P09601 (HMOX1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Heme oxygenase 1
Short name=HO-1
EC=1.14.99.3

Gene names

Name:	HMOX1
Synonyms:	HO, HO1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	288 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed.
Catalytic activity	Heme + 3 AH2 + 3 O2 = biliverdin + Fe2+ + CO + 3 A + 3 H2O.
Subcellular location	Microsome. Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side Ref.12.
Tissue specificity	Expressed at higher levels in renal cancer tissue than in normal tissue (at protein level). Ref.9
Induction	Heme oxygenase 1 activity is highly inducible by its substrate heme and by various non-heme substances such as heavy metals, bromobenzene, endotoxin, oxidizing agents and UVA.
Involvement in disease	Heme oxygenase 1 deficiency (HMOX1D) [MIM:614034]: A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7
Sequence similarities	Belongs to the heme oxygenase family.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane Microsome
Coding sequence diversity	Polymorphism
Ligand	Heme Iron Metal-binding
Molecular function	Oxidoreductase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Traceable author statement PubMed 12239590. Source: BHF-UCL cell death Inferred from sequence or structural similarity. Source: BHF-UCL cellular iron ion homeostasis Traceable author statement. Source: Reactome cellular response to cadmium ion Inferred from electronic annotation. Source: Compara cellular response to hypoxia Inferred from expression pattern PubMed 12511571. Source: UniProtKB cellular response to nutrient Inferred from electronic annotation. Source: Compara endothelial cell proliferation Traceable author statement PubMed 12239590. Source: BHF-UCL erythrocyte homeostasis Inferred from mutant phenotype Ref.7. Source: BHF-UCL excretion Inferred by curator PubMed 17915953. Source: BHF-UCL heme catabolic process Inferred from direct assay PubMed 17915953. Source: BHF-UCL heme oxidation Inferred from direct assay PubMed 17915953. Source: BHF-UCL intracellular protein kinase cascade Traceable author statement PubMed 17652371. Source: BHF-UCL intrinsic apoptotic signaling pathway in response to DNA damage Inferred from electronic annotation. Source: Compara low-density lipoprotein particle clearance Traceable author statement Ref.7. Source: BHF-UCL negative regulation of DNA binding Inferred from electronic annotation. Source: Compara negative regulation of apoptotic process Inferred from mutant phenotype PubMed 18202225. Source: BHF-UCL negative regulation of leukocyte migration Traceable author statement PubMed 14525760. Source: BHF-UCL negative regulation of mast cell cytokine production Inferred from electronic annotation. Source: Compara negative regulation of mast cell degranulation Inferred from electronic annotation. Source: Compara negative regulation of neuron apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara negative regulation of smooth muscle cell proliferation Inferred from direct assay PubMed 17600318. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from mutant phenotype PubMed 12761501. Source: UniProtKB positive regulation of angiogenesis Inferred from electronic annotation. Source: Compara positive regulation of chemokine biosynthetic process Traceable author statement PubMed 17652371. Source: BHF-UCL positive regulation of smooth muscle cell proliferation Inferred from direct assay PubMed 17600318. Source: UniProtKB positive regulation of vasodilation Inferred by curator PubMed 17915953. Source: BHF-UCL protein homooligomerization Inferred from direct assay PubMed 19556236. Source: UniProtKB regulation of angiogenesis Traceable author statement PubMed 17652371. Source: BHF-UCL regulation of blood pressure Inferred from electronic annotation. Source: Compara regulation of sequence-specific DNA binding transcription factor activity Inferred from sequence or structural similarity. Source: BHF-UCL regulation of transcription from RNA polymerase II promoter in response to oxidative stress Inferred from sequence or structural similarity. Source: BHF-UCL response to estrogen stimulus Inferred from electronic annotation. Source: Compara response to hydrogen peroxide Inferred from sequence or structural similarity. Source: BHF-UCL response to nicotine Inferred from direct assay PubMed 18205746. Source: BHF-UCL small GTPase mediated signal transduction Inferred from electronic annotation. Source: Compara small molecule metabolic process Traceable author statement. Source: Reactome smooth muscle hyperplasia Traceable author statement PubMed 18289072. Source: BHF-UCL transmembrane transport Traceable author statement. Source: Reactome wound healing involved in inflammatory response Inferred from mutant phenotype Ref.7. Source: BHF-UCL
Cellular_component	caveola Inferred from electronic annotation. Source: Compara cytosol Inferred from electronic annotation. Source: Compara endoplasmic reticulum membrane Traceable author statement. Source: Reactome extracellular space Traceable author statement PubMed 18307065. Source: BHF-UCL nucleolus Inferred from electronic annotation. Source: Compara nucleus Inferred from sequence or structural similarity. Source: BHF-UCL
Molecular_function	enzyme binding Inferred from sequence or structural similarity PubMed 15516695. Source: BHF-UCL heme binding Inferred from direct assay PubMed 17915953. Source: BHF-UCL heme oxygenase (decyclizing) activity Inferred from mutant phenotype PubMed 19556236. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW phospholipase D activity Inferred from electronic annotation. Source: Compara protein homodimerization activity Inferred from direct assay PubMed 19556236. Source: UniProtKB signal transducer activity Inferred from mutant phenotype PubMed 12761501. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 288

