P48637 (GSHB_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Glutathione synthetase
Short name=GSH synthetase
Short name=GSH-S
EC=6.3.2.3

Alternative name(s):
Glutathione synthase

Gene names

Name:

GSS

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	474 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)

Catalytic activity	ATP + gamma-L-glutamyl-L-cysteine + glycine = ADP + phosphate + glutathione.
Cofactor	Binds 1 magnesium ion per subunit. Ref.11
Pathway	Sulfur metabolism; glutathione biosynthesis; glutathione from L-cysteine and L-glutamate: step 2/2.
Subunit structure	Homodimer. Ref.11
Involvement in disease	Defects in GSS are the cause of glutathione synthetase deficiency (GSS deficiency) [MIM:266130]; also known as 5-oxoprolinuria or pyroglutamic aciduria. It is a severe form characterized by an increased rate of hemolysis and defective function of the central nervous system. Defects in GSS are the cause of glutathione synthetase deficiency of erythrocytes (GLUSYNDE)[MIM:231900]. Glutathione synthetase deficiency of erythrocytes is a mild form causing hemolytic anemia.
Sequence similarities	Belongs to the eukaryotic GSH synthase family.

Ontologies

Keywords
Biological process	Glutathione biosynthesis
Coding sequence diversity	Polymorphism
Disease	Disease mutation Hereditary hemolytic anemia
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Ligase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	nervous system development Traceable author statement. Source: ProtInc response to oxidative stress Traceable author statement. Source: ProtInc xenobiotic metabolic process Traceable author statement. Source: Reactome
Cellular component	cytosol Traceable author statement. Source: Reactome
Molecular function	ATP binding Inferred from direct assay Ref.11. Source: UniProtKB glutathione binding Inferred from direct assay Ref.11. Source: UniProtKB glutathione synthase activity Traceable author statement. Source: Reactome magnesium ion binding Inferred from direct assay Ref.11. Source: UniProtKB protein homodimerization activity Inferred from direct assay Ref.11. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

Chain

2 – 474

473

Glutathione synthetase

PRO_0000211260

Regions

Nucleotide binding

364 – 373

10

ATP

Nucleotide binding

398 – 401

4

ATP

Region

148 – 151

4

Substrate binding

Region

214 – 216

3

Substrate binding

Region

267 – 270

4

Substrate binding

Region

461 – 462

2

Substrate binding

Sites

Metal binding

144

1

Magnesium

Metal binding

146

1

Magnesium

Metal binding

368

1

Magnesium

Binding site

125

1

Substrate

Binding site

144

1

ATP

Binding site

220

1

Substrate

Binding site

305

1

ATP

Binding site

375

1

ATP

Binding site

425

1

ATP

Binding site

450

1

Substrate

Binding site

452

1

ATP

Binding site

458

1

ATP; via carbonyl oxygen

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.9

Natural variations

Natural variant

26

1

A → D in GSS deficiency.

VAR_003602

Natural variant

188

1

L → P in GSS deficiency; 100-fold reduction of activity.

VAR_003603

Natural variant

219

1

D → A in GSS deficiency.

VAR_003604

Natural variant

219

1

D → G in GSS deficiency. Ref.12
Corresponds to variant rs28938472 [ dbSNP | Ensembl ].

VAR_003605

Natural variant

236

1

R → Q. Ref.4
Corresponds to variant rs34239729 [ dbSNP | Ensembl ].

VAR_025047

Natural variant

254

1

L → R in GSS deficiency.

VAR_003606

Natural variant

267

1

R → W in GSS deficiency. Ref.12

VAR_003607

Natural variant

270

1

Y → C in GSS deficiency; 100-fold reduction of activity.

VAR_003608

Natural variant

270

1

Y → H in GSS deficiency; 100-fold reduction of activity.

VAR_003609

Natural variant

283

1

R → C in GSS deficiency; 10-fold reduction of activity. Ref.12

VAR_003610

Natural variant

286

1

L → Q in GSS deficiency.

VAR_003611

Natural variant

330

1

R → C in GSS deficiency.

VAR_003612

Natural variant

437

1

K → E. Ref.3 Ref.4
Corresponds to variant rs34852238 [ dbSNP | Ensembl ].

VAR_025048

Natural variant

464

1

G → V in GSS deficiency.

VAR_003613

Natural variant

469

1

D → E in GSS deficiency.

VAR_003614

Secondary structure

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474

Helix Strand Turn

Details...

