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胸苷激酶

維基百科，自由的百科全書
胸苷激酶
Crystal structure of a tetramer of thymidine kinase from U. urealyticum (where the monomers are color cyan, green, red, and magenta respectively) in complex with thymidine (space-filling model, carbon = white, oxygen = red, nitrogen = blue).[1]
識別碼
EC編號 2.7.1.21
CAS號 9002-06-6
數據庫
IntEnz IntEnz瀏覽
BRENDA（英語：BRENDA） BRENDA入口
ExPASy（英語：ExPASy） NiceZyme瀏覽
KEGG KEGG入口
MetaCyc（英語：MetaCyc） 代謝路徑
PRIAM（英語：PRIAM_enzyme-specific_profiles） 概述
PDB RCSB PDB PDBj PDBe PDBsum
基因本體 AmiGO / EGO
胸苷激酶
鑑定
標誌TK
PfamPF00265（舊版）
Pfam宗系CL0023（舊版）
InterPro（英語：InterPro）IPR001267
PROSITE（英語：PROSITE）PDOC00524
胸苷激酶1，可溶
識別
符號 TK1
Entrez 7083
HUGO 11830
OMIM 188300
RefSeq NM_003258
UniProt P04183
其他資料
EC編號 2.7.1.21
基因座 17 q23.2-25.3
胸苷激酶2，線粒體
識別
符號 TK2
Entrez 7084
HUGO 11831
OMIM 188250
RefSeq NM_004614
UniProt O00142
其他資料
EC編號 2.7.1.21
基因座 16 [1]

胸苷激酶（英語：thymidine kinase）是一種磷酸轉移酶（激酶）：2』-脫氧胸苷激酶，三磷酸腺苷-胸苷 5』-磷酸轉移酶，EC 2.7.1.21[2][3]存在於大部分活體細胞中。它以兩種同工酶的形式存在於哺乳動物細胞中，TK1和TK2。某些病毒同樣含有病毒性胸苷激酶表達的遺傳信息。

胸苷激酶催化以下反應：

•Thd + ATP → TMP + ADP

Thd是脫氧胸苷，ATP是5』-三磷酸-腺苷，TMP是5』-一磷酸-脫氧胸苷，ADP是5』-二磷酸-腺苷。

胸苷激酶的主要作用體現在細胞分裂過程中的DNA合成期，是介導脫氧胸苷進入DNA合成的旁路途經的一部分。脫氧胸苷存在於體液中，是食物細胞或機體細胞死亡後，DNA凋亡退化的產物。很多抗病毒藥物的反應都需要胸苷激酶的參與。

胸苷激酶可用於在生產單克隆抗體過程中，篩選雜交瘤細胞。臨床醫學中，胸苷激酶作為一種細胞增殖標誌物，用於惡性腫瘤的輔助診斷，治療監控和跟蹤隨訪。最近也有研究報道提出，胸苷激酶在早期癌症預防中的應用價值。

歷史

胸苷參與DNA合成的途經是在1950年前後發現的[4]，後來進一步明確，這一途經始於胸苷的磷酸化[5]；在1960年左右，參與此過程的激酶（胸苷激酶）被首次純化出來並進行了鑑定[6][7]。


分類

目前已得到鑑別的胸苷激酶可分為兩大類[8][9]：

一類存在於疱疹病毒與細胞胸苷激酶類似；

一類廣泛存在於脊椎動物，細菌，T4噬菌體，痘病毒，非洲豬瘟病毒（ASFV）和魚淋巴囊腫病毒（FLDV）。昆蟲虹彩病毒衣殼蛋白也屬於此類。

目前只確認了細胞胸苷激酶的蛋白位點模型。

生化特點

高等生物胸苷激酶以兩種同工酶形式存在，TK1和TK2，具有很大的化學差異性。

前一種最初在胎兒組織中發現，後一種大量存在於成人組織，所以最初，被分別命名為胎兒胸苷激酶和成人胸苷激酶。不久之後發現，TK1僅於細胞分裂初期（與細胞周期相關）存在於細胞質中[10][11]，而TK2定位於線粒體中，與細胞周期無關[12][13]。