288

Heme oxygenase 1

PRO_0000209687

Sites

Metal binding

25

1

Iron (heme axial ligand)

Binding site

18

1

Heme

Binding site

134

1

Heme

Binding site

183

1

Heme

Amino acid modifications

Modified residue

229

1

Phosphoserine Ref.10

Natural variations

Natural variant

7

1

D → H. Ref.3
Corresponds to variant rs2071747 [ dbSNP | Ensembl ].

VAR_019165

Natural variant

106

1

P → L.
Corresponds to variant rs9282702 [ dbSNP | Ensembl ].

VAR_022156

Experimental info

Mutagenesis

140

1

D → A: Inactive as a heme oxygenase but active as a peroxidase. Ref.14

Secondary structure

1

.

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288

Helix Strand Turn

Details...

Helix

13 – 20

8

Helix

22 – 30

9

Helix

32 – 38

7

Helix

44 – 68

25

Turn

72 – 74

3

Helix

75 – 77

3

Helix

80 – 83

4

Helix

86 – 97

12

Helix

101 – 103

3

Helix

109 – 124

16

Helix

126 – 128

3

Helix

129 – 155

27

Beta strand

159 – 161

3

Helix

165 – 167

3

Helix

175 – 188

14

Helix

193 – 220

28

Sequences

	Sequence		Length	Mass (Da)
	P09601 [UniParc]. Last modified July 1, 1989. Version 1. Checksum: AB47827778694064	FASTA	288	32,819
	10 20 30 40 50 60 MERPQPDSMP QDLSEALKEA TKEVHTQAEN AEFMRNFQKG QVTRDGFKLV MASLYHIYVA 70 80 90 100 110 120 LEEEIERNKE SPVFAPVYFP EELHRKAALE QDLAFWYGPR WQEVIPYTPA MQRYVKRLHE 130 140 150 160 170 180 VGRTEPELLV AHAYTRYLGD LSGGQVLKKI AQKALDLPSS GEGLAFFTFP NIASATKFKQ 190 200 210 220 230 240 LYRSRMNSLE MTPAVRQRVI EEAKTAFLLN IQLFEELQEL LTHDTKDQSP SRAPGLRQRA 250 260 270 280 SNKVQDSAPV ETPRGKPPLN TRSQAPLLRW VLTLSFLVAT VAVGLYAM

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human heme oxygenase cDNA and induction of its mRNA by hemin." Yoshida T., Biro P., Cohen T., Mueller R.M., Shibahara S. Eur. J. Biochem. 171:457-461(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"A genome annotation-driven approach to cloning the human ORFeome." Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A., Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J., Beare D.M., Dunham I. Genome Biol. 5:R84.1-R84.11(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	SeattleSNPs variation discovery resource Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT HIS-7.
[4]	"The DNA sequence of human chromosome 22." Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M. , Buck D., Burgess J., Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A., Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C., Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L., Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L., Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N., Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R., Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y., Wright H. Nature 402:489-495(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite." Keyse S.M., Tyrrell R.M. Proc. Natl. Acad. Sci. U.S.A. 86:99-103(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-103. Tissue: Foreskin.
[6]	"Structural organization of the human heme oxygenase gene and the function of its promoter." Shibahara S., Sato M., Muller R.M., Yoshida T. Eur. J. Biochem. 179:557-563(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-7.
[7]	"Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency." Yachie A., Niida Y., Wada T., Igarashi N., Kaneda H., Toma T., Ohta K., Kasahara Y., Koizumi S. J. Clin. Invest. 103:129-135(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN HMOX1D.
[8]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[9]	"CXCR3-B can mediate growth-inhibitory signals in human renal cancer cells by down-regulating the expression of heme oxygenase-1." Datta D., Banerjee P., Gasser M., Waaga-Gasser A.M., Pal S. J. Biol. Chem. 285:36842-36848(2010) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[10]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-229, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"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] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]	"Endoplasmic reticulum anchored heme-oxygenase 1 faces the cytosol." Gottlieb Y., Truman M., Cohen L.A., Leichtmann-Bardoogo Y., Meyron-Holtz E.G. Haematologica 97:1489-1493(2012) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[13]	"Crystal structure of human heme oxygenase-1." Schuller D.J., Wilks A., Ortiz de Montellano P.R., Poulos T.L. Nat. Struct. Biol. 6:860-867(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS).
[14]	"Crystal structures of the ferric, ferrous, and ferrous-NO forms of the Asp140Ala mutant of human heme oxygenase-1: catalytic implications." Lad L., Wang J., Li H., Friedman J., Bhaskar B., Ortiz de Montellano P.R., Poulos T.L. J. Mol. Biol. 330:527-538(2003) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 1-233 OF MUTANT ALA-140, HEME-BINDING SITES, MUTAGENESIS OF ASP-140.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X06985 mRNA. Translation: CAA30045.1.
CR456505 mRNA. Translation: CAG30391.1.
AY460337 Genomic DNA. Translation: AAR23262.1.
Z82244 Genomic DNA. Translation: CAB05109.1.
M23041 mRNA. Translation: AAA50403.1.
X14782 Genomic DNA. Translation: CAA32886.1.

