Reviewed, UniProtKB/Swiss-Prot P00390 (GSHR_HUMAN)

Names and origin

Protein names

Recommended name:
    Glutathione reductase, mitochondrial
      Short name=GRase
      Short name=GR
    EC=1.8.1.7

Gene names

Name:	GSR
Synonyms:	GLUR, GRD1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	522 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	Maintains high levels of reduced glutathione in the cytosol.
Catalytic activity	2 glutathione + NADP+ = glutathione disulfide + NADPH.
Cofactor	Binds 1 FAD per subunit.
Subunit structure	Homodimer; disulfide-linked. Ref.12
Subcellular location	Mitochondrion. Cytoplasm.
Domain	Each subunit can be divided into 4 domains that are consecutive along the polypeptide chain. Domains 1 and 2 bind FAD and NADPH, respectively. Domain 4 forms the interface.
Post-translational modification	The initiator Met-1 of isoform Cytoplasmic is removed. Isoform Cytoplasmic is acetylated at position 2.
Miscellaneous	The active site is a redox-active disulfide bond.
Sequence similarities	Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.

Ontologies

Keywords
Cellular component	Cytoplasm Mitochondrion
Coding sequence diversity	Alternative initiation Polymorphism
Domain	Redox-active center Transit peptide
Ligand	FAD Flavoprotein NADP
Molecular function	Oxidoreductase
PTM	Acetylation Disulfide bond Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	cell redox homeostasis Inferred from electronic annotation. Source: InterPro glutathione metabolic process Inferred from electronic annotation. Source: InterPro oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Inferred from Experiment. Source: Reactome mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	FAD binding Inferred from electronic annotation. Source: InterPro NADP or NADPH binding Inferred from electronic annotation. Source: InterPro electron carrier activity Traceable author statement. Source: UniProtKB glutathione-disulfide reductase activity Inferred from Experiment. Source: Reactome
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative initiation. [Align] [Select]

Isoform Mitochondrial (identifier: P00390-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Cytoplasmic (identifier: P00390-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-43: Missing.

Note: Initiator Met-1 is removed. Contains a N-acetylalanine at position 2.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 43

43

Mitochondrion Potential

Chain

44 – 522

479

Glutathione reductase, mitochondrial

PRO_0000030276

Regions

Nucleotide binding

94 – 102

9

FAD

Sites

Active site

511

1

Proton acceptor

Amino acid modifications

Modified residue

65

1

Phosphotyrosine Ref.8

Disulfide bond

102 ↔ 107

Redox-active Ref.12

Disulfide bond

134

Interchain Ref.12

Natural variations

Alternative sequence

1 – 43

43

Missing in isoform Cytoplasmic.

VSP_018972

Natural variant

153

1

R → C: dbSNP rs8190955. Ref.3

VAR_019079

Natural variant

232

1

G → R: dbSNP rs8190976. Ref.3

VAR_051775

Natural variant

232

1

G → S Ref.3

VAR_019080

Natural variant

261

1

I → V: dbSNP rs8190997. Ref.3

VAR_019081

Natural variant

297

1

E → D: dbSNP rs8191004. Ref.3

VAR_019082

Natural variant

314

1

P → H: dbSNP rs2020916.

VAR_014554

Secondary structure

1

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522

Helix Strand Turn

Details...

