組織蛋白酶Z

組織蛋白酶Z
已知的結構
PDB	直系同源搜索: PDBe RCSB
PDBID列表
	1DEU、1EF7
識別號
別名	CTSZ；, CTSX, cathepsin Z
外部ID	OMIM：603169 MGI：1891190 HomoloGene：1022 GeneCards：CTSZ
為以下藥物的標靶
	odanacatib
基因位置（人類）
染色體	20號染色體
終止	59,008,238 bp
基因位置（小鼠）
染色體	小鼠2號染色體
終止	174,280,832 bp
RNA表達模式
	查閱更多表達數據
基因本體
分子功能	• 血漿蛋白結合; • 肽酶活性; • 水解酶活性; • cysteine-type endopeptidase activity; • 半胱氨酸型肽酶活性; • carboxypeptidase activity;
細胞組分	• endoplasmic reticulum lumen; • COPII-coated ER to Golgi transport vesicle; • 細胞內膜結合細胞器; • 內質網; • 細胞膜; • endoplasmic reticulum-Golgi intermediate compartment membrane; • 外排體; • Golgi membrane; • 細胞外區域; • specific granule lumen; • ficolin-1-rich granule lumen; • 細胞外空間; • 溶酶體; • cell surface; • 生長錐; • cytoplasmic vesicle; • cell cortex region; • collagen-containing extracellular matrix;
生物學過程	• proteolysis involved in cellular protein catabolic process; • COPII vesicle coating; • endoplasmic reticulum to Golgi vesicle-mediated transport; • epithelial tube branching involved in lung morphogenesis; • angiotensin maturation; • neutrophil degranulation; • 蛋白酶解; • negative regulation of plasminogen activation; • negative regulation of neuron projection development; • negative regulation of protein binding; • positive regulation of neuron apoptotic process; • regulation of neuron death; • positive regulation of neural precursor cell proliferation;
	Sources:Amigo / QuickGO
直系同源
	1522
	64138
	ENSG00000101160
	ENSMUSG00000016256
	Q9UBR2
	Q9WUU7
	NM_001336
	NM_022325
	NP_001327
	NP_071720
	維基數據
檢視/編輯人類	檢視/編輯小鼠

組織蛋白酶Z，也稱為組織蛋白酶X或組織蛋白酶P，是一種在人體中由CTSZ基因編碼的蛋白質。^[6]^[7]它是半胱氨酸蛋白酶的半胱氨酸組織蛋白酶家族的成員，該家族有11個成員。^[8]作為11種組織蛋白酶之一，組織蛋白酶Z具有與眾不同的特徵。據報道，組織蛋白酶Z與惡性腫瘤和炎症有關。

結構

基因

CTSZ基因位於20號染色體的20q13.32，由6個外顯子組成。已發現該基因的至少兩種轉錄變體，但僅確定了其中一種的全長性質。^[7]

蛋白質

組織蛋白酶Z的特點是在假定的氧離子孔的穀氨酰胺和活性位點半胱氨酸之間的高度保守區域中插入了不尋常且獨特的3個氨基酸。組織蛋白酶Z的前區與其他組織蛋白酶家族序列沒有顯着相似性。^[9]它僅包含41個氨基酸殘基，沒有在其他半胱氨酸蛋白酶中發現的ERFNIN或GNFD的保守基序。此外，前區序列不含賴氨酸殘基。

功能

該基因編碼的蛋白質是一種溶酶體半胱氨酸蛋白酶，是肽酶C1家族的成員。它表現出羧單肽酶和羧二肽酶活性。迄今為止，已鑑定出11種人類半胱氨酸蛋白酶，包括組織蛋白酶B、組織蛋白酶C、組織蛋白酶F、組織蛋白酶H、組織蛋白酶K、組織蛋白酶L1、組織蛋白酶L2或V、組織蛋白酶O、組織蛋白酶S、組織蛋白酶Z和組織蛋白酶W。這些半胱氨酸蛋白酶屬於木瓜蛋白酶家族，是溶酶體蛋白酶解系統的主要成分。除了在蛋白質降解和轉換中發揮關鍵作用外，這些蛋白酶似乎在許多正常和病理條件下發揮細胞外作用。人類組織蛋白酶Z包含與其他人類半胱氨酸蛋白酶不同的特徵。^[10]它是一種具有嚴格羧肽酶活性的外肽酶，而大多數其他組織蛋白酶是內肽酶。^[8]組織蛋白酶Z在酶的前肽內具有暴露的整合素結合Arg-Gly-Asp基序，已顯示組織蛋白酶Z在正常體內平衡、免疫過程和癌症期間通過該基序與幾種整合素相互作用。^[11]^[12]^[13]^[14]它還顯示與細胞表面的硫酸肝素蛋白聚糖結合，表明可能在細胞黏附和吞噬作用中發揮作用。^[15]

