P32929 (CGL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cystathionine gamma-lyase
EC=4.4.1.1

Alternative name(s):
Cysteine-protein sulfhydrase
Gamma-cystathionase

Gene names

Name:

CTH

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

General annotation (Comments)

Function	Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function. Ref.8 Ref.10 Ref.11
Catalytic activity	L-cystathionine + H2O = L-cysteine + NH3 + 2-oxobutanoate. Ref.7 Ref.11
Cofactor	Pyridoxal phosphate. Ref.7 Ref.11 Ref.13
Enzyme regulation	Inhibited by propargylglycine, trifluoroalanine and aminoethoxyvinylglycine. Ref.7 Ref.11
Pathway	Amino-acid biosynthesis; L-cysteine biosynthesis; L-cysteine from L-homocysteine and L-serine: step 2/2.
Subunit structure	Homotetramer. Interacts with CALM in a calcium-dependent manner By similarity. Ref.7 Ref.11 Ref.13
Subcellular location	Cytoplasm.
Involvement in disease	Cystathioninuria (CSTNU) [MIM:219500]: Autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12 Ref.13
Sequence similarities	Belongs to the trans-sulfuration enzymes family.
Biophysicochemical properties	Kinetic parameters: KM=0.5 mM for L-cystathionine Ref.7 Ref.13 KM=5.4 mM for homocysteine KM=3.5 mM for cysteine pH dependence: Optimum pH is 8.2.

Ontologies

Keywords
Biological process	Amino-acid biosynthesis Cysteine biosynthesis
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Ligand	Calmodulin-binding Pyridoxal phosphate
Molecular function	Lyase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular nitrogen compound metabolic process Traceable author statement. Source: Reactome cysteine biosynthetic process Inferred from direct assay Ref.7. Source: UniProtKB endoplasmic reticulum unfolded protein response Traceable author statement Ref.10. Source: UniProtKB hydrogen sulfide biosynthetic process Inferred from direct assay Ref.11. Source: UniProtKB negative regulation of apoptotic process Inferred from electronic annotation. Source: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara positive regulation of NF-kappaB transcription factor activity Inferred from electronic annotation. Source: Compara protein homotetramerization Inferred from physical interaction Ref.11. Source: UniProtKB protein sulfhydration Inferred from mutant phenotype Ref.10. Source: UniProtKB protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine Inferred from direct assay Ref.11. Source: UniProtKB sulfur amino acid catabolic process Traceable author statement. Source: Reactome transsulfuration Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleus Inferred from direct assay. Source: HPA
Molecular_function	L-cysteine desulfhydrase activity Traceable author statement. Source: Reactome L-cystine L-cysteine-lyase (deaminating) Inferred from mutant phenotype Ref.10. Source: UniProtKB cystathionine gamma-lyase activity Inferred from direct assay Ref.7Ref.11. Source: UniProtKB homocysteine desulfhydrase activity Traceable author statement. Source: Reactome pyridoxal phosphate binding Inferred from direct assay Ref.7Ref.11. Source: UniProtKB
Complete GO annotation...

Alternative products

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

Isoform 1 (identifier: P32929-1)

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 2 (identifier: P32929-2)

The sequence of this isoform differs from the canonical sequence as follows:
     153-196: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 405

405

Cystathionine gamma-lyase

PRO_0000114749

Sites

Binding site

62

1

Substrate

Binding site

114

1

Substrate

Binding site

119

1

Substrate

Binding site

339

1

Substrate

Amino acid modifications

Modified residue

212

1

N6-(pyridoxal phosphate)lysine By similarity

Modified residue

282

1

Phosphoserine By similarity

Modified residue

377

1

Phosphoserine By similarity

Natural variations

Alternative sequence

153 – 196

44

Missing in isoform 2.

VSP_006306

Natural variant

67

1

T → I in CSTNU; reduces catalytic activity and affinity for pyridoxal phosphate. Ref.12 Ref.13
Corresponds to variant rs28941785 [ dbSNP | Ensembl ].

VAR_015450

Natural variant

240

1

Q → E in CSTNU; strongly reduces catalytic activity and affinity for pyridoxal phosphate. Ref.12 Ref.13
Corresponds to variant rs28941786 [ dbSNP | Ensembl ].

VAR_015451

Natural variant

403

1

S → I. Ref.1 Ref.3 Ref.12
Corresponds to variant rs1021737 [ dbSNP | Ensembl ].

VAR_015452

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

405

Helix Strand Turn

Details...

