Summary: Biliverdin reductase, catalytic
This is the Wikipedia entry entitled "Biliverdin reductase". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at email@example.com and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Biliverdin reductase Edit Wikipedia article
Crystallographic structure of human biliverdin reductase A.
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|biliverdin reductase A|
Crystallographic structure of human biliverdin reductase A based on the PDB 2H63 coordinates. The enzyme is displayed as a rainbow colored cartoon (N-terminus = blue, C-terminus = red) while the NADP cofactor is displayed as space-filling model (carbon = white, oxygen = red, nitrogen = blue, phosphorus = orange).
|Locus||Chr. 7 p14-cen|
|biliverdin reductase B|
|Locus||Chr. 19 q13.1-13.2|
|Biliverdin reductase, catalytic|
crystal structure of a biliverdin reductase enzyme-cofactor complex
Biliverdin reductase (BVR) is an enzyme (EC 22.214.171.124) found in all tissues under normal conditions, but especially in reticulo-macrophages of the liver and spleen. BVR facilitates the conversion of biliverdin to bilirubin via the reduction of a double-bond between the second and third pyrrole ring into a single-bond.
There are two isozymes, in humans, each encoded by its own gene, biliverdin reductase A (BLVRA) and biliverdin reductase B (BLVRB).
 Mechanism of catalysis
BVR acts on biliverdin by reducing its double-bond between the pyrrole rings into a single-bond. It accomplishes this using NADPH + H+ as an electron donor, forming bilirubin and NADP+ as products.
BVR catalyzes this reaction through an overlapping binding site including Lys18, Lys22, Lys179, Arg183, and Arg185 as key residues. This binding site attaches to biliverdin, and causes its dissociation from heme oxygenase (HO) (which catalyzes reaction of ferric heme --> biliverdin), causing the subsequent reduction to bilirubin.
BVR is composed of two closely packed domains, between 247-415 amino acids long and containing a Rossmann fold. BVR has also been determined to be a zinc-binding protein with each enzyme protein having one strong-binding zinc atom.
The C-terminal half of BVR contains the catalytic domain, which adopts a structure containing a six-stranded beta-sheet that is flanked on one face by several alpha-helices. This domain contains the catalytic active site, which reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor.
BVR works with the biliverdin/bilirubin redox cycle. It converts biliverdin to bilirubin (a strong antioxidant), which is then converted back into biliverdin through the actions of reactive oxygen species (ROS). This cycle allows for the neutralization of ROS, and the reuse of biliverdin products. Biliverdin also is replenished in the cycle with its formation from heme units through heme oxygenase (HO) localized from the endoplasmic reticulum.
Bilirubin, being one of the last products of heme degradation in the liver, is further processed and excreted in bile after conjugation with glucuronic acid. In this way, BVR is essential in many mammals for the disposal of heme catabolites – especially in the fetus where the placental membranes are bilirubin-permeable but not biliverdin-permeable - aiding in the removal of potentially toxic protein build-up.
BVR has also more recently been recognized as a regulator of glucose metabolism and in cell growth and apoptosis control, due to its dual-specificity kinase character. This control over glucose metabolism indicates that BVR may play a role in pathogenesis of multiple metabolic diseases - the notable one being diabetes, by control of the upstream activator of insulin growth factor-1 (IGF-1) and mitogen-activated protein kinase (MAPK) signaling pathway.
 Disease relevance
BVR acts as a means to regenerate bilirubin in a repeating redox cycle without significantly modifying the concentration of available bilirubin. With these levels maintained, it appears that BVR represents a new strategy for the treatment of multiple sclerosis and other types of oxidative stress-mediated diseases. The mechanism is due to the amplification of the potent antioxidant actions of bilirubin, as this can ameliorate free radical-mediated diseases.
Studies have shown that the BVR redox cycle is essential in providing physiological cytoprotection. Genetic knock-outs and reduced BVR levels have demonstrated increased formation of ROS, and results in augmented cell death. Cells that experienced a 90% reduction in BVR experienced three times normal ROS levels. Through this protective and amplifying cycle, BVR allows low concentrations of bilirubin to overcome 10,000-fold higher concentrations of ROS.
- PDB 1GCU; Kikuchi A, Park SY, Miyatake H, Sun D, Sato M, Yoshida T, Shiro Y (March 2001). "Crystal structure of rat biliverdin reductase". Nat. Struct. Biol. 8 (3): 221–5. doi:10.1038/84955. PMID 11224565.
- Rigney E, Mantle TJ (November 1988). "The reaction mechanism of bovine kidney biliverdin reductase". Biochim. Biophys. Acta 957 (2): 237–42. doi:10.1016/0167-4838(88)90278-6. PMID 3191141.
- Wang J, de Montellano PR. (March 2003). "The binding sites on human heme oxygenase-1 for cytochrome p450 reductase and biliverdin reductase". J. Biol. Chem. 278 (22): 20069–76. doi:10.1074/jbc.M300989200. PMID 12626517.