1970年代中期定位了兩種酶的基因[14][15]，TK1基因的克隆和測序完成[16]，其所對應蛋白的分子量為25kD；通常以二聚體的形式出現在組織中，能夠被ATP激活；激活後，轉化為四聚體。重組後的TK1無法被激活也無法轉化為四聚體，表明這種存在於細胞中的激酶在合成後性狀已經發生了改變[17][18][19]。

細胞中TK1的合成發生在細胞分裂周期的S期。細胞分裂完成後，TK1在細胞內部降解，因此在正常細胞分裂中，TK1一般不會進入體液[20]。細胞中胸苷激酶的反饋調節作用機理：三磷酸胸苷（TTP：胸苷磷酸化後的終產物）扮演着胸苷激酶抑制劑的角色[21][22][23][24]。這一機制確保了核酸合成所需的TTP量維持在平衡狀態，而不會出現過飽和。5'-氨基胸苷是一種無毒性的胸苷類似物，能夠干擾這一調控機理，因此，胸苷類似物作為一種細胞毒性物質被應用於很多抗腫瘤藥物[25][26][27][28][29][30][31]。

一些病毒的特殊胸苷激酶基因也已經得到了鑑別，如單純疱疹病毒，水痘帶狀疱疹病毒和EB病毒（一種疱疹病毒）[32][33][34][35][36][37][38]。

生理學背景

胸苷激酶催化反應的產物——一磷酸脫氧胸苷，會繼續被胸苷酸激酶催化生成二磷酸脫氧胸苷，之後再被二磷酸核苷激酶催化生成三磷酸脫氧胸苷。在互補DNA和DNA聚合酶的催化作用下（或是逆轉錄過程中，在RNA和逆轉錄酶的作用下），三磷酸脫氧胸苷進入了DNA分子。

一磷酸脫氧胸苷可由兩種不同的反應得到——一種是前文所述的脫氧胸苷磷酸化反應得到；還有一種是在不動用胸苷的情況下，通過胸苷酸磷酸酶催化其他代謝途徑產生的脫氧尿苷甲基化反應得到。細胞在正常情況下（非細胞分裂狀態）採用第二種途徑為DNA修復提供充足的一磷酸脫氧胸苷。但當細胞準備分裂時，需要構建一組全新的DNA，對組成DNA的材料，如三磷酸脫氧胸苷的需求也增加了。在準備細胞分裂的過程中，一些細胞分裂所必需的酶開始產生。

這些酶平時不存在於細胞中，當細胞分裂完成後，在調控下濃度降低，最終降解。這一類酶被稱為補救酶。胸苷激酶1（TK1）就是一種補救酶，但胸苷激酶2（TK2）卻與細胞周期不相關[39][40][41][42][43][44][45][46][47]。

用途

鑑別處於分裂期的細胞

胸苷激酶在生化研究中的第一種直接應用是聯合放射性標記的胸苷和後繼用來測定放射活性的放射自顯影技術來鑑別處於分裂期的細胞。為了達到此目的，氚化的胸苷需保存在培養基中。[48] 儘管技術上存在缺陷，該技術仍被用來測定惡性腫瘤細胞的增殖比例和研究免疫過程中淋巴細胞的活性。

PET 掃描活體腫瘤

3』-脫氧-3』-[氟18]氟化胸苷是一種胸苷類似物。它由胸苷激酶1調控，被迅速增殖的腫瘤組織優先攝取。同位素氟18是一種在正電子發射型斷層顯像技術（PET）中常用的正電子發射體。這種標記物和另一常用的標記物2-[氟18]氟基-2-脫氧-D-葡萄糖相比，在對增殖狀態的活體腫瘤的PET成像方面更有優勢[49][50][51][52][53]。