Helix

18 – 24

7

Helix

29 – 31

3

Beta strand

36 – 38

3

Helix

66 – 79

14

Beta strand

82 – 88

7

Helix

90 – 98

9

Beta strand

106 – 112

7

Helix

115 – 123

9

Helix

125 – 128

4

Beta strand

131 – 135

5

Helix

140 – 146

7

Beta strand

151 – 159

9

Turn

161 – 163

3

Helix

169 – 176

8

Beta strand

178 – 180

3

Beta strand

183 – 187

5

Turn

189 – 191

3

Turn

193 – 195

3

Turn

198 – 202

5

Beta strand

204 – 209

6

Turn

210 – 215

6

Beta strand

223 – 227

5

Helix

230 – 243

14

Helix

249 – 259

11

Helix

262 – 281

20

Beta strand

286 – 290

5

Helix

300 – 306

7

Beta strand

312 – 320

9

Helix

322 – 331

10

Beta strand

333 – 337

5

Beta strand

342 – 345

4

Beta strand

347 – 349

3

Turn

351 – 358

8

Helix

361 – 367

7

Beta strand

373 – 377

5

Helix

383 – 397

15

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 10, 2003. Version 3. Checksum: 003246D7C1D16723	FASTA	405	44,508
	10 20 30 40 50 60 MQEKDASSQG FLPHFQHFAT QAIHVGQDPE QWTSRAVVPP ISLSTTFKQG APGQHSGFEY 70 80 90 100 110 120 SRSGNPTRNC LEKAVAALDG AKYCLAFASG LAATVTITHL LKAGDQIICM DDVYGGTNRY 130 140 150 160 170 180 FRQVASEFGL KISFVDCSKI KLLEAAITPE TKLVWIETPT NPTQKVIDIE GCAHIVHKHG 190 200 210 220 230 240 DIILVVDNTF MSPYFQRPLA LGADISMYSA TKYMNGHSDV VMGLVSVNCE SLHNRLRFLQ 250 260 270 280 290 300 NSLGAVPSPI DCYLCNRGLK TLHVRMEKHF KNGMAVAQFL ESNPWVEKVI YPGLPSHPQH 310 320 330 340 350 360 ELVKRQCTGC TGMVTFYIKG TLQHAEIFLK NLKLFTLAES LGGFESLAEL PAIMTHASVL 370 380 390 400 KNDRDVLGIS DTLIRLSVGL EDEEDLLEDL DQALKAAHPP SGSHS
	Isoform 2 [UniParc]. Checksum: D6AE74B370664D23	FASTA	361	39,505
	10 20 30 40 50 60 MQEKDASSQG FLPHFQHFAT QAIHVGQDPE QWTSRAVVPP ISLSTTFKQG APGQHSGFEY 70 80 90 100 110 120 SRSGNPTRNC LEKAVAALDG AKYCLAFASG LAATVTITHL LKAGDQIICM DDVYGGTNRY 130 140 150 160 170 180 FRQVASEFGL KISFVDCSKI KLLEAAITPE TKRPLALGAD ISMYSATKYM NGHSDVVMGL 190 200 210 220 230 240 VSVNCESLHN RLRFLQNSLG AVPSPIDCYL CNRGLKTLHV RMEKHFKNGM AVAQFLESNP 250 260 270 280 290 300 WVEKVIYPGL PSHPQHELVK RQCTGCTGMV TFYIKGTLQH AEIFLKNLKL FTLAESLGGF 310 320 330 340 350 360 ESLAELPAIM THASVLKNDR DVLGISDTLI RLSVGLEDEE DLLEDLDQAL KAAHPPSGSH S

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and nucleotide sequence of human liver cDNA encoding for cystathionine gamma-lyase." Lu Y., O'Dowd B.F., Orrego H., Israel Y. Biochem. Biophys. Res. Commun. 189:749-758(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), VARIANT ILE-403. Tissue: Liver.
[2]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[3]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ILE-403. Tissue: Kidney.
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	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].
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Skin.
[7]	"Kinetics and inhibition of recombinant human cystathionine gamma-lyase. Toward the rational control of transsulfuration." Steegborn C., Clausen T., Sondermann P., Jacob U., Worbs M., Marinkovic S., Huber R., Wahl M.C. J. Biol. Chem. 274:12675-12684(1999) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, SUBUNIT, COFACTOR, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
[8]	"H2S biogenesis by human cystathionine gamma-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia." Chiku T., Padovani D., Zhu W., Singh S., Vitvitsky V., Banerjee R. J. Biol. Chem. 284:11601-11612(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[9]	"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].
[10]	"H2s-induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response." Krishnan N., Fu C., Pappin D.J., Tonks N.K. Sci. Signal. 4:RA86-RA86(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS CYSTEINE-PROTEIN SULFHYDRASE.
[11]	"Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S." Sun Q., Collins R., Huang S., Holmberg-Schiavone L., Anand G.S., Tan C.-H., van-den-Berg S., Deng L.-W., Moore P.K., Karlberg T., Sivaraman J. J. Biol. Chem. 284:3076-3085(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-402 IN COMPLEXES WITH PYRODOXAL PHOSPHATE; NITRATE AND PROPARGYLGLYCINE, FUNCTION, SUBUNIT, ENZYME REGULATION, CATALYTIC ACTIVITY, COFACTOR.
[12]	"Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH)." Wang J., Hegele R.A. Hum. Genet. 112:404-408(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CSTNU ILE-67 AND GLU-240, VARIANT ILE-403.
[13]	"Kinetic properties of polymorphic variants and pathogenic mutants in human cystathionine gamma-lyase." Zhu W., Lin A., Banerjee R. Biochemistry 47:6226-6232(2008) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS CSTNU ILE-67 AND GLU-240, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