臨床意義

該基因在癌細胞系和原發性腫瘤中普遍表達，並且與該家族的其他成員一樣，可能參與腫瘤發生。例如，組織蛋白酶Z通過非催化機制促進侵襲和遷移，這表明多種細胞侵襲模式可能與惡性腫瘤有關。^[14]組織蛋白酶Z在炎症性胃病中也具有保護作用，但不是蛋白酶解作用。^[16]在另一項研究中顯示，組織蛋白酶Z可能是導致多巴胺神經元死亡的原因，因此參與了致病級聯事件。^[17]組織蛋白酶Z中的單核苷酸多態性被發現與結核病易感性有關，表明涉及該蛋白質的途徑可以產生結核病的新療法。^[18]

相互作用

組織蛋白酶Z已被證明與以下蛋白質相互作用：CEP55, FBXO6, KIFC1, KRT40, KRTAP5-9, KRTAP5-9, LYPLAL1, MID2, MSN, MTUS2, NOTCH2NL, PLK2, PLSCR1, SGOL2, and SPRED2.^[19]

還發現組織蛋白酶Z與以下物質相互作用：

參考文獻

^ 對Cathepsin Z起作用的藥物；在維基數據上查看/編輯參考.
^ ^2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000101160 - Ensembl, May 2017
^ ^3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000016256 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Santamaría I, Velasco G, Pendás AM, Fueyo A, López-Otín C. Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a unique chromosomal location. The Journal of Biological Chemistry. July 1998, 273 (27): 16816–23. PMID 9642240. doi:10.1074/jbc.273.27.16816 .
^ ^7.0 ^7.1 Entrez Gene: CTSZ cathepsin Z. [2022-11-01]. （原始內容存檔於2010-03-08）.
^ ^8.0 ^8.1 Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, Turk D. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. January 2012, 1824 (1): 68–88. PMC 7105208 . PMID 22024571. doi:10.1016/j.bbapap.2011.10.002 .
^ Nägler DK, Zhang R, Tam W, Sulea T, Purisima EO, Ménard R. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity. Biochemistry. September 1999, 38 (39): 12648–54. PMID 10504234. doi:10.1021/bi991371z.
^ Nägler DK, Ménard R. Human cathepsin X: a novel cysteine protease of the papain family with a very short proregion and unique insertions. FEBS Letters. August 1998, 434 (1–2): 135–9. PMID 9738465. S2CID 22899822. doi:10.1016/s0014-5793(98)00964-8 .
^ Lechner AM, Assfalg-Machleidt I, Zahler S, Stoeckelhuber M, Machleidt W, Jochum M, Nägler DK. RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties. The Journal of Biological Chemistry. December 2006, 281 (51): 39588–97. PMID 17065156. doi:10.1074/jbc.M513439200 .
^ Kos J, Jevnikar Z, Obermajer N. The role of cathepsin X in cell signaling. Cell Adhesion & Migration. April–June 2009, 3 (2): 164–6. PMC 2679876 . PMID 19262176. doi:10.4161/cam.3.2.7403.
^ Obermajer N, Svajger U, Bogyo M, Jeras M, Kos J. Maturation of dendritic cells depends on proteolytic cleavage by cathepsin X. Journal of Leukocyte Biology. November 2008, 84 (5): 1306–15. PMC 3252843 . PMID 18701767. doi:10.1189/jlb.0508285.
^ ^14.0 ^14.1 ^14.2 Akkari L, Gocheva V, Kester JC, Hunter KE, Quick ML, Sevenich L, Wang HW, Peters C, Tang LH, Klimstra DS, Reinheckel T, Joyce JA. Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix. Genes & Development. October 2014, 28 (19): 2134–50. PMC 4180975 . PMID 25274726. doi:10.1101/gad.249599.114.
^ ^15.0 ^15.1 Teller A, Jechorek D, Hartig R, Adolf D, Reißig K, Roessner A, Franke S. Dysregulation of apoptotic signaling pathways by interaction of RPLP0 and cathepsin X/Z in gastric cancer. Pathology, Research and Practice. January 2015, 211 (1): 62–70. PMID 25433997. doi:10.1016/j.prp.2014.09.005.
^ Krueger S, Bernhardt A, Kalinski T, Baldensperger M, Zeh M, Teller A, Adolf D, Reinheckel T, Roessner A, Kuester D. Induction of premalignant host responses by cathepsin x/z-deficiency in Helicobacter pylori-infected mice. PLOS ONE. 2013, 8 (7): e70242. PMC 3728094 . PMID 23936173. doi:10.1371/journal.pone.0070242 .
^ Pišlar AH, Zidar N, Kikelj D, Kos J. Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells. Neuropharmacology. July 2014, 82: 121–31. PMID 23958447. S2CID 22499368. doi:10.1016/j.neuropharm.2013.07.040.
^ Adams LA, Möller M, Nebel A, Schreiber S, van der Merwe L, van Helden PD, Hoal EG. Polymorphisms in MC3R promoter and CTSZ 3'UTR are associated with tuberculosis susceptibility. European Journal of Human Genetics. June 2011, 19 (6): 676–81. PMC 3110050 . PMID 21368909. doi:10.1038/ejhg.2011.1.
^ CTSZ interaction network. BioGRID. [6 August 2016]. （原始內容存檔於2022-11-01）.
^ Hafner A, Glavan G, Obermajer N, Živin M, Schliebs R, Kos J. Neuroprotective role of γ-enolase in microglia in a mouse model of Alzheimer's disease is regulated by cathepsin X. Aging Cell. August 2013, 12 (4): 604–14. PMID 23621429. S2CID 23835547. doi:10.1111/acel.12093 .

