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血管紧张素转化酶2：修订间差异

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==冠狀病毒受體==
==冠狀病毒受體==
血管紧张素转化酶2被許多[[冠狀病毒]]用來當作感染細胞的受體，包括造成[[普通感冒]]的[[人類冠狀病毒NL63]]<ref name="NCBI_ACE2">{{cite web|title=Gene: ACE2, angiotensin I converting enzyme 2 |work=[[National Center for Biotechnology Information]] (NCBI) |publisher=U.S. National Library of Medicine | date=2020-02-28 | url=https://www.ncbi.nlm.nih.gov/gene/59272 }}</ref>、造成[[SARS]]的[[SARS病毒]]<ref name="Fehr_2015">{{cite book | vauthors = Fehr AR, Perlman S | title = Coronaviruses | chapter = Coronaviruses: an overview of their replication and pathogenesis | series = Methods in Molecular Biology | volume = 1282 | pages = 1–23 | year = 2015 | pmid = 25720466 | pmc = 4369385 | doi = 10.1007/978-1-4939-2438-7_1 | publisher = Springer New York | isbn = 978-1-4939-2437-0 | quote = Many α-coronaviruses utilize aminopeptidase N (APN) as their receptor, SARS-CoV and HCoV-NL63 use angiotensin-converting enzyme 2 (ACE2) as their receptor, MHV enters through CEACAM1, and the recently identified MERS-CoV binds to dipeptidyl-peptidase 4 (DPP4) to gain entry into human cells (See Table 1 for a list of known CoV receptors). }}</ref><ref>{{cite journal | vauthors = Li F | title = Receptor recognition and cross-species infections of SARS coronavirus | journal = Antiviral Research | volume = 100 | issue = 1 | pages = 246–54 | date = October 2013 | pmid = 23994189 | pmc = 3840050 | doi = 10.1016/j.antiviral.2013.08.014 }}</ref>和造成[[2019冠狀病毒病]]的[[SARS-CoV-2]]<ref>{{cite web |title=What are the official names of the disease and the virus that causes it? |url=https://www.who.int/news-room/q-a-detail/q-a-coronaviruses |website=Q&A on coronaviruses |publisher=World Health Organization |access-date=22 February 2020 |archive-url=https://web.archive.org/web/20200305015146/https://www.who.int/news-room/q-a-detail/q-a-coronaviruses |archive-date=5 March 2020}}</ref>，這些病毒刺突蛋白S1結構域中的[[受體結合結構域]]（receptor binding domain；RBD）可和ACE2胞外的區域結合後，刺突蛋白可能被細胞表面的[[跨膜丝氨酸蛋白酶2]]（TMPRSS2）切割，促使病毒外膜和宿主[[細胞膜]]融合而讓病毒進入[[細胞質]]<ref>{{Cite journal|last1=Akhmerov Akbarshakh|last2=Marban Eduardo|title=COVID-19 and the Heart|journal=Circulation Research|year=2020|volume=0|issue=10|pages=1443–1455|doi=10.1161/CIRCRESAHA.120.317055|pmid=32252591|pmc=7188058}}</ref>；此外SARS-CoV與SARS-CoV-2<ref name="pmid32221306">{{cite journal| author=Ou X, Liu Y, Lei X, Li P, Mi D, Ren L | display-authors=etal| title=Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. | journal=Nat Commun | year= 2020 | volume= 11 | issue= 1 | pages= 1620 | pmid=32221306 | doi=10.1038/s41467-020-15562-9 | pmc=7100515 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32221306 }} </ref>還可能在不被TMPRSS2切割的情況下，與ACE2受體一起藉由[[內吞作用]]進入細胞，隨後其刺突蛋白在[[溶體]]中被{{le|組織蛋白酶|Cathepsin}}切割後，再從溶體進入細胞質中<ref name="Wang_2008">{{cite journal | vauthors = Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, Jiang C | title = SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway | journal = Cell Research | volume = 18 | issue = 2 | pages = 290–301 | date = February 2008 | pmid = 18227861 | pmc = 7091891 | doi = 10.1038/cr.2008.15 }}</ref><ref name="Millet_2018">{{cite journal | vauthors = Millet JK, Whittaker GR | title = Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells | journal = Virology | volume = 517 | pages = 3–8 | date = April 2018 | pmid = 29275820 | pmc = 7112017 | doi = 10.1016/j.virol.2017.12.015 }}</ref><ref name="pmid16339146">{{cite journal| author=Huang IC, Bosch BJ, Li F, Li W, Lee KH, Ghiran S | display-authors=etal| title=SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. | journal=J Biol Chem | year= 2006 | volume= 281 | issue= 6 | pages= 3198-203 | pmid=16339146 | doi=10.1074/jbc.M508381200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339146}}</ref>。