篩選雜交瘤細胞

雜交瘤細胞是腫瘤細胞（具有無限分裂能力）和B淋巴細胞融合後獲得的。雜交瘤細胞能夠持續、大量地產生具有專屬特異性的免疫球蛋白（單克隆抗體）。但問題是如何在細胞融合後，從大量的多餘的未融合細胞中，挑選出雜交瘤細胞。

一種解決該問題的方法就是使用胸苷激酶陰性（TK-）的腫瘤細胞系進行融合。在增殖的腫瘤細胞系中加入胸苷類似物，將殺死胸苷激酶陽性（TK+）細胞，如此就得到了胸苷激酶陰性細胞。然後，這些陰性細胞用來與胸苷激酶陽性的（TK+）B淋巴細胞進行融合。融合之後，細胞需在添加了氨甲蝶呤[54]或氨基蝶呤[55]的培養基中培養，以防止二氫葉酸還原酶阻礙一磷酸胸苷的重新合成。培養基一般選用HAT培養基（含有次黃嘌呤，氨基蝶呤，胸腺嘧啶脫氧核苷）。 胸苷激酶陰性細胞系中的未融合細胞將由於一磷酸胸苷的斷供而死亡。而未融合淋巴細胞的死亡則是由於它們不是「不朽」的（不具備腫瘤細胞的無限分裂能力）。只有雜交瘤細胞由於同時繼承了腫瘤細胞系的「不朽」和B淋巴細胞的胸苷激酶得以倖存。這樣，可以用於生產所需抗體的雜交瘤細胞就篩選出來了，在培養後用於生產單克隆抗體。[56][57][58][59][60]

不過，採用相同原理，也可以通過篩選另一種次黃嘌呤-鳥嘌呤磷酸核糖轉移酶（HGPRT）細胞系來達到篩選雜交瘤細胞的目的從而替代胸苷激酶，該酶在補救合成途經中調控鳥嘌呤核苷酸合成所必須的次黃嘌呤的合成。

應用案例

臨床應用

胸苷激酶是一種補救酶，僅在細胞分裂前出現。由於細胞具有特殊的調控機制能夠降解細胞分裂後不再需要的酶和蛋白，所以在正常的細胞分裂後，胸苷激酶不會從細胞釋放。[61]因此一般條件下，血清或血漿中的胸苷激酶含量很低。腫瘤細胞釋放胸苷激酶進入循環系統，可能是與已經死亡或即將死亡的腫瘤細胞的瓦解有關。因此，血清胸苷激酶水平能夠用來評估腫瘤的增殖程度，並可以此來直接評估腫瘤的攻擊力。有一個令人關注的情況，存在於循環系統中的胸苷激酶與基因編碼的酶並不一致：基因編碼的酶分子量為25kD。二聚體分子量為50kD，被ATP激活轉化為四聚體後，分子量為100kD。[62]而循環系統中具有活性的酶的分子量為730kD，很有可能是與其他蛋白綁定形成了複合物[63] 。

目前胸苷激酶檢測在臨床應用中的價值主要體現在以下幾點：

1、評估放化療效果：由於胸苷激酶水平與腫瘤細胞惡性增殖程度具有相關性，治療前後的胸苷激酶水平變化情況能為治療評估提供輔助參考；

2、評估手術效果：通過比較腫瘤患者手術前後腫瘤細胞的增殖情況，為手術效果評價提供參考；

3、評估腫瘤復發風險：對腫瘤患者手術及治療恢復期的殘留腫瘤細胞的增殖狀態進行動態評估，較影像學更早發現復發轉移風險。[64]