閱讀

Nägler DK, Ménard R. Human cathepsin X: a novel cysteine protease of the papain family with a very short proregion and unique insertions. FEBS Letters. August 1998, 434 (1–2): 135–9. PMID 9738465. S2CID 22899822. doi:10.1016/S0014-5793(98)00964-8 .
Pungercar J, Ivanovski G. Identification and molecular cloning of cathepsin P, a novel human putative cysteine protease of the papain family. Pflügers Archiv. 2000, 439 (3 Suppl): R116–8. PMID 10653162. S2CID 22775842. doi:10.1007/s004240000112.
Pungercar J, Viyjak A, Ivanovski G, Krizaj I. Tissue expression and immunolocalization of a novel human cathepsin P. Pflügers Archiv. 2000, 439 (3 Suppl): R119–21. PMID 10653163. S2CID 22728027. doi:10.1007/s004240000113.
Sivaraman J, Nägler DK, Zhang R, Ménard R, Cygler M. Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine. Journal of Molecular Biology. January 2000, 295 (4): 939–51. PMID 10656802. doi:10.1006/jmbi.1999.3410.
Guncar G, Klemencic I, Turk B, Turk V, Karaoglanovic-Carmona A, Juliano L, Turk D. Crystal structure of cathepsin X: a flip-flop of the ring of His23 allows carboxy-monopeptidase and carboxy-dipeptidase activity of the protease. Structure. March 2000, 8 (3): 305–13 [2022-11-01]. PMID 10745011. doi:10.1016/S0969-2126(00)00108-8. （原始內容存檔於2022-03-08）.
Deussing J, von Olshausen I, Peters C. Murine and human cathepsin Z: cDNA-cloning, characterization of the genes and chromosomal localization. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. April 2000, 1491 (1–3): 93–106. PMID 10760573. doi:10.1016/s0167-4781(00)00021-x.
Bonthron DT, Hayward BE, Moran V, Strain L. Characterization of TH1 and CTSZ, two non-imprinted genes downstream of GNAS1 in chromosome 20q13. Human Genetics. August 2000, 107 (2): 165–75. PMID 11030415. S2CID 25570066. doi:10.1007/s004390000344.
Hartley JL, Temple GF, Brasch MA. DNA cloning using in vitro site-specific recombination. Genome Research. November 2000, 10 (11): 1788–95. PMC 310948 . PMID 11076863. doi:10.1101/gr.143000.
Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S. Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. EMBO Reports. September 2000, 1 (3): 287–92. PMC 1083732 . PMID 11256614. doi:10.1093/embo-reports/kvd058.
Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A. From ORFeome to biology: a functional genomics pipeline. Genome Research. October 2004, 14 (10B): 2136–44. PMC 528930 . PMID 15489336. doi:10.1101/gr.2576704.
Puzer L, Barros NM, Oliveira V, Juliano MA, Lu G, Hassanein M, Juliano L, Mason RW, Carmona AK. Defining the substrate specificity of mouse cathepsin P. Archives of Biochemistry and Biophysics. March 2005, 435 (1): 190–6. PMID 15680921. doi:10.1016/j.abb.2004.12.007.
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. The LIFEdb database in 2006. Nucleic Acids Research. January 2006, 34 (Database issue): D415–8. PMC 1347501 . PMID 16381901. doi:10.1093/nar/gkj139.
Lechner AM, Assfalg-Machleidt I, Zahler S, Stoeckelhuber M, Machleidt W, Jochum M, Nägler DK. RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties. The Journal of Biological Chemistry. December 2006, 281 (51): 39588–97. PMID 17065156. doi:10.1074/jbc.M513439200 .

