Q16873 (LTC4S_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Leukotriene C4 synthase
Short name=LTC4 synthase
EC=4.4.1.20

Alternative name(s):
Leukotriene-C(4) synthase

Gene names

Name:

LTC4S

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	150 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4.
Catalytic activity	Leukotriene C4 = leukotriene A4 + glutathione.
Subunit structure	Homotrimer. Interacts with ALOX5AP and ALOX5. Ref.12 Ref.13 Ref.14
Subcellular location	Nucleus outer membrane; Multi-pass membrane protein. Endoplasmic reticulum membrane; Multi-pass membrane protein Ref.7 Ref.11 Ref.12.
Tissue specificity	Detected in lung, platelets and the myelogenous leukemia cell line KG-1 (at protein level). LTC4S activity is present in eosinophils, basophils, mast cells, certain phagocytic mononuclear cells, endothelial cells, vascular smooth muscle cells and platelets. Ref.7
Involvement in disease	Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:246530]. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.
Sequence similarities	Belongs to the MAPEG family.

Ontologies

Keywords
Biological process	Leukotriene biosynthesis
Cellular component	Endoplasmic reticulum Membrane Nucleus
Coding sequence diversity	Polymorphism
Domain	Transmembrane Transmembrane helix
Molecular function	Lyase
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	leukotriene biosynthetic process Inferred from Biological aspect of Ancestor. Source: RefGenome leukotriene production involved in inflammatory response Inferred from Biological aspect of Ancestor. Source: RefGenome prostanoid metabolic process Traceable author statement. Source: Reactome
Cellular component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Traceable author statement. Source: ProtInc microsome Inferred from Biological aspect of Ancestor. Source: RefGenome nuclear outer membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	enzyme activator activity Inferred from electronic annotation. Source: InterPro glutathione peroxidase activity Inferred from Biological aspect of Ancestor. Source: RefGenome leukotriene-C4 synthase activity Inferred from direct assay. Source: MGI lipid binding Inferred from direct assay. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 150

150

Leukotriene C4 synthase

PRO_0000217748

Regions

Topological domain

1 – 6

6

Cytoplasmic Ref.11 Ref.13 Ref.14

Transmembrane

7 – 27

21

Helical

Topological domain

28 – 48

21

Lumenal Ref.11 Ref.13 Ref.14

Transmembrane

49 – 69

21

Helical

Topological domain

70 – 73

4

Cytoplasmic Ref.11 Ref.13 Ref.14

Transmembrane

74 – 94

21

Helical

Topological domain

95 – 104

10

Lumenal Ref.11 Ref.13 Ref.14

Transmembrane

105 – 124

20

Helical

Topological domain

125 – 150

26

Cytoplasmic Ref.11 Ref.13 Ref.14

Region

51 – 55

5

Glutathione binding

Region

58 – 59

2

Glutathione binding

Region

93 – 97

5

Glutathione binding

Sites

Active site

31

1

Proton donor Probable

Active site

104

1

Proton acceptor Probable

Binding site

30

1

Glutathione

Natural variations

Natural variant

142

1

R → Q. Ref.5
Corresponds to variant rs11541078 [ dbSNP | Ensembl ].

VAR_042736

Experimental info

Sequence conflict

21

1

Y → G AA sequence Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

150

Helix Strand Turn

Details...

