Reviewed, UniProtKB/Swiss-Prot P16930 (FAAA_HUMAN)

Names and origin

Protein names

Recommended name:
    Fumarylacetoacetase
      Short name=FAA
    EC=3.7.1.2
Alternative name(s):
    Fumarylacetoacetate hydrolase
    Beta-diketonase

Gene names

Name:

FAH

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	419 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	4-fumarylacetoacetate + H2O = acetoacetate + fumarate.
Cofactor	Calcium By similarity. Magnesium By similarity.
Pathway	Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 6/6.
Subunit structure	Homodimer.
Tissue specificity	Mainly in liver and kidney. Lower levels are also detected in many other tissues.
Involvement in disease	Defects in FAH are the cause of tyrosinemia type 1 (TYRO1) [MIM:276700]. TYRO1 is an inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, and hepatorenal manifestations. Typical features include hepatic necrosis, renal tubular injury, episodic weakness, self-mutilation, and seizures. Renal tubular dysfunction is associated with phosphate loss and hypophosphataemic rickets. Progressive liver disease can lead to the development of hepatocellular carcinoma. Dietary treatment with restriction of tyrosine and phenylalanine alleviates the rickets, but liver transplantation has so far been the only definite treatment. TYRO1 is a rare condition, except in the Saguenay-lac-St-Jean region (province of Quebec, Canada) where the frequency is high as the result of a founder effect. Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19
Sequence similarities	Belongs to the FAH family.