外部連結

The MEROPS online database for peptidases and their inhibitors: C01.013^{[失效連結]}
PDB中UniProt可用的所有結構信息之概述：Q9UBR2 (Cathepsin Z) 在PDBe-KB（英語：PDBe-KB）。

[1] 對Cathepsin Z起作用的藥物；在維基數據上查看/編輯參考.

[refGRCh38Ensembl-2] 2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000101160 - Ensembl, May 2017

[refGRCm38Ensembl-3] 3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000016256 - Ensembl, May 2017

[4] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9642240-6] Santamaría I, Velasco G, Pendás AM, Fueyo A, López-Otín C. Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a unique chromosomal location. The Journal of Biological Chemistry. July 1998, 273 (27): 16816–23. PMID 9642240. doi:10.1074/jbc.273.27.16816 .

[entrez-7] 7.0 ^7.1 Entrez Gene: CTSZ cathepsin Z. [2022-11-01]. （原始內容存檔於2010-03-08）.

[pmid22024571-8] 8.0 ^8.1 Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, Turk D. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. January 2012, 1824 (1): 68–88. PMC 7105208 . PMID 22024571. doi:10.1016/j.bbapap.2011.10.002 .

[pmid10504234-9] Nägler DK, Zhang R, Tam W, Sulea T, Purisima EO, Ménard R. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity. Biochemistry. September 1999, 38 (39): 12648–54. PMID 10504234. doi:10.1021/bi991371z.

[pmid9738465-10] Nägler DK, Ménard R. Human cathepsin X: a novel cysteine protease of the papain family with a very short proregion and unique insertions. FEBS Letters. August 1998, 434 (1–2): 135–9. PMID 9738465. S2CID 22899822. doi:10.1016/s0014-5793(98)00964-8 .

[pmid17065156-11] Lechner AM, Assfalg-Machleidt I, Zahler S, Stoeckelhuber M, Machleidt W, Jochum M, Nägler DK. RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties. The Journal of Biological Chemistry. December 2006, 281 (51): 39588–97. PMID 17065156. doi:10.1074/jbc.M513439200 .

[pmid19262176-12] Kos J, Jevnikar Z, Obermajer N. The role of cathepsin X in cell signaling. Cell Adhesion & Migration. April–June 2009, 3 (2): 164–6. PMC 2679876 . PMID 19262176. doi:10.4161/cam.3.2.7403.

[pmid18701767-13] Obermajer N, Svajger U, Bogyo M, Jeras M, Kos J. Maturation of dendritic cells depends on proteolytic cleavage by cathepsin X. Journal of Leukocyte Biology. November 2008, 84 (5): 1306–15. PMC 3252843 . PMID 18701767. doi:10.1189/jlb.0508285.

[pmid25274726-14] 14.0 ^14.1 ^14.2 Akkari L, Gocheva V, Kester JC, Hunter KE, Quick ML, Sevenich L, Wang HW, Peters C, Tang LH, Klimstra DS, Reinheckel T, Joyce JA. Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix. Genes & Development. October 2014, 28 (19): 2134–50. PMC 4180975 . PMID 25274726. doi:10.1101/gad.249599.114.

[pmid25433997-15] 15.0 ^15.1 Teller A, Jechorek D, Hartig R, Adolf D, Reißig K, Roessner A, Franke S. Dysregulation of apoptotic signaling pathways by interaction of RPLP0 and cathepsin X/Z in gastric cancer. Pathology, Research and Practice. January 2015, 211 (1): 62–70. PMID 25433997. doi:10.1016/j.prp.2014.09.005.