IPI

IPI00215893.

PIR

S00325.

RefSeq

NP_002124.1. NM_002133.2.

UniGene

Hs.517581.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1N3U	X-ray	2.58	A/B	1-233	[»]
1N45	X-ray	1.50	A/B	1-233	[»]
1NI6	X-ray	2.10	A/B/C/D	1-224	[»]
1OYK	X-ray	2.59	A/B	1-233	[»]
1OYL	X-ray	1.59	A/B	1-233	[»]
1OZE	X-ray	2.19	A/B	1-233	[»]
1OZL	X-ray	1.58	A/B	1-233	[»]
1OZR	X-ray	1.74	A/B	1-233	[»]
1OZW	X-ray	1.55	A/B	1-233	[»]
1S13	X-ray	2.29	A/B	1-233	[»]
1S8C	X-ray	2.19	A/B/C/D	1-233	[»]
1T5P	X-ray	2.11	A/B	1-233	[»]
1TWN	X-ray	2.20	A/B	1-233	[»]
1TWR	X-ray	2.10	A/B	1-233	[»]
1XJZ	X-ray	1.88	A/B	1-233	[»]
1XK0	X-ray	2.18	A/B	1-233	[»]
1XK1	X-ray	2.08	A/B	1-233	[»]
1XK2	X-ray	2.20	A/B	1-233	[»]
1XK3	X-ray	2.08	A/B	1-233	[»]
3CZY	X-ray	1.54	A/B	1-233	[»]
3HOK	X-ray	2.19	A/B	1-233	[»]
3K4F	X-ray	2.17	A/B	1-233	[»]
3TGM	X-ray	2.85	A/B	1-233	[»]

ProteinModelPortal

P09601.

ModBase

Search...

Protein-protein interaction databases

IntAct

P09601. 7 interactions.

STRING

9606.ENSP00000216117.

PTM databases

PhosphoSite

P09601.

Polymorphism databases

DMDM

123446.

Proteomic databases

PaxDb

P09601.

PRIDE

P09601.

Protocols and materials databases

DNASU

3162.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000216117; ENSP00000216117; ENSG00000100292.

GeneID

3162.

KEGG

hsa:3162.

UCSC

uc003ant.2. human.

Organism-specific databases

CTD

3162.

GeneCards

GC22P035776.

HGNC

HGNC:5013. HMOX1.

HPA

CAB017444.
HPA000635.

MIM

141250. gene.
614034. phenotype.

neXtProt

NX_P09601.

PharmGKB

PA29341.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5398.

HOGENOM

HOG000233221.

HOVERGEN

HBG005982.

InParanoid

P09601.

KO

K00510.

OMA

YAPLYFP.

OrthoDB

EOG4TF0KR.

PhylomeDB

P09601.

Enzyme and pathway databases

BioCyc

MetaCyc:HS02027-MONOMER.

Pathway_Interaction_DB

hif1_tfpathway. HIF-1-alpha transcription factor network.

Reactome

REACT_111217. Metabolism.
REACT_15518. Transmembrane transport of small molecules.

Gene expression databases

ArrayExpress

P09601.

Bgee

P09601.

CleanEx

HS_HMOX1.

Genevestigator

P09601.

GermOnline

ENSG00000100292. Homo sapiens.

Family and domain databases

Gene3D

1.20.910.10. 1 hit.

InterPro

IPR002051. Haem_Oase.
IPR016053. Haem_Oase-like.
IPR016084. Haem_Oase-like_multi-hlx.
IPR018207. Haem_oxygenase_CS.
[Graphical view]

PANTHER

PTHR10720. PTHR10720. 1 hit.

Pfam

PF01126. Heme_oxygenase. 1 hit.
[Graphical view]

PIRSF

PIRSF000343. Haem_Oase. 1 hit.

PRINTS

PR00088. HAEMOXYGNASE.

SUPFAM

SSF48613. Heme_oxygenase. 1 hit.

PROSITE

PS00593. HEME_OXYGENASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P09601.

ChEMBL

CHEMBL2823.

DrugBank

DB00157. NADH.

EvolutionaryTrace

P09601.

GenomeRNAi

3162.

NextBio

12538.

SOURCE

Search...

Entry information

Entry name

HMOX1_HUMAN

Accession

Primary (citable) accession number: P09601

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	July 1, 1989
Last modified:	May 1, 2013
This is version 145 of the entry and version 1 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.