P16930 (FAAA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Fumarylacetoacetase
Short name=FAA
EC=3.7.1.2

Alternative name(s):
Beta-diketonase
Fumarylacetoacetate hydrolase

Gene names

Name:

FAH

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	419 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
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 expressed in liver and kidney. Lower levels are also detected in many other tissues.
Involvement in disease	Tyrosinemia 1 (TYRO1) [MIM:276700]: 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23
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
PTM	Acetylation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	L-phenylalanine catabolic process Traceable author statement. Source: Reactome arginine catabolic process Inferred from electronic annotation. Source: Compara cellular nitrogen compound metabolic process Traceable author statement. Source: Reactome tyrosine catabolic process Traceable author statement PubMed 9305902. Source: ProtInc
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	fumarylacetoacetase activity Inferred from experiment. Source: Reactome metal 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
	Initiator methionine	1	1	Removed Ref.6
	Chain	2 – 419	418	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
Amino acid modifications
	Modified residue	2	1	N-acetylserine Ref.6
Natural variations
	Natural variant	16	1	N → I in TYRO1; loss of activity. Ref.10 Ref.22		VAR_005205
	Natural variant	35	1	A → T in TYRO1; atypical mild phenotype. Ref.23		VAR_065454
	Natural variant	62	1	F → C in TYRO1; loss of activity. Ref.22		VAR_005206
	Natural variant	64	1	Q → H in TYRO1.		VAR_005207
	Natural variant	134	1	A → D in TYRO1; loss of activity. Ref.11 Ref.15 Ref.22		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 Ref.22		VAR_005211
	Natural variant	207	1	G → D in TYRO1.		VAR_005212
	Natural variant	233	1	D → V in TYRO1; loss of activity. Ref.13 Ref.22		VAR_005213
	Natural variant	234	1	W → G in TYRO1; loss of activity. Ref.17 Ref.22		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	279	1	Q → R in TYRO1; may affect splicing resulting in skipping of exon 8 alone or together with exon 9; lower activity as compared to wild type. Ref.20 Ref.21 Ref.22		VAR_065455
	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; pseudo-deficient phenotype; lower activity. Ref.14 Ref.22 Corresponds to variant rs11555096 [ dbSNP | Ensembl ].		VAR_005219
	Natural variant	342	1	P → L in TYRO1; loss of activity. Ref.15		VAR_005220
	Natural variant	366	1	Missing in TYRO1. Ref.19		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

Sequences

	Sequence		Length	Mass (Da)
	P16930 [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[6]	Bienvenut W.V. Submitted (JAN-2010) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-25; 32-47; 83-95 AND 195-211, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT SER-2, MASS SPECTROMETRY. Tissue: Ovarian carcinoma.
[7]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 71-419. Tissue: Liver.
[8]	"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] [Europe PMC] [Abstract] Cited for: REVIEW ON VARIANTS.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: VARIANTS TYRO1 ASP-158; LEU-261; SER-366 DEL AND HIS-405.
[20]	"Hepatocellular carcinoma despite long-term survival in chronic tyrosinaemia I." Kim S.Z., Kupke K.G., Ierardi-Curto L., Holme E., Greter J., Tanguay R.M., Poudrier J., D'Astous M., Lettre F., Hahn S.H., Levy H.L. J. Inherit. Metab. Dis. 23:791-804(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TYRO1 ARG-279.
[21]	"A missense mutation (Q279R) in the fumarylacetoacetate hydrolase gene, responsible for hereditary tyrosinemia, acts as a splicing mutation." Dreumont N., Poudrier J.A., Bergeron A., Levy H.L., Baklouti F., Tanguay R.M. BMC Genet. 2:9-9(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TYRO1 ARG-279.
[22]	"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] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS TYRO1 ILE-16; CYS-62; ASP-134; ARG-193; VAL-233; GLY-234; ARG-279 AND TRP-341.
[23]	"A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report." Cassiman D., Zeevaert R., Holme E., Kvittingen E.A., Jaeken J. Orphanet J. Rare Dis. 4:28-28(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TYRO1 THR-35.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	M55150 mRNA. Translation: AAA52422.1. BT007160 mRNA. Translation: AAP35824.1. AK313951 mRNA. Translation: BAG36668.1. CH471136 Genomic DNA. Translation: EAW99120.1. CH471136 Genomic DNA. Translation: EAW99121.1. BC002527 mRNA. Translation: AAH02527.1. X51728 mRNA. Translation: CAA36016.1.
IPI	IPI00031708.
PIR	A37926.
RefSeq	NP_000128.1. NM_000137.2.
UniGene	Hs.73875.
3D structure databases
ProteinModelPortal	P16930.
ModBase	Search...
Protein-protein interaction databases
IntAct	P16930. 1 interaction.
STRING	9606.ENSP00000261755.
PTM databases
PhosphoSite	P16930.
Polymorphism databases
DMDM	119778.
2D gel databases
OGP	P16930.
REPRODUCTION-2DPAGE	IPI00031708.
Proteomic databases
PaxDb	P16930.
PeptideAtlas	P16930.
PRIDE	P16930.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000261755; ENSP00000261755; ENSG00000103876. ENST00000407106; ENSP00000385080; ENSG00000103876. ENST00000561421; ENSP00000453347; ENSG00000103876.
GeneID	2184.
KEGG	hsa:2184.
UCSC	uc002bfm.2. human.
Organism-specific databases
CTD	2184.
GeneCards	GC15P080445.
HGNC	HGNC:3579. FAH.
HPA	HPA041370. HPA044093.
MIM	276700. phenotype. 613871. gene.
neXtProt	NX_P16930.
Orphanet	882. Tyrosinemia type 1.
PharmGKB	PA27977.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0179.
HOGENOM	HOG000256845.
HOVERGEN	HBG001919.
InParanoid	P16930.
KO	K01555.
OMA	MLELSWK.
OrthoDB	EOG4Q2DFM.
PhylomeDB	P16930.
Enzyme and pathway databases
BioCyc	MetaCyc:HS02536-MONOMER.
Reactome	REACT_111217. Metabolism.
UniPathway	UPA00139; UER00341.
Gene expression databases
ArrayExpress	P16930.
Bgee	P16930.
CleanEx	HS_FAH.
Genevestigator	P16930.
GermOnline	ENSG00000103876. Homo sapiens.
Family and domain databases
Gene3D	2.30.30.230. 1 hit. 3.90.850.10. 1 hit.
InterPro	IPR005959. Fumarylacetoacetase. IPR002529. Fumarylacetoacetase_C. IPR011234. Fumarylacetoacetase_C-rel. IPR015377. Fumarylacetoacetase_N. [Graphical view]
PANTHER	PTHR11820:SF1. PTHR11820:SF1. 1 hit.
Pfam	PF09298. DUF1969. 1 hit. PF01557. FAA_hydrolase. 1 hit. [Graphical view]
SUPFAM	SSF56529. Fumarylacetoacetase_C-rel. 1 hit. SSF63433. Fumarylacetoacetase_N. 1 hit.
TIGRFAMs	TIGR01266. fum_ac_acetase. 1 hit.
ProtoNet	Search...
Other
ChiTaRS	FAH. human.
GenomeRNAi	2184.
NextBio	8817.
SOURCE	Search...

Entry information

Entry name

FAAA_HUMAN

Accession

Primary (citable) accession number: P16930
Secondary accession number(s): B2R9X1, D3DW95

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1990
Last sequence update:	August 1, 1992
Last modified:	May 1, 2013
This is version 136 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.