[pmid23936173-16] Krueger S, Bernhardt A, Kalinski T, Baldensperger M, Zeh M, Teller A, Adolf D, Reinheckel T, Roessner A, Kuester D. Induction of premalignant host responses by cathepsin x/z-deficiency in Helicobacter pylori-infected mice. PLOS ONE. 2013, 8 (7): e70242. PMC 3728094 . PMID 23936173. doi:10.1371/journal.pone.0070242 .

[pmid23958447-17] Pišlar AH, Zidar N, Kikelj D, Kos J. Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells. Neuropharmacology. July 2014, 82: 121–31. PMID 23958447. S2CID 22499368. doi:10.1016/j.neuropharm.2013.07.040.

[pmid21368909-18] Adams LA, Möller M, Nebel A, Schreiber S, van der Merwe L, van Helden PD, Hoal EG. Polymorphisms in MC3R promoter and CTSZ 3'UTR are associated with tuberculosis susceptibility. European Journal of Human Genetics. June 2011, 19 (6): 676–81. PMC 3110050 . PMID 21368909. doi:10.1038/ejhg.2011.1.

[19] CTSZ interaction network. BioGRID. [6 August 2016]. （原始內容存檔於2022-11-01）.

[pmid23621429-20] Hafner A, Glavan G, Obermajer N, Živin M, Schliebs R, Kos J. Neuroprotective role of γ-enolase in microglia in a mouse model of Alzheimer's disease is regulated by cathepsin X. Aging Cell. August 2013, 12 (4): 604–14. PMID 23621429. S2CID 23835547. doi:10.1111/acel.12093 .

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閱論編蛋白酶類：半胱氨酸蛋白酶類（EC 3.4.22)
胱天蛋白酶	胱天蛋白酶1 胱天蛋白酶2 胱天蛋白酶3 胱天蛋白酶4 胱天蛋白酶5 胱天蛋白酶6 胱天蛋白酶7 胱天蛋白酶8 胱天蛋白酶9 胱天蛋白酶10 胱天蛋白酶11 胱天蛋白酶12 胱天蛋白酶13 胱天蛋白酶14
來自果實	木瓜蛋白酶無花果蛋白酶（英語：Ficain）鳳梨蛋白酶獼猴桃蛋白酶
鈣蛋白酶	CAPN1 CAPN2 CAPN3 CAPN5 CAPN6 CAPN7 CAPN8 CAPN9 CAPN10 CAPN11 CAPN12 CAPN13 CAPN14 CAPNS1 CAPNS2
組織蛋白酶	B C F H K L1/L2 O S T W Z
其它	梭菌蛋白酶癌性促凝物質分離酶（英語：Separase） Autophagin Cruzipain 3C樣蛋白酶
EC 1.1/2/3/4/5/6/7/8/9/10/11/12/13/14/15/16/17/18/19/20/21/22 · 2.1/2/3/4/5/6/7(2.7.10/11-12)/8/9 · 3.1/2/3/4(3.4.21/22/23/24)/5/6/7/8/9/10/11/12/13 · 4.1/2/3/4/5/6 · 5.1/2/3/4/5/99 · 6.1-3（英語：Template:Ligases CO CS and CN）/4/5-6

閱論編酶
活性	活性位點結合位點催化三聯體負氧離子洞酶催化混雜（英語：Enzyme promiscuity）催化最適酶（英語：Catalytically perfect enzyme）輔因子輔酶酶促反應
調節	別構調節協同性（英語：Cooperativity）酶抑制劑酶激活劑
分類	EC編號蛋白質超家族蛋白質家族酶列表
動力學	酶動力學伊迪-霍夫斯蒂圖（英語：Eadie–Hofstee diagram）哈尼斯-伍爾夫圖（英語：Hanes–Woolf plot）雙倒數圖米氏動力學
類型	EC1 氧化還原酶（列表（英語：List of EC numbers (EC 1)）） EC2 轉移酶（列表（英語：List of EC numbers (EC 2)）） EC3 水解酶（列表（英語：List of EC numbers (EC 3)）） EC4 裂合酶（列表（英語：List of EC numbers (EC 4)）） EC5 異構酶（列表（英語：List of EC numbers (EC 5)）） EC6 連接酶（列表（英語：List of EC numbers (EC 6)）） EC7 移位酶（英語：Translocase）（列表（英語：List of EC numbers (EC 7)））