Summary

Fumarylacetoacetate (FAA) hydrolase family

This family consists of fumarylacetoacetate (FAA) hydrolase, or fumarylacetoacetate hydrolase (FAH) and it also includes HHDD isomerase/OPET decarboxylase from E. coli strain W. FAA is the last enzyme in the tyrosine catabolic pathway, it hydrolyses fumarylacetoacetate into fumarate and acetoacetate which then join the citric acid cycle [1]. Mutations in FAA cause type I tyrosinemia in humans this is an inherited disorder mainly affecting the liver leading to liver cirrhosis, hepatocellular carcinoma, renal tubular damages and neurologic crises amongst other symptoms [1]. The enzymatic defect causes the toxic accumulation of phenylalanine/tyrosine catabolites [3]. The E. coli W enzyme HHDD isomerase/OPET decarboxylase contains two copies of this domain and functions in fourth and fifth steps of the homoprotocatechuate pathway; here it decarboxylates OPET to HHDD and isomerises this to OHED. The final products of this pathway are pyruvic acid and succinic semialdehyde. This family also includes various hydratases and 4-oxalocrotonate decarboxylases which are involved in the bacterial meta-cleavage pathways for degradation of aromatic compounds. 2-hydroxypentadienoic acid hydratase encoded by mhpD in E. coli P77608 is involved in the phenylpropionic acid pathway of E. coli and catalyses the conversion of 2-hydroxy pentadienoate to 4-hydroxy-2-keto-pentanoate and uses a Mn2+ co-factor [5]. OHED hydratase encoded by hpcG in E. coli P42270 is involved in the homoprotocatechuic acid (HPC) catabolism [6]. XylI in P. putida P49155 is a 4-Oxalocrotonate decarboxylase [7].

Literature references

St-Louis M, Tanguay RM; , Hum Mutat 1997;9:291-299.: Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview. PUBMED:9101289
Prieto MA, Diaz E, Garcia JL; , J Bacteriol 1996;178:111-120.: Molecular characterization of the 4-hydroxyphenylacetate catabolic pathway of Escherichia coli W: engineering a mobile aromatic degradative cluster. PUBMED:8550403
Fernandez-Canon JM, Penalva MA; , Proc Natl Acad Sci U S A 1995;92:9132-9136.: Fungal metabolic model for human type I hereditary tyrosinaemia. PUBMED:7568087
Roper DI, Cooper RA; , Eur J Biochem 1993;217:575-580.: Purification, nucleotide sequence and some properties of a bifunctional isomerase/decarboxylase from the homoprotocatechuate degradative pathway of Escherichia coli C. PUBMED:8223600
Pollard JR, Bugg TD; , Eur J Biochem 1998;251:98-106.: Purification, characterisation and reaction mechanism of monofunctional 2-hydroxypentadienoic acid hydratase from Escherichia coli. PUBMED:9492273
Roper DI, Stringfellow JM, Cooper RA; , Gene 1995;156:47-51.: Sequence of the hpcC and hpcG genes of the meta-fission homoprotocatechuic acid pathway of Escherichia coli C: nearly 40% amino- acid identity with the analogous enzymes of the catechol pathway. PUBMED:7737515
Harayama S, Rekik M; , Mol Gen Genet 1993;239:81-89.: Comparison of the nucleotide sequences of the meta-cleavage pathway genes of TOL plasmid pWW0 from Pseudomonas putida with other meta- cleavage genes suggests that both single and multiple nucleotide substitutions contribute to enzyme evolution. PUBMED:8510667

InterPro entry IPR002529

Fumarylacetoacetase (; also known as fumarylacetoacetate hydrolase or FAH) catalyses the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate to yield fumarate and acetoacetate as the final step in phenylalanine and tyrosine degradation PUBMED:11154690. This is an essential metabolic function in humans, the lack of FAH causing type I tyrosinaemia, which is associated with liver and kidney abnormalities and neurological disorders PUBMED:9101289, PUBMED:16602095. The enzyme mechanism involves a catalytic metal ion, a Glu/His catalytic dyad, and a charged oxyanion hole PUBMED:10508789. FAH folds into two domains: an N-terminal domain SH3-like beta-barrel, and a C-terminal with an unusual fold consisting of three layers of beta-sheet structures PUBMED:10508789.

This entry represents the C-terminal domain of fumarylacetoacetase, as well as other domains that share a homologous sequence, including:

5-carboxymethyl-2-hydroxymuconate delta-isomerase (CHM isomerase; ), which catalyses the conversion of 5-carboxymethyl-2-hydroxymuconate to 5-carboxy-2-oxohept-3-enedioate PUBMED:2194841.
5-oxopent-3-ene-1,2,5-tricarboxylate decarboxylase (OPET decarboxylase; ), which catalyses the conversion of 5-oxopent-3-ene-1,2,5-tricarboxylate to 2-oxohept-3-enedioate and carbon dioxide.
Bifunctional enzyme HpcE (OPET decarboxylase /HHDD isomerase ), which is a duplication consisting of a tandem repeat of two FAH C-terminal-like domains. This enzyme is responsible for the degradation of 4-hydroxyphenylacetate, a product of tyrosine and phenylalanine metabolism also released by lignin catabolism PUBMED:11863436.

Clan

This family is a member of clan FAH (CL0377), which contains the following 2 members:

DUF2848 FAA_hydrolase

Gene Ontology

Molecular function	catalytic activity (GO:0003824)
Biological process	metabolic process (GO:0008152)

External database links

MIM:	276700
PANDIT:	PF01557
SCOP:	1qcn
SYSTERS:	FAA_hydrolase

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

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Alignment:	Seed (96) Full (4385) NCBI (7336) Metagenomics (4024)
Viewer:

Formatting options

Alignment:	Seed (96) Full (4385)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (96) Full (4385) NCBI (7336) Metagenomics (4024)
Full length sequences	Full-sequences (4385)

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER2.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

Pfam-B_641 (release 4.0) & Pfam-B_1228 (release 4.1)

Previous IDs:

none

Type:

Family

Author:

Bashton M, Bateman A

Number in seed:

96

Number in full:

4385

Average length of the domain:

215.30 aa

Average identity of full alignment:

24 %

Average coverage of the sequence by the domain:

74.35 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 9421015 -E 1000 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	23.9	23.9
Trusted cut-off	24.1	24.1
Noise cut-off	23.8	23.8

Model length:

217

Family (HMM) version:

11

Download:

download the raw HMM for this family

Species distribution

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

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Interactions

There are 3 interactions for this family. More...

DUF1969 DUF2437 FAA_hydrolase

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FAA_hydrolase domain has been found.

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Family: FAA_hydrolase (PF01557)

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