Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
16  structures 7030  species 1  interaction 9253  sequences 47  architectures

Family: HEM4 (PF02602)

Summary: Uroporphyrinogen-III synthase HemD

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Uroporphyrinogen III synthase". More...

Uroporphyrinogen III synthase Edit Wikipedia article

Uroporphyrinogen-III synthase
Uroporphyrinogen-III synthase monomer, Thermus thermophilus
EC number4.2.1.75
CAS number37340-55-9
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Uroporphyrinogen III synthase
NCBI gene7390
Other data
EC number4.2.1.75
LocusChr. 10 q25.2-26.3
Uroporphyrinogen-III synthase HemD
PDB 1wd7 EBI.jpg
crystal structure of uroporphyrinogen iii synthase from an extremely thermophilic bacterium thermus thermophilus hb8 (wild type, native, form-2 crystal)

Uroporphyrinogen III synthase EC is an enzyme involved in the metabolism of the cyclic tetrapyrrole compound porphyrin. It is involved in the conversion of hydroxymethyl bilane into uroporphyrinogen III. This enzyme catalyses the inversion of the final pyrrole unit (ring D) of the linear tetrapyrrole molecule, linking it to the first pyrrole unit (ring A), thereby generating a large macrocyclic structure, uroporphyrinogen III.[1] The enzyme folds into two alpha/beta domains connected by a beta-ladder, the active site being located between the two domains.[2]

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)


A deficiency is associated with Gunther's disease, also known as congenital erythropoietic porphyria (CEP). This is an autosomal recessive inborn error of metabolism that results from the markedly deficient activity of uroporphyrinogen III synthase.[3]


  1. ^ Raux E, Schubert HL, Warren MJ (December 2000). "Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum". Cell. Mol. Life Sci. 57 (13–14): 1880–93. doi:10.1007/PL00000670. PMID 11215515.
  2. ^ Mathews MA, Schubert HL, Whitby FG, Alexander KJ, Schadick K, Bergonia HA, Phillips JD, Hill CP (November 2001). "Crystal structure of human uroporphyrinogen III synthase". EMBO J. 20 (21): 5832–9. doi:10.1093/emboj/20.21.5832. PMC 125291. PMID 11689424.
  3. ^ To-Figueras J, Badenas C, Mascaro JM, Madrigal I, Merino A, Bastida P, Lecha M, Herrero C (2007). "Study of the genotype-phenotype relationship in four cases of congenital erythropoietic porphyria". Blood Cells Mol. Dis. 38 (3): 242–6. doi:10.1016/j.bcmd.2006.12.001. PMID 17270473.

External links

This article incorporates text from the public domain Pfam and InterPro: IPR003754

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Uroporphyrinogen-III synthase HemD Provide feedback

This family consists of uroporphyrinogen-III synthase HemD EC: also known as Hydroxymethylbilane hydrolyase (cyclizing) from eukaryotes, bacteria and archaea. This enzyme catalyses the reaction: Hydroxymethylbilane <=> uroporphyrinogen-III + H(2)O. Some members of this family are multi-functional proteins possessing other enzyme activities related to porphyrin biosynthesis, such as Q59294 with PF00590 however the aligned region corresponds with the uroporphyrinogen-III synthase EC: activity only. Uroporphyrinogen-III synthase is the fourth enzyme in the heme pathway [2]. Mutant forms of the Uroporphyrinogen-III synthase gene cause congenital erythropoietic porphyria in humans a recessive inborn error of metabolism also known as Gunther disease [1].

Literature references

  1. Xu W, Astrin KH, Desnick RJ; , Hum Mutat 1996;7:187-192.: Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene. PUBMED:8829650 EPMC:8829650

  2. Amillet JM, Labbe-Bois R; , Yeast 1995;11:419-424.: Isolation of the gene HEM4 encoding uroporphyrinogen III synthase in Saccharomyces cerevisiae. PUBMED:7597845 EPMC:7597845

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003754

This entry represents uroporphyrinogen III synthase (EC) which functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses the inversion of the final pyrrole unit (ring D) of the linear tetrapyrrole molecule, linking it to the first pyrrole unit (ring A), thereby generating a large macrocyclic structure called uroporphyrinogen III [PUBMED:11215515]. The enzyme folds into two alpha/beta domains connected by a beta-ladder, the active site being located between the two domains [PUBMED:11689424]. Congenital erythropoietic porphyria (CEP) is an autosomal recessive inborn error of metabolism that results from the markedly deficient activity of uroporphyrinogen III synthase [PUBMED:17270473].

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway [PUBMED:16564539]. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [PUBMED:17227226].

  • The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (EC), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (EC) to charge a tRNA with glutamate, glutamyl-tRNA reductase (EC) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (EC) to catalyse a transamination reaction to produce ALA.

  • The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase, EC) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase, EC) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (EC) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.

  • Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (EC). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (EC) [PUBMED:11215515].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

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

Loading domain graphics...


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

Representative proteomes UniProt
Jalview View  View  View  View  View  View  View  View  View 
HTML View                 
PP/heatmap 1                

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

Representative proteomes UniProt

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Representative proteomes UniProt
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

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

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...


This page displays the phylogenetic tree for this family's seed alignment. 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 alignment.

Note: You can also download the data file for the tree.

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 View help on the curation process

Seed source: COG1587
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Bashton M , Bateman A
Number in seed: 78
Number in full: 9253
Average length of the domain: 223.30 aa
Average identity of full alignment: 20 %
Average coverage of the sequence by the domain: 66.32 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.5 27.5
Trusted cut-off 27.6 27.6
Noise cut-off 27.4 27.4
Model length: 232
Family (HMM) version: 15
Download: download the raw HMM for this family

Species distribution

Sunburst controls


Weight segments by...

Change the size of the sunburst


Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls


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


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


There is 1 interaction for this family. More...



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 HEM4 domain has been found. There are 16 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

Loading structure mapping...