血管紧张素转化酶2被許多[[冠狀病毒]]用來當作感染細胞的受體，包括造成[[普通感冒]]的[[人類冠狀病毒NL63]]<ref name="NCBI_ACE2">{{cite web|title=Gene: ACE2, angiotensin I converting enzyme 2 |work=[[National Center for Biotechnology Information]] (NCBI) |publisher=U.S. National Library of Medicine | date=2020-02-28 | url=https://www.ncbi.nlm.nih.gov/gene/59272 }}</ref>、造成[[SARS]]的[[SARS病毒]]<ref name="Fehr_2015">{{cite book | vauthors = Fehr AR, Perlman S | title = Coronaviruses | chapter = Coronaviruses: an overview of their replication and pathogenesis | series = Methods in Molecular Biology | volume = 1282 | pages = 1–23 | year = 2015 | pmid = 25720466 | pmc = 4369385 | doi = 10.1007/978-1-4939-2438-7_1 | publisher = Springer New York | isbn = 978-1-4939-2437-0 | quote = Many α-coronaviruses utilize aminopeptidase N (APN) as their receptor, SARS-CoV and HCoV-NL63 use angiotensin-converting enzyme 2 (ACE2) as their receptor, MHV enters through CEACAM1, and the recently identified MERS-CoV binds to dipeptidyl-peptidase 4 (DPP4) to gain entry into human cells (See Table 1 for a list of known CoV receptors). }}</ref><ref>{{cite journal | vauthors = Li F | title = Receptor recognition and cross-species infections of SARS coronavirus | journal = Antiviral Research | volume = 100 | issue = 1 | pages = 246–54 | date = October 2013 | pmid = 23994189 | pmc = 3840050 | doi = 10.1016/j.antiviral.2013.08.014 }}</ref>和造成[[2019冠狀病毒病]]的[[SARS-CoV-2]]<ref>{{cite web |title=What are the official names of the disease and the virus that causes it? |url=https://www.who.int/news-room/q-a-detail/q-a-coronaviruses |website=Q&A on coronaviruses |publisher=World Health Organization |access-date=22 February 2020 |archive-url=https://web.archive.org/web/20200305015146/https://www.who.int/news-room/q-a-detail/q-a-coronaviruses |archive-date=5 March 2020}}</ref>，這些病毒刺突蛋白S1結構域中的[[受體結合結構域]]（receptor binding domain；RBD）可和ACE2胞外的區域結合後，刺突蛋白可能被細胞表面的[[跨膜丝氨酸蛋白酶2]]（TMPRSS2）切割，促使病毒外膜和宿主[[細胞膜]]融合而讓病毒進入[[細胞質]]<ref>{{Cite journal|last1=Akhmerov Akbarshakh|last2=Marban Eduardo|title=COVID-19 and the Heart|journal=Circulation Research|year=2020|volume=0|issue=10|pages=1443–1455|doi=10.1161/CIRCRESAHA.120.317055|pmid=32252591|pmc=7188058}}</ref>；此外SARS-CoV與SARS-CoV-2<ref name="pmid32221306">{{cite journal| author=Ou X, Liu Y, Lei X, Li P, Mi D, Ren L | display-authors=etal| title=Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. | journal=Nat Commun | year= 2020 | volume= 11 | issue= 1 | pages= 1620 | pmid=32221306 | doi=10.1038/s41467-020-15562-9 | pmc=7100515 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32221306 }} </ref>還可能在不被TMPRSS2切割的情況下，與ACE2受體一起藉由[[內吞作用]]進入細胞，隨後其刺突蛋白在[[溶體]]中被{{le|組織蛋白酶|Cathepsin}}切割後，再從溶體進入細胞質中<ref name="Wang_2008">{{cite journal | vauthors = Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, Jiang C | title = SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway | journal = Cell Research | volume = 18 | issue = 2 | pages = 290–301 | date = February 2008 | pmid = 18227861 | pmc = 7091891 | doi = 10.1038/cr.2008.15 }}</ref><ref name="Millet_2018">{{cite journal | vauthors = Millet JK, Whittaker GR | title = Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells | journal = Virology | volume = 517 | pages = 3–8 | date = April 2018 | pmid = 29275820 | pmc = 7112017 | doi = 10.1016/j.virol.2017.12.015 }}</ref><ref name="pmid16339146">{{cite journal| author=Huang IC, Bosch BJ, Li F, Li W, Lee KH, Ghiran S | display-authors=etal| title=SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. | journal=J Biol Chem | year= 2006 | volume= 281 | issue= 6 | pages= 3198-203 | pmid=16339146 | doi=10.1074/jbc.M508381200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339146}}</ref>。