Helix

6 – 9

4

Helix

12 – 28

17

Beta strand

32 – 34

3

Beta strand

43 – 47

5

Beta strand

50 – 53

4

Beta strand

56 – 58

3

Helix

59 – 67

9

Helix

69 – 81

13

Helix

83 – 91

9

Helix

93 – 96

4

Helix

98 – 113

16

Beta strand

119 – 132

14

Beta strand

134 – 136

3

Beta strand

138 – 146

9

Helix

153 – 158

6

Helix

160 – 169

10

Helix

173 – 176

4

Helix

184 – 199

16

Beta strand

205 – 209

5

Helix

217 – 228

12

Turn

229 – 231

3

Beta strand

234 – 237

4

Helix

239 – 245

7

Beta strand

246 – 248

3

Beta strand

254 – 256

3

Beta strand

259 – 268

10

Helix

272 – 274

3

Helix

277 – 288

12

Beta strand

289 – 295

7

Helix

297 – 301

5

Helix

305 – 310

6

Helix

316 – 320

5

Helix

325 – 333

9

Beta strand

338 – 340

3

Beta strand

342 – 344

3

Helix

345 – 356

12

Helix

358 – 360

3

Beta strand

361 – 366

6

Beta strand

369 – 371

3

Helix

376 – 386

11

Helix

390 – 394

5

Beta strand

395 – 399

5

Beta strand

406 – 411

6

Beta strand

418 – 435

18

Beta strand

438 – 453

16

Turn

461 – 464

4

Beta strand

467 – 469

3

Sequences

	Sequence		Length	Mass (Da)
	P48637 [UniParc]. Last modified February 1, 1996. Version 1. Checksum: 3C25EF7072EFE058	FASTA	474	52,385
	10 20 30 40 50 60 MATNWGSLLQ DKQQLEELAR QAVDRALAEG VLLRTSQEPT SSEVVSYAPF TLFPSLVPSA 70 80 90 100 110 120 LLEQAYAVQM DFNLLVDAVS QNAAFLEQTL SSTIKQDDFT ARLFDIHKQV LKEGIAQTVF 130 140 150 160 170 180 LGLNRSDYMF QRSADGSPAL KQIEINTISA SFGGLASRTP AVHRHVLSVL SKTKEAGKIL 190 200 210 220 230 240 SNNPSKGLAL GIAKAWELYG SPNALVLLIA QEKERNIFDQ RAIENELLAR NIHVIRRTFE 250 260 270 280 290 300 DISEKGSLDQ DRRLFVDGQE IAVVYFRDGY MPRQYSLQNW EARLLLERSH AAKCPDIATQ 310 320 330 340 350 360 LAGTKKVQQE LSRPGMLEML LPGQPEAVAR LRATFAGLYS LDVGEEGDQA IAEALAAPSR 370 380 390 400 410 420 FVLKPQREGG GNNLYGEEMV QALKQLKDSE ERASYILMEK IEPEPFENCL LRPGSPARVV 430 440 450 460 470 QCISELGIFG VYVRQEKTLV MNKHVGHLLR TKAIEHADGG VAAGVAVLDN PYPV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequencing and expression of a cDNA for human glutathione synthetase." Gali R.R., Board P.G. Biochem. J. 310:353-358(1995) [PubMed: 7646467] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	Shi Z.-Z., Galang R.L., Habib G.M., Lebovitz R.M., Lieberman M.W. Submitted (AUG-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Kidney.
[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], VARIANT GLU-437. Tissue: Substantia nigra.
[4]	NIEHS SNPs program Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLN-236 AND GLU-437.
[5]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"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]. Tissue: Lung.
[8]	Lubec G., Chen W.-Q., Sun Y. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 26-34; 113-125; 142-158; 222-230; 254-267; 274-283; 294-305; 419-434 AND 453-474, MASS SPECTROMETRY. Tissue: Fetal brain cortex.
[9]	"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 ALA-2, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[10]	"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].
[11]	"Molecular basis of glutathione synthetase deficiency and a rare gene permutation event." Polekhina G., Board P.G., Gali R.R., Rossjohn J., Parker M.W. EMBO J. 18:3204-3213(1999) [PubMed: 10369661] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 1-474 IN COMPLEX WITH ADP AND GLUTATHIONE, COFACTOR, SUBUNIT.
[12]	"Mutations in the glutathione synthetase gene cause 5-oxoprolinuria." Shi Z.-Z., Habib G.M., Rhead W.J., Gahl W.A., He X., Sazer S., Lieberman M.W. Nat. Genet. 14:361-365(1996) [PubMed: 8896573] [Abstract] Cited for: VARIANTS GSS DEFICIENCY GLY-219; TRP-267 AND CYS-283.
[13]	"Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction." Dahl N., Pigg M., Ristoff E., Gali R., Carlsson B., Mannervik B., Larsson A., Board P. Hum. Mol. Genet. 6:1147-1152(1997) [PubMed: 9215686] [Abstract] Cited for: VARIANTS GSS DEFICIENCY.
+	Additional computationally mapped references.