Helix

2 – 4

3

Helix

6 – 33

28

Helix

44 – 73

30

Helix

76 – 99

24

Helix

102 – 104

3

Helix

105 – 143

39

Sequences

	Sequence		Length	Mass (Da)
	Q16873 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 04E269B475063037	FASTA	150	16,567
	10 20 30 40 50 60 MKDEVALLAA VTLLGVLLQA YFSLQVISAR RAFRVSPPLT TGPPEFERVY RAQVNCSEYF 70 80 90 100 110 120 PLFLATLWVA GIFFHEGAAA LCGLVYLFAR LRYFQGYARS AQLRLAPLYA SARALWLLVA 130 140 150 LAALGLLAHF LPAALRAALL GRLRTLLPWA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4." Lam B.K., Penrose J.F., Freeman G.J., Austen K.F. Proc. Natl. Acad. Sci. U.S.A. 91:7663-7667(1994) [PubMed: 8052639] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 1-22 AND 35-48. Tissue: Bone marrow.
[2]	"Molecular cloning and expression of human leukotriene-C4 synthase." Welsch D.J., Creely D.P., Hauser S.D., Mathis K.J., Krivi G.G., Isakson P.C. Proc. Natl. Acad. Sci. U.S.A. 91:9745-9749(1994) [PubMed: 7937884] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Molecular cloning of the gene for human leukotriene C4 synthase. Organization, nucleotide sequence, and chromosomal localization to 5q35." Penrose J.F., Spector J., Baldasaro M., Xu K., Boyce J., Arm J.P., Austen K.F., Lam B.K. J. Biol. Chem. 271:11356-11361(1996) [PubMed: 8626689] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Molecular cloning of the human leukotriene C4 synthase gene and assignment to chromosome 5q35." Bigby T.D., Hodulik C.R., Arden K.C., Fu L. Mol. Med. 2:637-646(1996) [PubMed: 8898379] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [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], VARIANT GLN-142. Tissue: Brain.
[6]	"Purification to homogeneity and the N-terminal sequence of human leukotriene C4 synthase: a homodimeric glutathione S-transferase composed of 18-kDa subunits." Nicholson D.W., Ali A., Vaillancourt J.P., Calaycay J.R., Mumford R.A., Zamboni R.J., Ford-Hutchinson A.W. Proc. Natl. Acad. Sci. U.S.A. 90:2015-2019(1993) [PubMed: 8446623] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-35.
[7]	"Purification of human lung leukotriene C4 synthase and preparation of a polyclonal antibody." Penrose J.F., Spector J., Lam B.K., Friend D.S., Xu K., Jack R.M., Austen K.F. Am. J. Respir. Crit. Care Med. 152:283-289(1995) [PubMed: 7599836] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-19, SUBCELLULAR LOCATION, TISSUE SPECIFICITY. Tissue: Lung.
[8]	"Two step purification of human and murine leukotriene C4 synthase." Goppelt-Struebe M. Biochim. Biophys. Acta 1256:257-261(1995) [PubMed: 7766706] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-17. Tissue: Monocyte.
[9]	"Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome." Mayatepek E., Flock B. Lancet 352:1514-1517(1998) [PubMed: 9820300] [Abstract] Cited for: INVOLVEMENT IN LTC4 SYNTHASE DEFICIENCY.
[10]	"Defects in the synthesis of cysteinyl leukotrienes: a new group of inborn errors of metabolism." Mayatepek E., Zelezny R., Lehmann W.D., Hammond J.W., Hoffmann G.F. J. Inherit. Metab. Dis. 23:404-408(2000) [PubMed: 10896305] [Abstract] Cited for: INVOLVEMENT IN LTC4 SYNTHASE DEFICIENCY.
[11]	"Membrane localization and topology of leukotriene C4 synthase." Christmas P., Weber B.M., McKee M., Brown D., Soberman R.J. J. Biol. Chem. 277:28902-28908(2002) [PubMed: 12023288] [Abstract] Cited for: SUBCELLULAR LOCATION, TOPOLOGY.
[12]	"Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein." Strid T., Svartz J., Franck N., Hallin E., Ingelsson B., Soederstroem M., Hammarstroem S. Biochem. Biophys. Res. Commun. 381:518-522(2009) [PubMed: 19233132] [Abstract] Cited for: INTERACTION WITH ALOX5AP AND ALOX5, SUBCELLULAR LOCATION.
[13]	"Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis." Ago H., Kanaoka Y., Irikura D., Lam B.K., Shimamura T., Austen K.F., Miyano M. Nature 448:609-612(2007) [PubMed: 17632548] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) IN COMPLEX WITH GLUTATHIONE, ACTIVE SITE, TOPOLOGY, SUBUNIT.
[14]	"Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase." Martinez Molina D., Wetterholm A., Kohl A., McCarthy A.A., Niegowski D., Ohlson E., Hammarberg T., Eshaghi S., Haeggstroem J.Z., Nordlund P. Nature 448:613-616(2007) [PubMed: 17632546] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 2-150 IN COMPLEX WITH GLUTATHIONE, SUBUNIT, TOPOLOGY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U09353 mRNA. Translation: AAA20467.1.
U11552 mRNA. Translation: AAA50555.1.
U50136 Genomic DNA. Translation: AAC50476.1.
U62025 Genomic DNA. Translation: AAB06723.1.
BC029498 mRNA. Translation: AAH29498.1.

IPI

IPI00004509.

PIR

I38595.
JC5398.

RefSeq

NP_665874.1. NM_145867.1.

UniGene

Hs.706741.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2PNO	X-ray	3.30	A/B/C/D/E/F/G/H/I/J/K/L	1-150	[»]
2UUH	X-ray	2.15	A	2-150	[»]
2UUI	X-ray	2.00	A	2-150	[»]
3HKK	X-ray	2.90	A	2-150	[»]
3LEO	X-ray	2.10	A	2-150	[»]
3PCV	X-ray	1.90	A	1-150	[»]

ProteinModelPortal

Q16873.

SMR

Q16873. Positions 2-149.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-48473N.

STRING

Q16873.

PTM databases

PhosphoSite

Q16873.

Polymorphism databases

DMDM

2833283.

Proteomic databases

PRIDE

Q16873.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000292596; ENSP00000292596; ENSG00000213316.

GeneID

4056.

KEGG

hsa:4056.

NMPDR

fig|9606.3.peg.26311.

UCSC

uc003mko.1. human.

Organism-specific databases

CTD

4056.

GeneCards

GC05P179220.

HGNC

HGNC:6719. LTC4S.

MIM

246530. gene+phenotype.

neXtProt

NX_Q16873.

Orphanet

79507. Hypotonia - failure to thrive - microcephaly.

PharmGKB

PA235.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG18464.

GeneTree

ENSGT00430000030964.

HOGENOM

HBG594959.

HOVERGEN

HBG105513.

InParanoid

Q16873.

OMA

GIFFHEG.

OrthoDB

EOG4V1729.

PhylomeDB

Q16873.

Enzyme and pathway databases

BioCyc

MetaCyc:HS08566-MONOMER.

BRENDA

4.4.1.20. 2681.

Reactome

REACT_22258. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

Q16873.

CleanEx

HS_LTC4S.

Genevestigator

Q16873.

GermOnline

ENSG00000161021. Homo sapiens.

Family and domain databases

InterPro

IPR001446. 5_LipOase_AP.
IPR018295. FLAP/GST2/LTC4S_CS.
IPR023352. MAPEG-like_dom.
IPR001129. Membr-assoc_MAPEG.
[Graphical view]

Gene3D

G3DSA:1.20.120.550. G3DSA:1.20.120.550. 1 hit.

KO

K00807.

Pfam

PF01124. MAPEG. 1 hit.
[Graphical view]

PRINTS

PR00488. 5LPOXGNASEAP.

PROSITE

PS01297. FLAP_GST2_LTC4S. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00143. Glutathione.

NextBio

15892.

SOURCE

Search...

Entry information

Entry name

LTC4S_HUMAN

Accession

Primary (citable) accession number: Q16873
Secondary accession number(s): Q8N6P0, Q9UC73, Q9UD18

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1996
Last modified:	January 25, 2012
This is version 107 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.