Ontologies

Keywords
Biological process	Phenylalanine catabolism Tyrosine catabolism
Disease	Disease mutation
Ligand	Calcium Magnesium Metal-binding
Molecular function	Hydrolase
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	L-phenylalanine catabolic process Inferred from electronic annotation. Source: UniProtKB-KW tyrosine catabolic process Traceable author statement. Source: ProtInc
Cellular component	cytosol Ref.11 Inferred from Experiment. Source: Reactome
Molecular function	calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW fumarylacetoacetase activity Ref.1 Ref.11 Inferred from Experiment. Source: Reactome magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 419	419	Fumarylacetoacetase		PRO_0000156825
Sites
	Active site	133	1	Proton acceptor Probable
	Metal binding	126	1	Calcium By similarity
	Metal binding	199	1	Calcium By similarity
	Metal binding	201	1	Calcium By similarity
	Metal binding	233	1	Calcium By similarity
	Metal binding	233	1	Magnesium By similarity
	Metal binding	253	1	Magnesium By similarity
	Metal binding	257	1	Magnesium By similarity
	Binding site	128	1	Substrate By similarity
	Binding site	142	1	Substrate By similarity
	Binding site	240	1	Substrate By similarity
	Binding site	244	1	Substrate By similarity
	Binding site	350	1	Substrate By similarity
Natural variations
	Natural variant	16	1	N → I in TYRO1; loss of activity. Ref.10		VAR_005205
	Natural variant	62	1	F → C in TYRO1; loss of activity.		VAR_005206
	Natural variant	64	1	Q → H in TYRO1; many patients of Pakistani origin.		VAR_005207
	Natural variant	134	1	A → D in TYRO1; chronic; loss of activity. Ref.11 Ref.15		VAR_005208
	Natural variant	158	1	G → D in TYRO1. Ref.19		VAR_005209
	Natural variant	166	1	V → G in TYRO1. Ref.12		VAR_005210
	Natural variant	193	1	C → R in TYRO1; loss of activity. Ref.18		VAR_005211
	Natural variant	207	1	G → D in TYRO1.		VAR_005212
	Natural variant	233	1	D → V in TYRO1; loss of activity; many patients of Turkish origin. Ref.13		VAR_005213
	Natural variant	234	1	W → G in TYRO1; loss of activity. Ref.17		VAR_005214
	Natural variant	249	1	P → T in TYRO1.		VAR_005215
	Natural variant	261	1	P → L in TYRO1. Ref.19		VAR_005216
	Natural variant	294	1	T → P in TYRO1.		VAR_005217
	Natural variant	337	1	G → S in TYRO1. Ref.16		VAR_005218
	Natural variant	341	1	R → W in TYRO1 and FAH pseudodeficiency; lower activity. dbSNP rs11555096. Ref.14		VAR_005219
	Natural variant	342	1	P → L in TYRO1; chronic; loss of activity. Ref.15		VAR_005220
	Natural variant	366	1	Missing in TYRO1.		VAR_005221
	Natural variant	369	1	G → V in TYRO1. Ref.18		VAR_005222
	Natural variant	381	1	R → G in TYRO1; loss of activity. Ref.16		VAR_005223
	Natural variant	405	1	F → H in TYRO1; requires 2 nucleotide substitutions. Ref.19		VAR_005224
Experimental info
	Mutagenesis	279	1	Q → R: Lower activity. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	P16930-1 [UniParc]. Last modified August 1, 1992. Version 2. Checksum: 12EA8D8074C55BB2	FASTA	419	46,374
	10 20 30 40 50 60 MSFIPVAEDS DFPIHNLPYG VFSTRGDPRP RIGVAIGDQI LDLSIIKHLF TGPVLSKHQD 70 80 90 100 110 120 VFNQPTLNSF MGLGQAAWKE ARVFLQNLLS VSQARLRDDT ELRKCAFISQ ASATMHLPAT 130 140 150 160 170 180 IGDYTDFYSS RQHATNVGIM FRDKENALMP NWLHLPVGYH GRASSVVVSG TPIRRPMGQM 190 200 210 220 230 240 KPDDSKPPVY GACKLLDMEL EMAFFVGPGN RLGEPIPISK AHEHIFGMVL MNDWSARDIQ 250 260 270 280 290 300 KWEYVPLGPF LGKSFGTTVS PWVVPMDALM PFAVPNPKQD PRPLPYLCHD EPYTFDINLS 310 320 330 340 350 360 VNLKGEGMSQ AATICKSNFK YMYWTMLQQL THHSVNGCNL RPGDLLASGT ISGPEPENFG 370 380 390 400 410 SMLELSWKGT KPIDLGNGQT RKFLLDGDEV IITGYCQGDG YRIGFGQCAG KVLPALLPS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of the cDNA encoding human fumarylacetoacetate hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome 15." Phaneuf D., Labelle Y., Berube D., Arden K., Cavenee W., Gagne R., Tanguay R.M. Am. J. Hum. Genet. 48:525-535(1991) [PubMed: 1998338] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[6]	"Nucleotide sequence of cDNA encoding human fumarylacetoacetase." Agsteribbe E., van Faassen H., Hartog M.V., Reversma T., Taanman J.-W., Pannekoek H., Evers R.F., Welling G.M., Berger R. Nucleic Acids Res. 18:1887-1887(1990) [PubMed: 2336361] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 71-419. Tissue: Liver.
[7]	"Structural and functional analysis of missense mutations in fumarylacetoacetate hydrolase, the gene deficient in hereditary tyrosinemia type 1." Bergeron A., D'Astous M., Timm D.E., Tanguay R.M. J. Biol. Chem. 276:15225-15231(2001) [PubMed: 11278491] [Abstract] Cited for: MUTAGENESIS OF ASN-16; PHE-62; ALA-134; CYS-193; ASP-233; TRP-234; GLN-279 AND ARG-341.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]	"Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview." St Louis M., Tanguay R.M. Hum. Mutat. 9:291-299(1997) [PubMed: 9101289] [Abstract] Cited for: REVIEW ON VARIANTS.