SARS-CoV-2刺突蛋白的受體結構域有6個[[胺基酸]]為與宿主細胞的ACE2結合所需，包括[[白胺酸]]455、[[苯丙胺酸]]486、[[麩醯胺酸]]493、[[絲胺酸]]494、[[天門冬醯胺]]501與[[酪氨酸]]505<ref name="pmid32284615">{{cite journal| author=Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF| title=The proximal origin of SARS-CoV-2. | journal=Nat Med | year= 2020 | volume= 26 | issue= 4 | pages= 450-452 | pmid=32284615 | doi=10.1038/s41591-020-0820-9 | pmc=7095063 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32284615 }} </ref>。


==註腳==
==註腳==

2021年3月3日 (三) 00:28的版本

血管紧张素转化酶2
已知的結構
PDB直系同源搜索: PDBe RCSB
識別號
别名ACE2；, ACEH, angiotensin I converting enzyme 2, ACE 2
外部IDOMIM：300335 MGI：1917258 HomoloGene：41448 GeneCards：ACE2
基因位置（人类）
X染色體
染色体X染色體[1]
X染色體
血管紧张素转化酶2的基因位置
血管紧张素转化酶2的基因位置
基因座Xp22.2起始15,561,033 bp[1]
终止15,602,148 bp[1]
RNA表达模式


查阅更多表达数据
直系同源
物種人類小鼠
Entrez

59272

70008

Ensembl

ENSG00000130234

ENSMUSG00000015405

UniProt

Q9BYF1

Q8R0I0

mRNA​序列

NM_021804
​NM_001371415

NM_001130513
​NM_027286

蛋白序列

NP_068576
​NP_001358344

NP_001123985
​NP_081562

基因位置​（UCSC）Chr X: 15.56 – 15.6 MbChr X: 162.92 – 162.97 Mb
PubMed​查找[3][4]
維基數據
檢視/編輯人類檢視/編輯小鼠

血管紧张素转化酶2（英語：Angiotensin-converting enzyme 2；ACE2，人類的ACE2常被稱為hACE2[5]）在人類基因組中由X染色體上的基因編碼，是一種表現於肺、動脈、心臟、腎臟與腸道等組織細胞表面的膜蛋白，可分別將血管紧张素I和血管紧张素II轉化为血管收縮素(1-7)（英语：Angiotensin (1-7)）和血管收縮素(1-9)[6][7]。此外，ACE2还被SARS-CoV、SARS-CoV-2和人類冠狀病毒NL63等冠狀病毒用作感染細胞的受体[8]。

