P53004 (BIEA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Biliverdin reductase A
Short name=BVR A
EC=1.3.1.24

Alternative name(s):
Biliverdin-IX alpha-reductase

Gene names

Name:	BLVRA
Synonyms:	BLVR, BVR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	296 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)

Function	Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor.
Catalytic activity	Bilirubin + NAD(P)+ = biliverdin + NAD(P)H.
Cofactor	Binds 1 zinc ion per subunit.
Pathway	Porphyrin metabolism; protoheme degradation.
Subunit structure	Monomer.
Subcellular location	Cytoplasm.
Tissue specificity	Liver.
Involvement in disease	Defects in BLVRA are the cause of hyperbiliverdinemia (HBLVD) [MIM:614156]. HBLVD is a condition characterized by a green discoloration of the skin, urine, serum, and other bodily fluids. It is due to increased biliverdin resulting from inefficient conversion to bilirubin. Affected individuals appear to have symptoms only in the context of obstructive cholestasis and/or liver failure. In some cases, green jaundice can resolve after resolution of obstructive cholestasis. Ref.11
Miscellaneous	Uses the reactants NADH or NADPH depending on the pH; NADH is used at the acidic pH range (6-6.9) and NADPH at the alkaline range (8.5-8.7). NADPH, however, is the probable reactant in biological systems.
Sequence similarities	Belongs to the gfo/idh/mocA family. Biliverdin reductase subfamily.

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	Metal-binding NAD NADP Zinc
Molecular function	Oxidoreductase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	heme catabolic process Traceable author statement. Source: UniProtKB
Cellular component	cytosol Traceable author statement. Source: Reactome
Molecular function	biliverdin reductase activity Inferred from direct assay. Source: UniProtKB nucleotide binding Inferred from electronic annotation. Source: InterPro zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Propeptide

1 – 2

2

PRO_0000010852

Chain

3 – 296

294

Biliverdin reductase A Ref.2

PRO_0000010853

Regions

Nucleotide binding

15 – 20

6

NAD or NADP

Nucleotide binding

44 – 46

3

NAD or NADP

Nucleotide binding

77 – 80

4

NAD or NADP

Compositional bias

11 – 16

6

Poly-Val

Sites

Metal binding

280

1

Zinc Potential

Metal binding

281

1

Zinc Potential

Metal binding

292

1

Zinc Potential

Metal binding

293

1

Zinc Potential

Binding site

98

1

NAD or NADP; via carbonyl oxygen

Amino acid modifications

Modified residue

1

1

N-acetylmethionine Ref.10

Modified residue

174

1

Phosphothreonine Ref.12

Modified residue

178

1

Phosphoserine Ref.12

Modified residue

230

1

Phosphoserine Ref.9

Modified residue

237

1

Phosphoserine Ref.10

Modified residue

248

1

N6-acetyllysine Ref.13

Modified residue

253

1

N6-acetyllysine Ref.13

Natural variations

Natural variant

3

1

A → T. Ref.1 Ref.4 Ref.6
Corresponds to variant rs699512 [ dbSNP | Ensembl ].

VAR_019230

Natural variant

37

1

L → V. Ref.4
Corresponds to variant rs17245918 [ dbSNP | Ensembl ].

VAR_019231

Natural variant

56

1

Q → R. Ref.4
Corresponds to variant rs1050916 [ dbSNP | Ensembl ].

VAR_014851

Experimental info

Sequence conflict

121

1

L → S in AAH05902. Ref.6

Sequence conflict

154 – 155

2

AG → SD in CAA63635. Ref.2

Sequence conflict

160

1

E → D in CAA63635. Ref.2

Secondary structure

1

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296

Helix Strand Turn

Details...

