GSTK1

GSTK1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1YZX, 3RPN, 3RPP
Identifiers
Aliases	GSTK1 , GST, GST 13-13, GST13, GST13-13, GSTK1-1, hglutathione S-transferase kappa 1
External IDs	OMIM: 602321 MGI: 1923513 HomoloGene: 41075 GeneCards: GSTK1
Gene location (Human) Chr. Chromosome 7 (human) [1] Band 7q34 Start 143,244,093 bp [1] End 143,270,854 bp [1]
Gene location (Mouse) Chr. Chromosome 6 (mouse) [2] Band 6|6 B2.1 Start 42,222,869 bp [2] End 42,227,381 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver rectum monocyte right uterine tube left lobe of thyroid gland right lobe of thyroid gland gallbladder spleen minor salivary gland left adrenal gland Top expressed in left lobe of liver epithelium of stomach right ventricle duodenum mucous cell of stomach adrenal gland myocardium of ventricle pyloric antrum interventricular septum digastric muscle More reference expression data BioGPS n/a
Gene ontology Molecular function protein-disulfide reductase activity transferase activity glutathione peroxidase activity glutathione transferase activity signaling receptor binding protein binding Cellular component mitochondrial inner membrane mitochondrial matrix peroxisome extracellular exosome intracellular anatomical structure membrane mitochondrion peroxisomal matrix cytosol Biological process epithelial cell differentiation glutathione derivative biosynthetic process cellular oxidant detoxification glutathione metabolic process protein targeting to peroxisome Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 373156 76263 Ensembl ENSG00000197448 ENSMUSG00000029864 UniProt Q9Y2Q3 Q9DCM2 RefSeq (mRNA) NM_015917 NM_001143679 NM_001143680 NM_001143681 NM_029555 RefSeq (protein) NP_001137151 NP_001137152 NP_001137153 NP_057001 NP_083831 Location (UCSC) Chr 7: 143.24 – 143.27 Mb Chr 6: 42.22 – 42.23 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Glutathione S-transferase kappa 1 (GSTK1) is an enzyme that in humans is encoded by the GSTK1 gene which is located on chromosome seven. ^[5] It belongs to the superfamily of enzymes known as glutathione S-transferase (GST), which are mainly known for cellular detoxification. ^[6] The GSTK1 gene consists of eight exons and seven introns and although it is a member of the GST family, its structure has been found to be similar to bacterial HCCA (2-hydroxychromene-2-carboxylate) isomerases and bacterial disulphide-bond-forming DsbA oxidoreductase. This similarity has later allowed the enzyme GSTK1 to be renamed to DsbA-L. ^[7] Research has also suggested that several variations of the GSTK1 gene can be responsible for metabolic diseases and certain types of cancer. ^[7]

Structure

The GSTK1 enzyme is a homodimer and, like all GSTs, it contains a TRX-like domain and a helical domain. However, the GSTK1 is substantially different in its secondary structure compared to the other GSTs. The helical domain has been observed to be placed between the βαβ and ββα motifs of the TRX-like domain, rather than the TRX-like domain and the C-terminal helical domain being connected together by a short linker of alpha-helixes as normally seen in GSTs. ^[6] Also, the GSTK1 dimer employs a butterfly shape and not a V-shaped crevice like in the other classes. ^[6] As for the GSTK1 gene, it is ~5 kb long, has eight exons, is located on chromosome 7q34, and includes an initiator element at the transcription start site instead of a TATA or a CCAAT box. ^[5]

Function

GSTK1 has been suggested to promote adiponectin multimerization in the endoplasmic reticulum (ER), ^[8] but this has been contradicted by later studies. ^[9] GSTK1 can prevent ER stress and ER stress-induced adiponectin down-regulation, implying that GSTK1 assists the ER’s functions. GSTK1 is located in the ER and also in the mitochondria of hepatocytes. This indicates a potential role for GSTK1 in the interaction between the two organelles; though this is poorly understood. ^[8]

The discovery of GSTK1 in the peroxisome has led to studies based on its function. It has been suggested that, similar to GSTA, GSTK1 may play a role in the buffering of acyl-CoA and xenobiotic-CoA and be involved in their binding activities. GSTK1 may also be responsible for the detoxification of lipid peroxides created in the peroxisome based on the peroxidase activity towards three substrates: tert-butyl hydroperoxide, cumene hydroperoxide, and 15-S-hydroperoxy-5,8,11,13-eicosatetraenoic acid. ^[5]

Clinical significance

The amount of expression of adiponectin has been observed to be related to diseases such as insulin resistance, obesity, and type 2 diabetes. Decreased amounts of the protein indicates that there is a higher probability of receiving said diseases. Because the GSTK1 is seen to play a role in the multimerization of adiponectin, this enzyme can regulate the concentration of adiponectin and thus enhance insulin sensitivity and protect against diabetes. ^[7] Also, the GSTK1 gene is unregulated when it is inflicted with oxidative stress and are over expressed in many tumors leading to difficulties during cancer chemotherapy. ^[10] Moreover, GSTK1 gene expression has been seen to increase significantly in correlation to drug resistance in tumor cells such as erythroleukemia and mammary adenocarcinoma suggesting that it, along with GSTP1 and GSTA4, could be responsible for the drug resistance. ^[11]