Web resources

GeneReviews

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L42531 mRNA. Translation: AAA69492.1.
U34683 mRNA. Translation: AAB62390.1.
AK312492 mRNA. Translation: BAG35394.1.
DQ074975 Genomic DNA. Translation: AAY57328.1.
AL133324 Genomic DNA. Translation: CAB93423.1.
CH471077 Genomic DNA. Translation: EAW76239.1.
CH471077 Genomic DNA. Translation: EAW76240.1.
BC007927 mRNA. Translation: AAH07927.1.

IPI

IPI00010706.

PIR

S56748.

RefSeq

NP_000169.1. NM_000178.2.

UniGene

Hs.82327.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2HGS	X-ray	2.10	A	1-474	[»]

ProteinModelPortal

P48637.

SMR

P48637. Positions 3-474.

ModBase

Search...

Protein-protein interaction databases

IntAct

P48637. 1 interaction.

MINT

MINT-5001027.

STRING

P48637.

PTM databases

PhosphoSite

P48637.

Polymorphism databases

DMDM

1346191.

2D gel databases

OGP

P48637.

REPRODUCTION-2DPAGE

IPI00010706.

Proteomic databases

PeptideAtlas

P48637.

PRIDE

P48637.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000216951; ENSP00000216951; ENSG00000100983.

GeneID

2937.

KEGG

hsa:2937.

NMPDR

fig|9606.3.peg.20134.

UCSC

uc002xbg.1. human.

Organism-specific databases

CTD

2937.

GeneCards

GC20M033517.

H-InvDB

HIX0015755.

HGNC

HGNC:4624. GSS.

MIM

231900. phenotype.
266130. phenotype.
601002. gene.

neXtProt

NX_P48637.

Orphanet

32. Glutathione synthetase deficiency.

PharmGKB

PA29015.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG10689.

GeneTree

ENSGT00390000013764.

HOGENOM

HBG412445.

HOVERGEN

HBG002458.

InParanoid

P48637.

OMA

YMFQRSA.

OrthoDB

EOG47PX60.

PhylomeDB

P48637.

Enzyme and pathway databases

BioCyc

MetaCyc:MONOMER-10021.

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

P48637.

Bgee

P48637.

CleanEx

HS_GSS.

Genevestigator

P48637.

GermOnline

ENSG00000100983. Homo sapiens.

Family and domain databases

InterPro

IPR013816. ATP_grasp_subdomain_2.
IPR004887. Glutathione_synth_subst-bd_euk.
IPR014042. Glutathione_synthase_a-hlx_euk.
IPR005615. Glutathione_synthase_euk.
IPR014049. Glutathione_synthase_N_euk.
IPR016185. PreATP-grasp-like.
[Graphical view]

Gene3D

G3DSA:3.30.470.20. ATP_grasp_subdomain_2. 1 hit.
G3DSA:3.40.50.1760. Glutathione_synth_subst-bd_euk. 1 hit.
G3DSA:1.10.1080.10. Glutathione_synthase_a-hlx_euk. 2 hits.
G3DSA:3.30.1490.80. Glutathione_synthase_N_euk. 2 hits.

KO

K01920.

PANTHER

PTHR11130. GSH_synth_ATP_bd. 1 hit.

Pfam

PF03917. GSH_synth_ATP. 1 hit.
PF03199. GSH_synthase. 1 hit.
[Graphical view]

PIRSF

PIRSF001558. GSHase. 1 hit.

SUPFAM

SSF52440. PreATP-grasp-like. 1 hit.

TIGRFAMs

TIGR01986. Glut_syn_euk. 1 hit.

ProtoNet

Search...

Other

DrugBank

DB00143. Glutathione.
DB00145. Glycine.
DB00151. L-Cysteine.

NextBio

11639.

SOURCE

Search...

Entry information

Entry name

GSHB_HUMAN

Accession

Primary (citable) accession number: P48637
Secondary accession number(s): B2R697, E1P5P9, Q4TTD9

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	February 1, 1996
Last modified:	January 25, 2012
This is version 122 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.