S52784 mRNA. Translation: AAB24700.1.
S52028 mRNA. Translation: AAB24699.1.
BT006882 mRNA. Translation: AAP35528.1.
AK223376 mRNA. Translation: BAD97096.1.
AL354872 Genomic DNA. Translation: CAC12901.1.
AL354872 Genomic DNA. Translation: CAC12902.1.
CH471059 Genomic DNA. Translation: EAX06450.1.
BC015807 mRNA. Translation: AAH15807.1.

IPI

IPI00031557.
IPI00221301.

PIR

JC1362.

RefSeq

NP_001177392.1. NM_001190463.1.
NP_001893.2. NM_001902.5.
NP_714964.2. NM_153742.4.

UniGene

Hs.19904.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2NMP	X-ray	2.60	A/B/C/D	1-402	[»]
3COG	X-ray	2.00	A/B/C/D	1-402	[»]
3ELP	X-ray	2.40	A/B/C/D	1-405	[»]

ProteinModelPortal

P32929.

ModBase

Search...

Protein-protein interaction databases

IntAct

P32929. 1 interaction.

MINT

MINT-1479767.

STRING

9606.ENSP00000359976.

PTM databases

PhosphoSite

P32929.

Polymorphism databases

DMDM

27735163.

Proteomic databases

PaxDb

P32929.

PRIDE

P32929.

Protocols and materials databases

DNASU

1491.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000346806; ENSP00000311554; ENSG00000116761.
ENST00000370938; ENSP00000359976; ENSG00000116761.

GeneID

1491.

KEGG

hsa:1491.

UCSC

uc001dfd.3. human.
uc001dfe.3. human.

Organism-specific databases

CTD

1491.

GeneCards

GC01P070876.

HGNC

HGNC:2501. CTH.

HPA

HPA021591.
HPA023300.

MIM

219500. phenotype.
607657. gene.

neXtProt

NX_P32929.

Orphanet

212. Cystathioninuria.

PharmGKB

PA27004.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0626.

HOGENOM

HOG000246415.

HOVERGEN

HBG005322.

InParanoid

P32929.

KO

K01758.

OMA

SPIDCYL.

OrthoDB

EOG4FXR7K.

PhylomeDB

P32929.

Enzyme and pathway databases

BRENDA

4.4.1.1. 2681.

Reactome

REACT_111217. Metabolism.

SABIO-RK

P32929.

UniPathway

UPA00136; UER00202.

Gene expression databases

ArrayExpress

P32929.

Bgee

P32929.

CleanEx

HS_CTH.

Genevestigator

P32929.

GermOnline

ENSG00000116761. Homo sapiens.

Family and domain databases

Gene3D

3.40.640.10. 1 hit.
3.90.1150.10. 1 hit.

InterPro

IPR000277. Cys/Met-Metab_PyrdxlP-dep_enz.
IPR015424. PyrdxlP-dep_Trfase.
IPR015421. PyrdxlP-dep_Trfase_major_sub1.
IPR015422. PyrdxlP-dep_Trfase_major_sub2.
[Graphical view]

PANTHER

PTHR11808. PTHR11808. 1 hit.

Pfam

PF01053. Cys_Met_Meta_PP. 1 hit.
[Graphical view]

PIRSF

PIRSF001434. CGS. 1 hit.

SUPFAM

SSF53383. PyrdxlP-dep_Trfase_major. 1 hit.

PROSITE

PS00868. CYS_MET_METAB_PP. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00151. L-Cysteine.
DB00114. Pyridoxal Phosphate.

EvolutionaryTrace

P32929.

GenomeRNAi

1491.

NextBio

6127.

SOURCE

Search...

Entry information

Entry name

CGL_HUMAN

Accession

Primary (citable) accession number: P32929
Secondary accession number(s): Q53FB3 , Q53Y79, Q9H4W7, Q9H4W8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1993
Last sequence update:	January 10, 2003
Last modified:	May 1, 2013
This is version 136 of the entry and version 3 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.