結構

血管紧张素转化酶2
识别码
EC編號 3.4.17.23
数据库
IntEnz IntEnz浏览
BRENDA（英语：BRENDA） BRENDA入口
ExPASy（英语：ExPASy） NiceZyme浏览
KEGG KEGG入口
MetaCyc（英语：MetaCyc） 代谢路径
PRIAM（英语：PRIAM_enzyme-specific_profiles） 概述
PDB RCSB PDB PDBj PDBe PDBsum

血管紧张素转化酶2（ACE2）最早於2000年自cDNA基因庫中被發現，為血管紧张素转化酶（ACE）第一個被發現的旁系同源體（英语：Homology (chemistry)）[6]，ACE2的基因位於人類基因組中的X染色體，包括18個外顯子，編碼的蛋白由805個胺基酸組成，與ACE的胺基酸序列相似度為42%[9]，是一個帶有鋅離子的金屬蛋白，屬單次跨膜蛋白（英语：Bitopic protein）（第一型膜蛋白），其N端結構域為一M2多肽酶，位於細胞膜外側；C端則與另一種名為collectrin的蛋白同源，包括疏水的跨膜結構域和一個胺基酸轉運體（英语：Amino acid transporter）結構域，位於細胞內[10]。

ACE2因有跨膜區域而造成其結構測定的困難，過去僅知其N端多肽酶的結構，直到2020年科學家才用低溫電子顯微鏡測出了與另一蛋白B0AT1（英语：Sodium-dependent neutral amino acid transporter B(0)AT1）結合狀態的完整ACE2結構，發現兩個ACE2和兩個B0AT1組成一複合體，複合體中兩個ACE2有交互作用，B0AT1間則無交互作用，僅與鄰近的ACE2作用，因此研究人員推測細胞膜上的ACE2也可能會形成二聚體[11][12]。

表現組織

人體幾乎所有器官組織都有表現血管紧张素转化酶（ACE），而血管紧张素转化酶2則表現於II型肺泡細胞、小腸腸上皮細胞（英语：enterocyte）、血管內皮細胞、血管平滑肌細胞、腎臟上皮細胞等，腦部許多神經元與膠細胞可能也有表現ACE2[9][13]。

功能

切割多肽

血管紧张素转化酶2主要的功能是與血管紧张素Ⅰ转化酶（ACE）拮抗，ACE可將無活性的血管收縮素Ⅰ切割成血管收縮素II，後者可促進抗利尿激素與醛固酮的分泌，以及刺激血管平滑肌收縮，使血壓上升；ACE2則分解血管收縮素Ⅰ和血管收縮素II以抑制其作用，將其C端的胺基酸移除，分別將前者轉化成血管收縮素(1-9)，將後者轉化成血管收縮素(1-7)（英语：Angiotensin (1-7)）[註 1]，其中切割血管收縮素II比切割血管收縮素I的能力高出許多，切割的產物中，血管收縮素(1-9)的功能不明，血管收縮素(1-7)則可刺激一氧化氮合成、抑制MAPK/ERK途徑（英语：MAPK/ERK pathway）、抑制活性氧類的生成以及抑制TGFβ途徑（英语：TGF beta signaling pathway），因此在心血管組織中有抗氧化與抗發炎等功能[9][11]。許多研究結果顯示ACE2表現量的下降與數種心血管疾病有相關性[15]。

肺泡細胞表現的ACE2有保護肺組織的功能。血管收縮素II可促進肺泡細胞凋亡與肺纖維化[16]，因此ACE2將前者分解成也會將血管收縮素II切割成血管收縮素(1-7)，可保護肺免於損傷[17]，加上血管收縮素(1-7)可與MAS1（英语：Mas）受體結合，啟動下游反應以抑制血管收縮素II的作用[17][18]。