不同腫瘤類別的胸苷激酶應用案例：

1、血液學惡性腫瘤中胸苷激酶的增長具有規律性。例如，胸苷激酶1（TK1）用於監控非霍奇金淋巴瘤。這種腫瘤的攻擊性差別很大，有些屬於慢速增殖，很難覺察難以及時治療；還有一些屬於快速增殖，具有高攻擊性需要緊急治療。這些差異可以在血清胸苷激酶的水平高低上得以體現，與正常水平相近的對應慢速增殖腫瘤，具有很高水平的對應快速增殖腫瘤。[65][66][67][68][69][70][71][72] 淋巴瘤患者血清TK1水平升高，可能預示着腫瘤具有高活性和高攻擊性，因此通過監測血清TK1水平的變化，適合於腫瘤的治療評估。[73]

該模型也使用於其他類型血液惡性腫瘤中（白血病[74][75][76]，漿細胞骨髓瘤[77][78]，骨髓增生異常綜合症）。需要關注的是在骨髓增生異常綜合症中：有一部分病例會迅速轉變為進行白血病，但是還有一些在很長一段時間內進展緩慢。那如果能夠鑑別出是否有進展為白血病的趨勢將對治療非常重要。

2、實體腫瘤中胸苷激酶的升高往往也與腫瘤惡性增殖程度，治療效果，復發情況具有相關性[79][80][81][82]。有報告指出在前列腺癌症中，胸苷激酶能夠如同PSA（前列腺特異抗原，目前前列腺癌中使用最頻繁的腫瘤標誌物）一樣提供輔助參考。PSA提示腫瘤大小，而TK提示腫瘤增殖速度[83][84][85][86]。對於其他實體腫瘤，如小細胞肺癌[87][88][89]，乳腺癌[90][91][92]，胃癌[93]，腎癌[94]，膀胱癌[95]等都有應用價值。

非惡性腫瘤而造成血清胸苷激酶升高的原因有維生素B12缺乏引起的惡性貧血，[96][97]病毒感染（部分由於疱疹病毒）[97][98][99] 或正處於創傷、手術恢復期[100]。

惡性增殖風險評估

由於胸苷激酶1與細胞增殖的相關性，近些年來，有關於胸苷激酶1對於進展期癌前病變的檢測意義，及在癌症預防體檢中的應用價值的探討。

有研究指出胸苷激酶1水平高低與不同年齡結構，及所處不同生活、工作環境的腫瘤發生風險具有相關性，在進行長期跟蹤後，TK1水平的持續升高與所患癌前病變的惡性進程具有相關性，在早期惡性腫瘤病變預防中能夠發揮一定作用。[101][102]

治療

有些藥物專門針對分裂期細胞有效。一般被用來治療腫瘤和病毒性疾病（同時作用於逆轉錄病毒和其他病毒），這是由於病變細胞比正常細胞複製更快更頻繁，同時也會殺死一些複製迅速地非惡性腫瘤細胞。

有不同種類的藥物可以控制細胞分裂過快，能夠直接作用於胸苷代謝也因此與胸苷激酶有關聯[103][104][105][106]：

胸苷類似物作為DNA鏈終止物進入DNA鏈複製，但是由於結構已經改變所以抑制了DNA鏈的延長。作為胸苷類似物，更容易磷酸化生成5』-一磷酸複合物。一磷酸複合物進一步磷酸化生成三磷酸複合物參與到DNA鏈的複製。但類似物結構有所變化，一般不具有DNA鏈複製所必須的3』端羥基。如：疊氮胸苷（AZT；ATC：J05AF01）的3』端羥基被疊氮基替代；[107][108] 雙脫氧胸苷（ATC：J05AF04）能夠競爭性抑制胸苷。[109][110] AZT在一種檢測血清胸苷激酶的方法中被用做底物。[111] 這意味着AZT會干擾這一步驟或是作為一種抑制劑： AZT是針對HIV（艾滋病病毒）感染的HAART（Highly Active Antiretroviral Therapy 高活性抗逆轉錄病毒療法）療法的組分之一。AIDS的最終結果一般是淋巴癌，而胸苷激酶檢測的一項最重要的診斷應用就是監控淋巴癌。

