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7  structures 54  species 3  interactions 66  sequences 2  architectures

Family: Biliv-reduc_cat (PF09166)

Summary: Biliverdin reductase, catalytic

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Biliverdin reductase Edit Wikipedia article

biliverdin reductase
1hdo.jpg
Identifiers
EC number 1.3.1.24
CAS number 9074-10-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
biliverdin reductase A
BLVRA 2H63.png
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).
Identifiers
Symbol BLVRA
Alt. symbols BLVR
Entrez 644
HUGO 1062
OMIM 109750
RefSeq NM_000712
UniProt P53004
Other data
EC number 1.3.1.24
Locus Chr. 7 p14-cen
biliverdin reductase B
Identifiers
Symbol BLVRB
Alt. symbols FLR
Entrez 645
HUGO 1063
OMIM 600941
RefSeq NM_000713
UniProt P30043
Other data
EC number 1.3.1.24
Locus Chr. 19 q13.1-13.2
Biliverdin reductase, catalytic
PDB 1lc3 EBI.jpg
crystal structure of a biliverdin reductase enzyme-cofactor complex
Identifiers
Symbol Biliv-reduc_cat
Pfam PF09166
InterPro IPR015249
SCOP 1lc0
SUPERFAMILY 1lc0

Biliverdin reductase (BVR) is an enzyme (EC 1.3.1.24) 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.[1] 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.[2] 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.[3]

Reduction of biliverdin to bilirubin catalyzed by biliverdin reductase.

Structure

BVR is composed of two closely packed domains, between 247-415 amino acids long and containing a Rossmann fold.[4] BVR has also been determined to be a zinc-binding protein with each enzyme protein having one strong-binding zinc atom.[5][6]

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.[7]

Function

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.[8]

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.[9] 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.[10]

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.[11] 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.[12]

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.[13] The mechanism is due to the amplification of the potent antioxidant actions of bilirubin, as this can ameliorate free radical-mediated diseases.[14]

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.[15] Through this protective and amplifying cycle, BVR allows low concentrations of bilirubin to overcome 10,000-fold higher concentrations of ROS.[16]

References

  1. ^ Rigney E, Mantle TJ (Nov 1988). "The reaction mechanism of bovine kidney biliverdin reductase". Biochimica et Biophysica Acta 957 (2): 237–42. doi:10.1016/0167-4838(88)90278-6. PMID 3191141. 
  2. ^ Wang J, de Montellano PR (May 2003). "The binding sites on human heme oxygenase-1 for cytochrome p450 reductase and biliverdin reductase". The Journal of Biological Chemistry 278 (22): 20069–76. doi:10.1074/jbc.M300989200. PMID 12626517. 
  3. ^ Ahmad Z, Salim M, Maines MD (Mar 2002). "Human biliverdin reductase is a leucine zipper-like DNA-binding protein and functions in transcriptional activation of heme oxygenase-1 by oxidative stress". The Journal of Biological Chemistry 277 (11): 9226–32. doi:10.1074/jbc.M108239200. PMID 11773068. 
  4. ^ Bellamacina CR (Sep 1996). "The nicotinamide dinucleotide binding motif: a comparison of nucleotide binding proteins". FASEB Journal 10 (11): 1257–69. PMID 8836039. 
  5. ^ Maines MD, Polevoda BV, Huang TJ, McCoubrey WK (Jan 1996). "Human biliverdin IXalpha reductase is a zinc-metalloprotein. Characterization of purified and Escherichia coli expressed enzymes". European Journal of Biochemistry / FEBS 235 (1-2): 372–81. doi:10.1111/j.1432-1033.1996.00372.x. PMID 8631357. 
  6. ^ PDB: 1GCU​; Kikuchi A, Park SY, Miyatake H, Sun D, Sato M, Yoshida T, Shiro Y (Mar 2001). "Crystal structure of rat biliverdin reductase". Nature Structural Biology 8 (3): 221–5. doi:10.1038/84955. PMID 11224565. 
  7. ^ Whitby FG, Phillips JD, Hill CP, McCoubrey W, Maines MD (Jun 2002). "Crystal structure of a biliverdin IXalpha reductase enzyme-cofactor complex". Journal of Molecular Biology 319 (5): 1199–210. doi:10.1016/S0022-2836(02)00383-2. PMID 12079357. 
  8. ^ 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". The Journal of Biological Chemistry 279 (19): 19916–23. doi:10.1074/jbc.M314251200. PMID 14988408. 
  9. ^ Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR, Chowdhury NR, Jansen PL (Jul 1994). "Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man". The Journal of Biological Chemistry 269 (27): 17960–4. PMID 8027054. 
  10. ^ McDonagh AF, Palma LA, Schmid R (Jan 1981). "Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig". The Biochemical Journal 194 (1): 273–82. doi:10.1042/bj1940273. PMC 1162741. PMID 7305981. 
  11. ^ Florczyk UM, Jozkowicz A, Dulak J (January–February 2008). "Biliverdin reductase: new features of an old enzyme and its potential therapeutic significance". Pharmacological Reports 60 (1): 38–48. PMID 18276984. 
  12. ^ Kapitulnik J, Maines MD (Mar 2009). "Pleiotropic functions of biliverdin reductase: cellular signaling and generation of cytoprotective and cytotoxic bilirubin". Trends in Pharmacological Sciences 30 (3): 129–37. doi:10.1016/j.tips.2008.12.003. PMID 19217170. 
  13. ^ Maghzal GJ, Leck MC, Collinson E, Li C, Stocker R (Oct 2009). "Limited role for the bilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection by biliverdin reductase". The Journal of Biological Chemistry 284 (43): 29251–9. doi:10.1074/jbc.M109.037119. PMC 2785555. PMID 19690164. 
  14. ^ Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, Cynader M (Aug 2008). "Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis". Journal of Immunology 181 (3): 1887–97. doi:10.4049/jimmunol.181.3.1887. PMID 18641326. 
  15. ^ Baranano DE, Rao M, Ferris CD, Snyder SH (Dec 2002). "Biliverdin reductase: a major physiologic cytoprotectant". Proceedings of the National Academy of Sciences of the United States of America 99 (25): 16093–8. Bibcode:2002PNAS...9916093B. doi:10.1073/pnas.252626999. PMC 138570. PMID 12456881. 
  16. ^ Sedlak TW, Snyder SH (Jun 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. 

External links

This article incorporates text from the public domain Pfam and InterPro IPR015249

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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.

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 [1].

Literature references

  1. Whitby FG, Phillips JD, Hill CP, McCoubrey W, Maines MD; , J Mol Biol. 2002;319:1199-1210.: Crystal structure of a biliverdin IXalpha reductase enzyme-cofactor complex. PUBMED:12079357 EPMC:12079357


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].

Gene Ontology

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Domain organisation

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(13)
Full
(66)
Representative proteomes UniProt
(134)
NCBI
(311)
Meta
(0)
RP15
(8)
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RP55
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RP75
(62)
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Seed source: pdb_1lc0
Previous IDs: none
Type: Domain
Author: Sammut SJ
Number in seed: 13
Number in full: 66
Average length of the domain: 109.30 aa
Average identity of full alignment: 62 %
Average coverage of the sequence by the domain: 37.37 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.0 21.0
Trusted cut-off 21.0 35.5
Noise cut-off 19.9 20.4
Model length: 113
Family (HMM) version: 8
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Interactions

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

GFO_IDH_MocA GFO_IDH_MocA Biliv-reduc_cat

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 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.

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