Beta strand

66 – 70

5

Helix

74 – 85

12

Beta strand

90 – 96

7

Helix

100 – 104

5

Helix

107 – 125

19

Helix

127 – 129

3

Helix

140 – 164

25

Beta strand

168 – 172

5

Beta strand

183 – 186

4

Beta strand

189 – 192

4

Beta strand

196 – 198

3

Beta strand

202 – 204

3

Turn

209 – 211

3

Helix

215 – 217

3

Helix

221 – 224

4

Beta strand

232 – 237

6

Helix

241 – 253

13

Beta strand

256 – 260

5

Beta strand

262 – 266

5

Helix

272 – 284

13

Beta strand

288 – 290

3

Beta strand

293 – 301

9

Beta strand

304 – 311

8

Beta strand

319 – 331

13

Beta strand

335 – 338

4

Helix

344 – 346

3

Beta strand

370 – 372

3

Helix

374 – 377

4

Helix

383 – 398

16

Beta strand

413 – 415

3

Beta strand

421 – 425

5

Helix

428 – 435

8

Helix

437 – 439

3

Beta strand

440 – 447

8

Helix

450 – 454

5

Beta strand

461 – 468

8

Turn

469 – 472

4

Beta strand

473 – 481

9

Helix

484 – 496

13

Helix

501 – 505

5

Helix

515 – 519

5

Sequences

	Sequence		Length	Mass (Da)
	Isoform Mitochondrial [UniParc]. Last modified July 11, 2001. Version 2. Checksum: DD8E2BA9D6E3757B	FASTA	522	56,257
	10 20 30 40 50 60 MALLPRALSA GAGPSWRRAA RAFRGFLLLL PEPAALTRAL SRAMACRQEP QPQGPPPAAG 70 80 90 100 110 120 AVASYDYLVI GGGSGGLASA RRAAELGARA AVVESHKLGG TCVNVGCVPK KVMWNTAVHS 130 140 150 160 170 180 EFMHDHADYG FPSCEGKFNW RVIKEKRDAY VSRLNAIYQN NLTKSHIEII RGHAAFTSDP 190 200 210 220 230 240 KPTIEVSGKK YTAPHILIAT GGMPSTPHES QIPGASLGIT SDGFFQLEEL PGRSVIVGAG 250 260 270 280 290 300 YIAVEMAGIL SALGSKTSLM IRHDKVLRSF DSMISTNCTE ELENAGVEVL KFSQVKEVKK 310 320 330 340 350 360 TLSGLEVSMV TAVPGRLPVM TMIPDVDCLL WAIGRVPNTK DLSLNKLGIQ TDDKGHIIVD 370 380 390 400 410 420 EFQNTNVKGI YAVGDVCGKA LLTPVAIAAG RKLAHRLFEY KEDSKLDYNN IPTVVFSHPP 430 440 450 460 470 480 IGTVGLTEDE AIHKYGIENV KTYSTSFTPM YHAVTKRKTK CVMKMVCANK EEKVVGIHMQ 490 500 510 520 GLGCDEMLQG FAVAVKMGAT KADFDNTVAI HPTSSEELVT LR
	Isoform Cytoplasmic. Checksum: 3C0A194C96E880E7	FASTA	479	51,701
	10 20 30 40 50 60 MACRQEPQPQ GPPPAAGAVA SYDYLVIGGG SGGLASARRA AELGARAAVV ESHKLGGTCV 70 80 90 100 110 120 NVGCVPKKVM WNTAVHSEFM HDHADYGFPS CEGKFNWRVI KEKRDAYVSR LNAIYQNNLT 130 140 150 160 170 180 KSHIEIIRGH AAFTSDPKPT IEVSGKKYTA PHILIATGGM PSTPHESQIP GASLGITSDG 190 200 210 220 230 240 FFQLEELPGR SVIVGAGYIA VEMAGILSAL GSKTSLMIRH DKVLRSFDSM ISTNCTEELE 250 260 270 280 290 300 NAGVEVLKFS QVKEVKKTLS GLEVSMVTAV PGRLPVMTMI PDVDCLLWAI GRVPNTKDLS 310 320 330 340 350 360 LNKLGIQTDD KGHIIVDEFQ NTNVKGIYAV GDVCGKALLT PVAIAAGRKL AHRLFEYKED 370 380 390 400 410 420 SKLDYNNIPT VVFSHPPIGT VGLTEDEAIH KYGIENVKTY STSFTPMYHA VTKRKTKCVM 430 440 450 460 470 KMVCANKEEK VVGIHMQGLG CDEMLQGFAV AVKMGATKAD FDNTVAIHPT SSEELVTLR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and sequencing of mammalian glutathione reductase cDNA." Tutic M., Lu X.A., Schirmer R.H., Werner D. Eur. J. Biochem. 188:523-528(1990) [PubMed: 2185014] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM CYTOPLASMIC). Tissue: Placenta.