酶底物類似物的化學結構

其他胸苷類似物，如碘苷（ATC：J05AB02）能夠在隨後的複製循環中阻礙基礎配對，最終導致DNA合成鏈缺陷。[112]此物質結合化療能夠達到促使惡性腫瘤細胞凋亡的目的。[113]

一些抗病毒藥物，如阿昔洛韋（ATC：J05AB01）和更昔洛韋（ATC：J05AB06）與其他一些研究成功的核酸類似物一樣，[114]則是利用了對病毒胸苷激酶而非對人胸苷激酶的專屬特異性。[115]這些藥物機理如同前體藥物，本身不具有毒性，但是被病毒胸苷激酶磷酸化後，會轉變為細胞毒性藥物。感染了病毒的細胞由於產生出高細胞毒性的三磷酸核苷最終導致細胞的凋亡。而相反的，人胸苷激酶由於其專屬特異性，不會磷酸化而激活前體藥物。因此，只有感染了病毒的細胞對藥物敏感。這些藥物僅對具有特異的疱疹病毒類胸苷激酶的病毒有效。[116]

自1979年12月，WHO宣布天花病毒已經根除之後，牛痘接種項目也已經終止了。該病毒如果由於意外事故或被作為生化武器重新出現，將會在毫無防備的人群中爆發性傳播而難以控制。接種牛痘似乎是不道德的，因為唯一對天花有效的疫苗本身就含有用於刺激機體產生免疫效果反應的活性牛痘病毒。但出於安全問題考慮，有大量的疫苗需要長期儲備，其中以高效的抗天花葯物最為優先。一種可能的方式是利用痘病毒胸苷激酶的特異性來達到目的，作用機理與抗疱疹病毒類藥物類似。有一個難點是痘病毒胸苷激酶與人胸苷激酶屬於同一家族譜系，化學結構相似。目前痘病毒的結構已經探明並正在尋找潛在的抗病毒藥物。[117]但有效的抗痘病毒藥物研究尚無結果。

疱疹病毒胸苷激酶基因也當做「自殺基因」作為基因治療實驗中的安全系統，誘導細胞表達該基因後被更昔洛韋殺死。此種方法適用於通過重組基因誘發突變而最終導致的細胞增殖失控（誘導突變）。這些突變細胞產生的胸苷激酶擴散入周圍細胞中，會導致周圍細胞同樣對更昔洛韋敏感，該現象稱為「旁觀者效應」。此方法已用於動物體的腫瘤治療，有10%的惡性腫瘤細胞表達該基因並會被有效殺死。[118][119]利用一些腫瘤所特有的物質（腫瘤標誌物）也能實現類似的胸苷激酶應用。這些腫瘤標誌物，如CEA（癌胚抗原）和AFP（甲胎蛋白）。將這些腫瘤標誌物的基因作為胸苷激酶的啟動基因。胸苷激酶將在表達腫瘤標誌物基因的細胞中被激活，在正常細胞中則不會，因此使用更昔洛韋治療只會殺死腫瘤細胞。[120][121][122][123][124][125]儘管如此，這些基因治療方法仍在實驗階段，一些與基因轉移相關的問題，還未完全解決。

一種含硼元素的胸苷類似物已經被建議並用於BNCT法（硼-中子交互放射療法）治療腦部腫瘤的動物實驗。[126][127][128][129][130][131][132][133][134][135][136]

檢測方法

血清學

血清胸苷激酶檢測主要是檢測胸苷激酶1（TK1），檢測方法目前主要有兩類，一種是酶活性測定法；一種是酶濃度測定法。

使用酶活性測定法，一般通過將血清樣本和底物類似物共同培養來實現。最初的商業可行性技術是使用碘代脫氧尿苷，即使用放射性碘替代了胸苷的一個甲基。[137][138][139]該底物能夠被酶很好的識別。一磷酸化的碘代脫氧尿苷被添加在培養基中的氧化鋁所吸附。在傾倒和洗脫後，氧化鋁的放射性可換算出樣本中胸苷激酶的量。應用此原理的商業試劑盒由貝克曼公司和索靈公司提供。

