-access = free }}

* {{cite journal | vauthors = Kvittingen EA, Jellum E, Stokke O | title = Assay of fumarylacetoacetate fumarylhydrolase in human liver-deficient activity in a case of hereditary tyrosinemia | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 115 | issue = 3 | pages = 311–9 | date = Septemberseptembar 1981 | pmid = 7296877 | doi = 10.1016/0009-8981(81)90244-8 }}

* {{cite journal | vauthors = St-Louis M, Poudrier J, Phaneuf D, Leclerc B, Laframboise R, Tanguay RM | title = Two novel mutations involved in hereditary tyrosinemia type I | journal = Human Molecular Genetics | volume = 4 | issue = 2 | pages = 319–20 | date = Februaryfebruar 1995 | pmid = 7757089 | doi = 10.1093/hmg/4.2.319 }}

* {{cite journal | vauthors = Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, Yokoyama-Kobayashi M, Aoki T | title = Construction of a human full-length cDNA bank | journal = Gene | volume = 150 | issue = 2 | pages = 243–50 | date = Decemberdecembar 1994 | pmid = 7821789 | doi = 10.1016/0378-1119(94)90433-2 }}

* {{cite journal | vauthors = Rootwelt H, Berger R, Gray G, Kelly DA, Coşkun T, Kvittingen EA | title = Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1 | journal = American Journal of Human Genetics | volume = 55 | issue = 4 | pages = 653–8 | date = Octoberoktobar 1994 | pmid = 7942842 | pmc = 1918286 }}

* {{cite journal | vauthors = Rootwelt H, Brodtkorb E, Kvittingen EA | title = Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I | journal = American Journal of Human Genetics | volume = 55 | issue = 6 | pages = 1122–7 | date = Decemberdecembar 1994 | pmid = 7977370 | pmc = 1918441 }}

* {{cite journal | vauthors = Rootwelt H, Chou J, Gahl WA, Berger R, Coşkun T, Brodtkorb E, Kvittingen EA | title = Two missense mutations causing tyrosinemia type 1 with presence and absence of immunoreactive fumarylacetoacetase | journal = Human Genetics | volume = 93 | issue = 6 | pages = 615–9 | date = Junejuni 1994 | pmid = 8005583 | doi = 10.1007/BF00201558 | url = https://zenodo.org/record/1232397 }}

* {{cite journal | vauthors = Grompe M, St-Louis M, Demers SI, al-Dhalimy M, Leclerc B, Tanguay RM | title = A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I | journal = The New England Journal of Medicine | volume = 331 | issue = 6 | pages = 353–7 | date = Augustaugust 1994 | pmid = 8028615 | doi = 10.1056/NEJM199408113310603 }}

* {{cite journal | vauthors = St-Louis M, Leclerc B, Laine J, Salo MK, Holmberg C, Tanguay RM | title = Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I | journal = Human Molecular Genetics | volume = 3 | issue = 1 | pages = 69–72 | date = Januaryjanuar 1994 | pmid = 8162054 | doi = 10.1093/hmg/3.1.69 }}

* {{cite journal | vauthors = Labelle Y, Phaneuf D, Leclerc B, Tanguay RM | title = Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense mutation abolishing enzymatic activity | journal = Human Molecular Genetics | volume = 2 | issue = 7 | pages = 941–6 | date = Julyjuli 1993 | pmid = 8364576 | doi = 10.1093/hmg/2.7.941 }}

* {{cite journal | vauthors = Labelle Y, Puymirat J, Tanguay RM | title = Localization of cells in the rat brain expressing fumarylacetoacetate hydrolase, the deficient enzyme in hereditary tyrosinemia type 1 | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1180 | issue = 3 | pages = 250–6 | date = Januaryjanuar 1993 | pmid = 8422430 | doi = 10.1016/0925-4439(93)90046-4 }}

* {{cite journal | vauthors = Ploos van Amstel JK, Bergman AJ, van Beurden EA, Roijers JF, Peelen T, van den Berg IE, Poll-The BT, Kvittingen EA, Berger R | title = Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship | journal = Human Genetics | volume = 97 | issue = 1 | pages = 51–9 | date = Januaryjanuar 1996 | pmid = 8557261 | doi = 10.1007/bf00218833 }}

[[Kategorija: Geni na hromosomu 15]]

[[Kategorija: Ljudski proteini]]