[2]	"Structural organization of the human glutathione reductase (GSR) gene: determination of correct cDNA sequence and identification of a mitochondrial leader sequence." Kelner M.J., Montoya M.A. Biochem. Biophys. Res. Commun. 269:366-368(2000) [PubMed: 10708558] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], ALTERNATIVE INITIATION.
[3]	NIEHS SNPs program Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CYS-153; SER-232; VAL-261 AND ASP-297.
[4]	"DNA sequence and analysis of human chromosome 8." Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., Asakawa T. , Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N., Lander E.S. Nature 439:331-335(2006) [PubMed: 16421571] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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] (ISOFORM MITOCHONDRIAL). Tissue: Lung.
[6]	"Glutathione reductase from human erythrocytes. The sequences of the NADPH domain and of the interface domain." Krauth-Siegel R.L., Blatterspiel R., Saleh M., Schiltz E., Schirmer R.H., Untucht-Grau R. Eur. J. Biochem. 121:259-267(1982) [PubMed: 7060551] [Abstract] Cited for: PROTEIN SEQUENCE OF 45-522.
[7]	"Glutathione reductase from human erythrocytes. Isolation of the enzyme and sequence analysis of the redox-active peptide." Krohne-Ehrich G., Schirmer R.H., Untucht-Grau R. Eur. J. Biochem. 80:65-71(1977) [PubMed: 923580] [Abstract] Cited for: PROTEIN SEQUENCE OF 98-110. Tissue: Erythrocyte.
[8]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-65, MASS SPECTROMETRY.
[9]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[10]	"Three-dimensional structure of glutathione reductase at 2-A resolution." Thieme R., Pai E.F., Schirmer R.H., Schulz G.E. J. Mol. Biol. 152:763-782(1981) [PubMed: 7334521] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2 ANGSTROMS) OF 45-522.
[11]	"Refined structure of glutathione reductase at 1.54-A resolution." Karplus P.A., Schulz G.E. J. Mol. Biol. 195:701-729(1987) [PubMed: 3656429] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.57 ANGSTROMS) OF 45-522.
[12]	"Kinetics and crystallographic analysis of human glutathione reductase in complex with a xanthene inhibitor." Savvides S.N., Karplus P.A. J. Biol. Chem. 271:8101-8107(1996) [PubMed: 8626496] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 62-522, DISULFIDE BONDS.
[13]	"Glutathione reductase turned into trypanothione reductase: structural analysis of an engineered change in substrate specificity." Stoll V.S., Simpson S.J., Krauth-Siegel R.L., Walsh C.T., Pai E.F. Biochemistry 36:6437-6447(1997) [PubMed: 9174360] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 62-522.
[14]	"Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers." Becker K., Savvides S.N., Keese M., Schirmer R.H., Karplus P.A. Nat. Struct. Biol. 5:267-271(1998) [PubMed: 9546215] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 62-522.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Wikipedia