GSTK1 can also be a potential tool to help investigate cancer. Tyrosine phosphorylated proteins are responsible for many of the cell functions such as the cell’s growth, division, adhesion, and motility. These activities are also very related to cancer and thus studying this protein could allow access to information which could classify tumors for prognosis and prediction. ^[12] Due to GSTK1’s C-terminal SH2 domain, tyrosine phosphorylated proteins can bind to it and allow for easier detection to which the protein can be studied. ^[12]

Interactions

GSTK1 has been suggested to interact with:

• adiponectin ^[8]
• Erol-Lα ^[8]

References

1. GRCh38: Ensembl release 89: ENSG00000197448 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029864 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Morel F, Rauch C, Petit E, Piton A, Theret N, Coles B, Guillouzo A (Apr 2004). "Gene and protein characterization of the human glutathione S-transferase kappa and evidence for a peroxisomal localization". The Journal of Biological Chemistry. 279 (16): 16246–53. doi: 10.1074/jbc.M313357200 . PMID   14742434.
6. Li J, Xia Z, Ding J (Sep 2005). "Thioredoxin-like domain of human kappa class glutathione transferase reveals sequence homology and structure similarity to the theta class enzyme". Protein Science. 14 (9): 2361–9. doi:10.1110/ps.051463905. PMC   2253485 . PMID   16081649.
7. Gao F, Fang Q, Zhang R, Lu J, Lu H, Wang C, Ma X, Xu J, Jia W, Xiang K (2009). "Polymorphism of DsbA-L gene associates with insulin secretion and body fat distribution in Chinese population". Endocrine Journal. 56 (3): 487–94. doi: 10.1507/endocrj.k08e-322 . PMID   19225211.
8. Liu M, Chen H, Wei L, Hu D, Dong K, Jia W, Dong LQ, Liu F (Apr 2015). "Endoplasmic reticulum (ER) localization is critical for DsbA-L protein to suppress ER stress and adiponectin down-regulation in adipocytes". The Journal of Biological Chemistry. 290 (16): 10143–8. doi: 10.1074/jbc.M115.645416 . PMC   4400330 . PMID   25739441.
9. Theodoratos A, Blackburn AC, Coggan M, et al. (2012). "The impact of glutathione transferase kappa deficiency on adiponectin multimerisation in vivo". International Journal of Obesity. 36 (10): 1366–1369. doi: 10.1038/ijo.2011.267 . PMID   23201197.
10. Nebert DW, Vasiliou V (Nov 2004). "Analysis of the glutathione S-transferase (GST) gene family". Human Genomics. 1 (6): 460–4. doi: 10.1186/1479-7364-1-6-460 . PMC   3500200 . PMID   15607001.
11. Kalinina EV, Berozov TT, Shtil AA, Chernov NN, Glasunova VA, Novichkova MD, Nurmuradov NK (Nov 2012). "Expression of genes of glutathione transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 in tumor cells during the formation of drug resistance to cisplatin". Bulletin of Experimental Biology and Medicine. 154 (1): 64–7. doi:10.1007/s10517-012-1876-4. PMID   23330092. S2CID   42062131.
12. Qiu F, Huang D, Xiao H, Qiu F, Lu L, Nie J (Apr 2013). "Detection of tyrosine‑phosphorylated proteins in hepatocellular carcinoma tissues using a combination of GST‑Nck1‑SH2 pull‑down and two‑dimensional electrophoresis". Molecular Medicine Reports. 7 (4): 1209–14. doi: 10.3892/mmr.2013.1324 . PMID   23426619.

Further reading

• Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z (Oct 2000). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Research. 10 (10): 1546–60. doi:10.1101/gr.140200. PMC   310934 . PMID   11042152.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC   310948 . PMID   11076863.
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC   311072 . PMID   11230166.
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (Sep 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC   1083732 . PMID   11256614.
• Robinson A, Huttley GA, Booth HS, Board PG (May 2004). "Modelling and bioinformatics studies of the human Kappa-class glutathione transferase predict a novel third glutathione transferase family with similarity to prokaryotic 2-hydroxychromene-2-carboxylate isomerases". The Biochemical Journal. 379 (Pt 3): 541–52. doi:10.1042/BJ20031656. PMC   1224102 . PMID   14709161.
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC   528930 . PMID   15489336.
• Li J, Xia Z, Ding J (Sep 2005). "Thioredoxin-like domain of human kappa class glutathione transferase reveals sequence homology and structure similarity to the theta class enzyme". Protein Science. 14 (9): 2361–9. doi:10.1110/ps.051463905. PMC   2253485 . PMID   16081649.
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415-8. doi:10.1093/nar/gkj139. PMC   1347501 . PMID   16381901.
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC   1847948 . PMID   17353931.