Beta strand

9 – 14

6

Helix

18 – 28

11

Helix

33 – 36

4

Beta strand

37 – 43

7

Beta strand

50 – 53

4

Helix

59 – 64

6

Beta strand

70 – 73

4

Helix

77 – 89

13

Beta strand

93 – 98

6

Helix

104 – 117

14

Beta strand

121 – 124

4

Helix

126 – 129

4

Helix

131 – 140

10

Beta strand

145 – 154

10

Helix

159 – 162

4

Helix

165 – 168

4

Helix

170 – 180

11

Beta strand

182 – 193

12

Beta strand

198 – 207

10

Beta strand

212 – 219

8

Beta strand

226 – 235

10

Helix

250 – 262

13

Helix

268 – 290

23

Sequences

	Sequence		Length	Mass (Da)
	P53004 [UniParc]. Last modified October 10, 2002. Version 2. Checksum: 2CF2AA7F1CDDB707	FASTA	296	33,428
	10 20 30 40 50 60 MNAEPERKFG VVVVGVGRAG SVRMRDLRNP HPSSAFLNLI GFVSRRELGS IDGVQQISLE 70 80 90 100 110 120 DALSSQEVEV AYICSESSSH EDYIRQFLNA GKHVLVEYPM TLSLAAAQEL WELAEQKGKV 130 140 150 160 170 180 LHEEHVELLM EEFAFLKKEV VGKDLLKGSL LFTAGPLEEE RFGFPAFSGI SRLTWLVSLF 190 200 210 220 230 240 GELSLVSATL EERKEDQYMK MTVCLETEKK SPLSWIEEKG PGLKRNRYLS FHFKSGSLEN 250 260 270 280 290 VPNVGVNKNI FLKDQNIFVQ KLLGQFSEKE LAAEKKRILH CLGLAEEIQK YCCSRK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of the cDNA encoding human biliverdin-IX alpha reductase." Komuro A., Tobe T., Nakano Y., Yamaguchi T., Tomita M. Biochim. Biophys. Acta 1309:89-99(1996) [PubMed: 8950184] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT THR-3.
[2]	"Human biliverdin IXalpha reductase is a zinc-metalloprotein. Characterization of purified and Escherichia coli expressed enzymes." Maines M.D., Polevoda B.V., Huang T.-J., McCoubrey W.K. Jr. Eur. J. Biochem. 235:372-381(1996) [PubMed: 8631357] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Skeletal muscle.
[4]	NIEHS SNPs program Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS THR-3; VAL-37 AND ARG-56.
[5]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed: 12853948] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT THR-3. Tissue: Brain and Prostate.
[7]	"Purification and characterization of human biliverdin reductase." Maines M.D., Trakshel G.M. Arch. Biochem. Biophys. 300:320-326(1993) [PubMed: 8424666] [Abstract] Cited for: PROTEIN SEQUENCE OF 3-36; 48-74 AND 228-248. Tissue: Liver.
[8]	"Biliverdin-IX alpha reductase and biliverdin-IX beta reductase from human liver. Purification and characterization." Yamaguchi T., Komoda Y., Nakajima H. J. Biol. Chem. 269:24343-24348(1994) [PubMed: 7929092] [Abstract] Cited for: PROTEIN SEQUENCE OF 3-22. Tissue: Liver.
[9]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-237, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[11]	"A novel mutation in the biliverdin reductase-A gene combined with liver cirrhosis results in hyperbiliverdinaemia (green jaundice)." Gafvels M., Holmstrom P., Somell A., Sjovall F., Svensson J.O., Stahle L., Broome U., Stal P. Liver Int. 29:1116-1124(2009) [PubMed: 19580635] [Abstract] Cited for: INVOLVEMENT IN HBLVD.
[12]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-174 AND SER-178, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[13]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-248 AND LYS-253, MASS SPECTROMETRY.
[14]	"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: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]	"Crystal structure of human biliverdin reductase A." Structural genomics consortium (SGC) Submitted (FEB-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 7-296 IN COMPLEX WITH NADP.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U34877 mRNA. Translation: AAC35588.1.
X93086 mRNA. Translation: CAA63635.1.
AK291862 mRNA. Translation: BAF84551.1.
AY616754 Genomic DNA. Translation: AAT11126.1.
AC005189 Genomic DNA. No translation available.
AC004939 Genomic DNA. Translation: AAD05025.1.
AC004985 Genomic DNA. Translation: AAP21879.1.
BC005902 mRNA. Translation: AAH05902.1.
BC008456 mRNA. Translation: AAH08456.1.

IPI

IPI00294158.

PIR

G02066.
S62624.

RefSeq

NP_000703.2. NM_000712.3.

UniGene

Hs.488143.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2H63	X-ray	2.70	A/B/C/D	7-296	[»]

ProteinModelPortal

P53004.

SMR

P53004. Positions 7-291.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-42180N.

MINT

MINT-1212210.

STRING

P53004.

PTM databases

PhosphoSite

P53004.

Polymorphism databases

DMDM

23830892.

2D gel databases

OGP

P53004.

REPRODUCTION-2DPAGE

IPI00294158.

Proteomic databases

PeptideAtlas

P53004.

PRIDE

P53004.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000265523; ENSP00000265523; ENSG00000106605.
ENST00000402924; ENSP00000385757; ENSG00000106605.

GeneID

644.

KEGG

hsa:644.

UCSC

uc003tir.1. human.

Organism-specific databases

CTD

644.

GeneCards

GC07P043764.

H-InvDB

HIX0006633.

HGNC

HGNC:1062. BLVRA.

HPA

HPA042865.

MIM

109750. gene.
614156. phenotype.

neXtProt

NX_P53004.

PharmGKB

PA25373.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG14479.

GeneTree

ENSGT00390000011072.

HOGENOM

HBG717259.

HOVERGEN

HBG003218.

InParanoid

P53004.

OMA

ERKEDQY.

OrthoDB

EOG46HGB7.

PhylomeDB

P53004.

Enzyme and pathway databases

BioCyc

MetaCyc:MONOMER-13862.

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

P53004.

Bgee

P53004.

CleanEx

HS_BLVRA.

Genevestigator

P53004.

GermOnline

ENSG00000106605. Homo sapiens.

Family and domain databases

InterPro

IPR017094. Biliverdin_Rdtase_A.
IPR015249. Biliverdin_Rdtase_cat.
IPR016040. NAD(P)-bd_dom.
IPR000683. Oxidoreductase_N.
[Graphical view]

Gene3D

G3DSA:3.40.50.720. NAD(P)-bd. 1 hit.

KO

K00214.

Pfam

PF09166. Biliv-reduc_cat. 1 hit.
PF01408. GFO_IDH_MocA. 1 hit.
[Graphical view]

PIRSF

PIRSF037032. Biliverdin_reductase_A. 1 hit.

ProDom

PD040165. Biliverdin_Rdtase_cat. 1 hit.
[Graphical view] [Entries sharing at least one domain]

ProtoNet

Search...

Other

DrugBank

DB00157. NADH.

NextBio

2614.

SOURCE

Search...

Entry information

Entry name

BIEA_HUMAN

Accession

Primary (citable) accession number: P53004
Secondary accession number(s): A8K747 , O95019, Q86UX0, Q96QL4, Q9BRW8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 10, 2002
Last modified:	January 25, 2012
This is version 115 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.