Glutathione reductase entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

X15722 mRNA. Translation: CAA33744.1.
AF228703 Genomic DNA. Translation: AAF37572.1.
AF228703 Genomic DNA. Translation: AAF37573.1.
AF228704 mRNA. Translation: AAF37574.1.
AY338490 Genomic DNA. Translation: AAP88037.1. Different initiation.
AF215848 Genomic DNA. No translation available.
BC069244 mRNA. Translation: AAH69244.1.

IPI

IPI00016862.
IPI00759575.

PIR

RDHUU. S08979.

RefSeq

NP_000628.2.

UniGene

Hs.271510

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ALG	NMR	-	A	480-503	[»]
1BWC	X-ray	2.10	A	45-522	[»]
1DNC	X-ray	1.70	A	45-522	[»]
1GRA	X-ray	2.00	A	45-522	[»]
1GRB	X-ray	1.85	A	45-522	[»]
1GRE	X-ray	2.00	A	45-522	[»]
1GRF	X-ray	2.00	A	45-522	[»]
1GRG	X-ray	2.00	A	45-522	[»]
1GRH	X-ray	3.00	A	45-522	[»]
1GRT	X-ray	2.30	A	45-522	[»]
1GSN	X-ray	1.70	A	45-522	[»]
1K4Q	X-ray	1.90	A	62-522	[»]
1XAN	X-ray	2.00	A	62-522	[»]
2AAQ	X-ray	2.60	A	44-522	[»]
2GH5	X-ray	1.70	A/B	45-522	[»]
2GRT	X-ray	2.70	A	62-522	[»]
3DJG	X-ray	1.80	X	62-522	[»]
3DJJ	X-ray	1.10	A	45-522	[»]
3DK4	X-ray	1.20	A	45-522	[»]
3DK8	X-ray	1.10	A	62-522	[»]
3DK9	X-ray	0.95	A	45-522	[»]
3GRS	X-ray	1.54	A	45-522	[»]
3GRT	X-ray	2.50	A	62-522	[»]
4GR1	X-ray	2.40	A	45-522	[»]
4GRT	X-ray	2.80	A	62-522	[»]
5GRT	X-ray	2.40	A	62-522	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P00390. 1 interaction.

PTM databases

PhosphoSite

P00390.

2-D gel databases

REPRODUCTION-2DPAGE

IPI00759575.

Proteomic databases

PRIDE

P00390.

Genome annotation databases

Ensembl

ENSG00000104687. Homo sapiens. [Contig view]

GeneID

2936.

KEGG

hsa:2936.

NMPDR

fig|9606.3.peg.30146.

UCSC

uc003xih.1. human.

Organism-specific databases

GeneCards

GC08M030655.

H-InvDB

HIX0034273.

HGNC

HGNC:4623. GSR.

HPA

CAB008632.
HPA001538.

MIM

138300. gene+phenotype.

Orphanet

90030. Hemolytic anemia due to glutathione reductase deficiency.

PharmGKB

PA29014.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P00390.

HOVERGEN

P00390.

OMA

P00390. HRQPCKM.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-9902.

BRENDA

1.8.1.7. 247.

Reactome

REACT_1698. Metablism of nucleotides.

Gene expression databases

ArrayExpress

P00390.

Bgee

P00390.

CleanEx

HS_GSR.

GermOnline

ENSG00000104687. Homo sapiens.

Family and domain databases

InterPro

IPR013027. FAD_pyr_nucl-diS_OxRdtase.
IPR006322. Glut_reduct_1.
IPR000815. Hg_reductase.
IPR004099. Pyr_nucl-diS_OxRdtase_dimer.
IPR012999. Pyr_OxRdtase_I_AS.
IPR001327. Pyr_OxRdtase_NAD_bd.
[Graphical view]

Gene3D

G3DSA:3.30.390.30. Pyr_redox_dim. 1 hit.

Pfam

PF00070. Pyr_redox. 1 hit.
PF07992. Pyr_redox_2. 1 hit.
PF02852. Pyr_redox_dim. 1 hit.
[Graphical view]

PRINTS

PR00368. FADPNR.
PR00945. HGRDTASE.

ProDom

PD000139. FAD_pyr_redox. 1 hit.
[Graphical view] [Entries sharing at least one domain]

TIGRFAMs

TIGR01421. gluta_reduc_1. 1 hit.

PROSITE

PS00076. PYRIDINE_REDOX_1. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00262. Carmustine.
DB00143. Glutathione.
DB00157. NADH.

NextBio

11635.

SOURCE

Search...

Entry information

Entry name

GSHR_HUMAN

Accession

Primary (citable) accession number: P00390
Secondary accession number(s): Q7Z5C9, Q9NP63

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 11, 2001
Last modified:	July 7, 2009
This is version 141 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)