此外索靈公司還研究出一種非放射性分析方法。在該技術中3』-疊氮-2』，3』-脫氧胸苷（AZT：疊氮胸苷）首先被樣本中的TK1磷酸化生成5』-一磷酸-AZT（AZTMP：疊氮胸苷一磷酸）。AZTMP通過免疫學方法測定，使用抗-AZTMP抗體為AZTMP標記上過氧化物。測定需在索靈公司提供的封閉式實驗工作系統內進行。[140][111]

另一種新研發的技術是使用胸苷類似物——溴化尿苷，作為酶底物。反應產物（在微量滴定板中）吸附在滴定板各孔的底部。再通過ELISA方法測定：在各孔中加入抗溴化尿苷的單克隆抗體溶液。單克隆抗體上結合有鹼性磷酸酶。洗脫掉過量的結合有鹼性磷酸酶的抗體，加入含有鹼性磷酸酶底物——4-硝基苯酚的溶液。反應產物4-硝基酚在磷酸pH環境中是黃色能夠通過光度法測定。[141]此種分析方法能夠進行更加靈敏的檢測。商業試劑盒由Biovica公司提供。

使用酶濃度測定法，一般對抗TK1抗體的靈敏度要求很高，之前很長一段時間內沒有突破。20世紀末至21世紀初，瑞典karolinska醫學院利用鳥類特異性IgY抗體，開發出一種新型多克隆抗體——抗人TK1-IgY抗體，並申請了國際專利，此抗體具有很高的靈敏度和特異性，能夠識別人血清中低濃度TK1。[142]此抗體在結合化學發光檢測技術後，進一步提高了檢測靈敏度。商用試劑盒由SSTK公司（中國，深圳）提供。

組織學

從組織提取物樣本中能夠檢測到胸苷激酶。但尚沒有標準的組織提取或分析方法，組織和細胞提取物中的TK檢測與實際臨床問題的相關性也未得到證實。見Romain等[143]和Arnér等[144]。有一種方法使用5』-溴-2』-脫氧尿苷作為底物類似物特異性檢測細胞提取物中的TK2。[145]但在使用此方法的其他研究中，報告的結果差異很大方法可行性不佳。

處於發展階段的胎兒組織的TK1水平比之後要高。[146][147][148]

某些非惡性腫瘤細胞和組織中的TK1水平也會出現明顯升高：如存在單核細胞增多症時的周圍淋巴細胞，[149]和存在惡性貧血是的骨髓細胞。[150][151]

由於TK1存在於處於分裂期的細胞中，因此有理由認為惡性腫瘤組織中的TK活性應比正常組織中的要高。這已在大部分的研究中得到證實。腫瘤組織中TK活性比一般組織要高[146][152][153][154]，如腦瘤[155]，血液系統惡性腫瘤[156]，結腸癌和結腸息肉[157][158][159][160][161][162]，乳腺癌[163][164][165][166][167][168]，肺癌[169][170][171]，胃癌[172]，卵巢癌[173]，間皮瘤[174]，黑色素瘤[175]，和甲狀腺腫瘤[176][177]。

對於白血病[178][179]和乳腺癌[180]，治療對細胞增殖速率的影響與對TK值的影響是由相關性的。

免疫組織化學染色

抗胸苷激酶抗體可以用於免疫組化檢測。[181]胸苷激酶染色就是一種可靠的用於鑑別2期乳腺癌患者的技術。胸苷激酶和Ki-67染色技術的聯合使用已經使相當多的患者得到了診斷。[182][183]

該技術對肺癌[182][184]，結直腸癌[185]，非小細胞肺癌[186]和腎癌[187]具有同樣價值。

標籤

胸苷激酶1；疱疹病毒胸苷激酶；胸苷酸激酶；二磷酸核苷激酶；胸苷酸合成酶

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