[10]	"Type 1 hereditary tyrosinemia. Evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient." Phaneuf D., Lambert M., Laframboise R., Mitchell G., Lettre F., Tanguay R.M. J. Clin. Invest. 90:1185-1192(1992) [PubMed: 1401056] [Abstract] Cited for: VARIANT TYRO1 ILE-16.
[11]	"Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense mutation abolishing enzymatic activity." Labelle Y., Phaneuf D., Leclerc B., Tanguay R.M. Hum. Mol. Genet. 2:941-946(1993) [PubMed: 8364576] [Abstract] Cited for: VARIANT TYRO1 ASP-134.
[12]	"Mutations of the fumarylacetoacetate hydrolase gene in four patients with tyrosinemia, type I." Grompe M., Al-Dhalimy M. Hum. Mutat. 2:85-93(1993) [PubMed: 8318997] [Abstract] Cited for: VARIANT TYRO1 GLY-166.
[13]	"Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1." Rootwelt H., Berger R., Gray G., Kelly D.A., Coskun T., Kvittingen E.A. Am. J. Hum. Genet. 55:653-658(1994) [PubMed: 7942842] [Abstract] Cited for: VARIANT TYRO1 VAL-233.
[14]	"Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I." Rootwelt H., Brodtkorb E., Kvittingen E.A. Am. J. Hum. Genet. 55:1122-1127(1994) [PubMed: 7977370] [Abstract] Cited for: VARIANT TYRO1 TRP-341.
[15]	"Two missense mutations causing tyrosinemia type 1 with presence and absence of immunoreactive fumarylacetoacetase." Rootwelt H., Chou J., Gahl W.A., Berger R., Coskun T., Brodtkorb E., Kvittingen E.A. Hum. Genet. 93:615-619(1994) [PubMed: 8005583] [Abstract] Cited for: VARIANTS TYRO1 ASP-134 AND LEU-342.
[16]	"Two novel mutations involved in hereditary tyrosinemia type I." St Louis M., Poudrier J., Phaneuf D., Leclerc B., Laframboise R., Tanguay R.M. Hum. Mol. Genet. 4:319-320(1995) [PubMed: 7757089] [Abstract] Cited for: VARIANTS TYRO1 SER-337 AND GLY-381.
[17]	"Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1." Hahn S.H., Krasnewich D., Brantly M., Kvittingen E.A., Gahl W.A. Hum. Mutat. 6:66-73(1995) [PubMed: 7550234] [Abstract] Cited for: VARIANT TYRO1 GLY-234.
[18]	"Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship." Ploos van Amstel J.K., Bergman A.J.I.W., van Beurden E.A.C.M., Roijers J.F.M., Peelen T., van den Berg I.E.T., Poll-The B.T., Kvittingen E.A., Berger R. Hum. Genet. 97:51-59(1996) [PubMed: 8557261] [Abstract] Cited for: VARIANTS TYRO1 ARG-193 AND VAL-369.
[19]	"Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type 1 patients in northwestern Europe and Mediterranean countries." Bergman A.J.I.W., van den Berg I.E.T., Brink W., Poll-The B.T., Ploos van Amstel J.K., Berger R. Hum. Mutat. 12:19-26(1998) [PubMed: 9633815] [Abstract] Cited for: VARIANTS TYRO1 ASP-158; LEU-261; SER-366 DEL AND HIS-405.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	M55150 mRNA. Translation: AAA52422.1. BT007160 mRNA. Translation: AAP35824.1. AK313951 mRNA. Translation: BAG36668.1. CH471136 Genomic DNA. Translation: EAW99120.1. BC002527 mRNA. Translation: AAH02527.1. X51728 mRNA. Translation: CAA36016.1.
IPI	IPI00031708.
PIR	A37926.
RefSeq	NP_000128.1.
UniGene	Hs.73875
3D structure databases
HSSP	HSSP built from PDB template 1HYO based on UniProtKB P35505.
SMR	P16930. Positions 1-416.
ModBase	Search...
Protein-protein interaction databases
STRING	P16930.
PTM databases
PhosphoSite	P16930.
2-D gel databases
OGP	P16930.
REPRODUCTION-2DPAGE	IPI00031708.
Proteomic databases
PeptideAtlas	P16930.
PRIDE	P16930.
Genome annotation databases
Ensembl	ENST00000261755; ENSP00000261755; ENSG00000103876; Homo sapiens. [Genome view] ENST00000407106; ENSP00000385080; ENSG00000103876; Homo sapiens. [Genome view]
GeneID	2184.
KEGG	hsa:2184.
UCSC	uc002bfj.1. human.
Organism-specific databases
CTD	2184.
GeneCards	GC15P078232.
H-InvDB	HIX0012491.
HGNC	HGNC:3579. FAH.
MIM	276700. gene+phenotype.
Orphanet	882. Tyrosinemia type 1.
PharmGKB	PA27977.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P16930.
HOVERGEN	P16930.
OMA	DFELEMA.
Enzyme and pathway databases
BioCyc	MetaCyc:MON-12049.
BRENDA	3.7.1.2. 247.
Reactome	REACT_13. Metabolism of amino acids.
Gene expression databases
ArrayExpress	P16930.
Bgee	P16930.
CleanEx	HS_FAH.
Genevestigator	P16930.
GermOnline	ENSG00000103876. Homo sapiens.
Family and domain databases
InterPro	IPR005959. Fumarylacetoacetase. IPR002529. Fumarylacetoacetase_C-like. IPR011234. Fumarylacetoacetase_C-rel. IPR015377. Fumarylacetoacetase_N. [Graphical view]
Gene3D	G3DSA:3.90.850.10. Fumarylacetoacetase_C-rel. 1 hit. G3DSA:2.30.30.230. Fumarylacetoacetase_N. 1 hit.
PANTHER	PTHR11820:SF1. Fum_ac_acetase. 1 hit.
Pfam	PF09298. DUF1969. 1 hit. PF01557. FAA_hydrolase. 1 hit. [Graphical view]
TIGRFAMs	TIGR01266. fum_ac_acetase. 1 hit.
ProtoNet	Search...
Other Resources
NextBio	8817.
SOURCE	Search...

Entry information

Entry name

FAAA_HUMAN

Accession

Primary (citable) accession number: P16930
Secondary accession number(s): B2R9X1

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1990
Last sequence update:	August 1, 1992
Last modified:	November 3, 2009
This is version 103 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.