在骨骼肌中，血管收縮素II與血管收縮素(1-7)均有重要功能。血管收縮素II透過多種途徑降低肌肉蛋白質的合成，包括抑制Akt－mTOR（英语：mTOR）途徑、促進肌萎缩素1（英语：FBXO32）與肌环指蛋白1（英语：TRIM63）的合成、生成活性氧物質而活化胱天蛋白酶途徑使細胞凋亡等，肌肉蛋白合成與分解的失衡會造成肌萎缩（英语：muscular atrophy）、肌纖維化等症狀[19][20]。將血管收縮素II轉化成血管收縮素(1-7)可停止其作用，且後者還可與MAS1（英语：Mas）受體結合，活化另一條反應途徑而抑制肌纖維化[11][21]。相較之下ACE2在骨骼肌的直接影響還有待更多研究闡明，有初步研究結果顯示在萎縮的肌肉組織中，ACE2可能可降低纖維化[11][22]。

其他

除了切割多肽外，ACE2還有些與其蛋白酶活性無關的功能。有研究顯示ACE2可與整合素結合，有助於細胞黏附（英语：cell adhesion）[11][23]。此外ACE2還參與了另一蛋白B0AT1（英语：Sodium-dependent neutral amino acid transporter B(0)AT1）的膜囊泡運輸過程，為其伴護蛋白，與B0AT1形成一複合體，協助將其轉運至細胞膜上[12]。

移除

ACE2的跨膜結構域可被一種稱為金屬蛋白酶17（英语：MMP17）（MMP17）的脱落酶（英语：sheddase）切割，將其胞外部分釋放到血液中，進而從組織間移除[24][25]，此過程受到許多調控，例如有一種鈣調蛋白可與ACE2結合以抑制MMP17的切割[26]，血管收縮素II也可促進MMP17的活性，把會將其分解的ACE2移除[27]，另外許多病理狀況、發炎反應也可促進MMP17對ACE2的切割。脫落酶的切割會造成心血管組織中ACE2的流失、血液中ACE2的濃度升高，因此後者可當作心臟衰竭、心房顫動、動脈粥樣硬化、慢性腎臟病、心肌梗塞與中風等多種疾病的生物標記[11][28]。

冠狀病毒受體

血管紧张素转化酶2被許多冠狀病毒用來當作感染細胞的受體，包括造成普通感冒的人類冠狀病毒NL63[29]、造成SARS的SARS病毒[30][31]和造成2019冠狀病毒病的SARS-CoV-2[32]，這些病毒刺突蛋白S1結構域中的受體結合結構域（receptor binding domain；RBD）可和ACE2胞外的區域結合後，刺突蛋白可能被細胞表面的跨膜丝氨酸蛋白酶2（TMPRSS2）切割，促使病毒外膜和宿主細胞膜融合而讓病毒進入細胞質[33]；此外SARS-CoV與SARS-CoV-2[34]還可能在不被TMPRSS2切割的情況下，與ACE2受體一起藉由內吞作用進入細胞，隨後其刺突蛋白在溶體中被組織蛋白酶切割後，再從溶體進入細胞質中[35][36][37]。

SARS-CoV-2刺突蛋白的受體結構域有6個胺基酸為與宿主細胞的ACE2結合所需，包括白胺酸455、苯丙胺酸486、麩醯胺酸493、絲胺酸494、天門冬醯胺501與酪氨酸505[38]。

註腳

  1. ^ ACE2將血管收縮素ⅠI切割為血管收縮素(1-7)，是控制組織間血管收縮素濃度的主要蛋白，但還有另一種蛋白中性肽鏈內切酶（英语：Neprilysin）可直接將血管收縮素Ⅰ切割為血管收縮素(1-7)[11][14]。

参考文献

  1. ^ 1.0 1.1 1.2 GRCh38: Ensembl release 89: ENSG00000130234 - Ensembl, May 2017
  2. ^ 2.0 2.1 2.2 GRCm38: Ensembl release 89: ENSMUSG00000015405 - Ensembl, May 2017
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参见

外部連結

3.4.11～19：外肽酶
其它/未分组
3.4.21～24：内肽酶
3.4.99：未知
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（英语：Template:Ligases CO CS and CN）/4/5-6
活性
调节
分类
动力学
类型
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