- Ahmad Z, Salim M, Maines MD. (December 2001). "Human biliverdin reductase is a leucine zipper-like DNA-binding protein and functions in transcriptional activation of heme oxygenase-1 by oxidate stress". J. Biol. Chem. 277 (11): 9226–32. doi:10.1074/jbc.M108239200. PMID 11773068.
- Bellamacina CR (September 1996). "The nicotinamide dinucleotide binding motif: a comparison of nucleotide binding proteins". FASEB J. 10 (11): 1257–69. PMID 8836039.
- Maines MD, Polevoda BV, Huang TJ, McCoubrey WK (January 1996). "Human biliverdin IXalpha reductase is a zinc-metalloprotein. Characterization of purified and Escherichia coli expressed enzymes". Eur. J. Biochem. 235 (1–2): 372–81. doi:10.1111/j.1432-1033.1996.00372.x. PMID 8631357.
- Whitby FG, Phillips JD, Hill CP, McCoubrey W, Maines MD (June 2002). "Crystal structure of a biliverdin IXalpha reductase enzyme-cofactor complex". J. Mol. Biol. 319 (5): 1199–210. doi:10.1016/S0022-2836(02)00383-2. PMID 12079357.
- Kravets A, Hu Z, Miralem T, Torno MD, Maines MD (May 2004). "Biliverdin reductase, a novel regulator for induction of activating transcription factor-2 and heme oxygenase-1". J. Biol. Chem. 279 (19): 19916–23. doi:10.1074/jbc.M314251200. PMID 14988408.
- Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR, Chowdhury NR, Jansen PL (July 1994). "Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man". J. Biol. Chem. 269 (27): 17960–4. PMID 8027054.
- McDonagh AF, Palma LA, Schmid R (January 1981). "Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig". Biochem. J. 194 (1): 273–82. PMC 1162741. PMID 7305981.
- Florczyk UM, Jozkowicz A, Dulak J. (January–February 2008). "Biliverdin reductase: new features of an old enzyme and its potential therapeutic significance". Pharmacol. Rep. 60 (1): 38–48. PMID 18276984.
- Kapitulnik J, Maines MD. (March 2009). "Pleiotropic functions of biliverdin reductase: cellular signaling and generation of cytoprotective and cytotoxic bilirubin". Trends Pharmacol. Sci. 30 (3): 129–37. doi:10.1016/j.tips.2008.12.003. PMID 19217170.
- Maghzal GJ, Leck MC, Collinson E, Li C, Stocker R. (October 2009). "Limited role for the bilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection by biliverdin reductase". J. Biol. Chem. 284 (43): 29251–9. doi:10.1074/jbc.M109.037119. PMC 2785555. PMID 19690164.
- Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, Cynader M (August 2008). "Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis". J. Immunol. 181 (3): 1887–97. PMID 18641326.
- Baranano DE, Rao M, Ferris CD, Snyder SH (December 2002). "Biliverdin reductase: a major physiologic cytoprotectant". Proc. Natl. Acad. Sci. U.S.A. 99 (25): 16093–8. Bibcode:2002PNAS...9916093B. doi:10.1073/pnas.252626999. PMC 138570. PMID 12456881.
- Sedlak TW, Snyder SH (June 2004). "Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle". Pediatrics 113 (6): 1776–82. doi:10.1542/peds.113.6.1776. PMID 15173506.
Biliverdin reductase, catalytic Provide feedback
Members of this family adopt a structure consisting of four alpha helices and six beta sheets, in an alpha-beta-alpha-alpha-alpha-beta-beta-beta-beta-beta arrangement. They contain a catalytic active site, capable of reducing the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor .
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR015249
This entry represents the biliverdin reductase, catalytic domain, which adopts a structure ccontaining a six-stranded beta-sheet that is flanked on one face by several alpha-helices. This domain contains the catalytic active site which reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor [PUBMED:12079357].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||zinc ion binding (GO:0008270)|
|biliverdin reductase activity (GO:0004074)|
|Biological process||heme catabolic process (GO:0042167)|
|oxidation-reduction process (GO:0055114)|
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Loading domain graphics...
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
If you find these logos useful in your own work, please consider citing the following article:
Note: You can also download the data file for the tree.
Curation and family details
|Number in seed:||4|
|Number in full:||55|
|Average length of the domain:||111.70 aa|
|Average identity of full alignment:||61 %|
|Average coverage of the sequence by the domain:||38.98 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||5|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
How the sunburst is generated
Colouring and labels
Anomalies in the taxonomy tree
Missing taxonomic levels
Unmapped species names
Too many species/sequences
The tree shows the occurrence of this domain across different species. More...
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 Biliv-reduc_cat domain has been found. There are 7 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 seqence.
Loading structure mapping...