低氧与HIF-1对谷氨酰胺代谢的影响
Effects of Hypoxia and HIF-1 on Glutamine Metabolism

作者: 刘梦琦 , 王冬杨 , 邬超越 , 曹诣斌 :浙江师范大学,化学与生命科学学院,浙江 金华;

关键词: 低氧HIF-1谷氨酰胺糖代谢TCA循环 Hypoxia HIF-1 Glutamine Glucose Metabolism TCA Cycle

摘要:
在氧气充足的情况下,葡萄糖可以通过糖酵解和线粒体柠檬酸(TCA)循环为细胞提供能源和碳源。低氧会使TCA循环和电子传递链(ECT)受到抑制,葡萄糖无法被完全氧化,细胞缺乏能源和碳源。为了补充碳源和能源,低氧细胞促进谷氨酰胺代谢途径合成的柠檬酸参与TCA循环,为细胞提供必要的能源和碳源,低氧诱导因子(HIF-1)参与了这一调控。本文主要介绍了低氧环境下的谷氨酰胺代谢,分析了HIF-1与谷氨酰胺代谢之间的相互作用,为低氧糖代谢的调控机制提供理论依据。

Abstract: When oxygen is sufficient, glucose can provide energy and carbon source for cells through glycolysis and mitochondrial citric acid (TCA) cycle. Hypoxia can inhibit TCA cycle and electron transport chain (ECT), glucose cannot be completely oxidized, and cells lack energy and carbon sources. In order to supplement carbon source and energy, hypoxic cells promote glutamine metabolism, synthesize citric acid, participate in TCA cycle, and provide necessary energy and carbon source for cells. Hypoxia inducible factor-1 (HIF-1) is involved in this regulation. This paper mainly introduces glutamine metabolism in hypoxic environment, analyzes the interaction between HIF-1 and glutamine metabolism, and provides theoretical basis for the regulation mechanism of hypoxic glucose metabolism.

1. 引言

低氧诱导因子-1 (hypoxia inducible factor-1, HIF-1)是低氧条件下广泛存在于哺乳动物和人体内的一种转录因子 [1],它通过调控一系列与适应低氧相关的基因(如糖代谢 [2] ),对维持机体内的氧稳态平衡发挥着重要的生理学作用。巴斯德效应(Pasteur effect)首次描述了低氧细胞中葡萄糖向乳酸转化增加的现象。由于缺少氧气,细胞中的三羧酸循环(TCA循环)和电子传递链被抑制,葡萄糖转化成丙酮酸后,无法被丙酮酸脱氢酶(PDH)催化合成柠檬酸参与TCA循环,而是与NH3结合生成乳酸,排出体外。葡萄糖无法被利用,细胞缺乏生长所必需的碳源和能源。最近的研究发现,低氧下细胞能够通过增加谷氨酰胺(Gln)的摄取,为低氧细胞提供能源和碳源。而HIF-1能够通过促进谷氨酰胺代谢,为细胞提供碳源,帮助细胞适应低氧环境。本文对低氧下谷氨酰胺的代谢过程以及HIF-1与谷氨酰胺代谢之间的相互作用进行了综述,为低氧细胞的代谢适应提供理论基础。

2. HIF-1概述

上世纪90年代初,Semenza [1] 和Wang [3] 在低氧条件下培养的哺乳动物细胞中,发现了一种能够与红细胞生成素EPO基因上的低氧反应元件(HRE)特异性结合的蛋白质,后来发现它广泛存在于低氧细胞内,将它命名为低氧诱导因子(HIFs)。HIFs是异二聚体,由一个氧敏感性α亚单位(HIF-1α、HIF-2α、HIF-3α)和氧不敏感的HIF-1β亚单位组成。低氧诱导因子-1 (HIF-1)由HIF-1α (如图1)和HIF-1β两个亚基组成,都属于bHLH-PAS转录因子家族 [4]。HIF-1α由位于N端和C端的两个转录激活域,以及PAS结构域、bHLH结构域和氧依赖性降解域(ODDD)组成 [4]。

Figure 1. Structure of HIF-1 α

图1. HIF-1α的结构图

HIF-1的转录活性主要取决于α亚基的活性 [5],β亚基对氧不敏感,在常氧或低氧状态下均持续性表达,α亚基对氧浓度敏感,受氧浓度严格调控,其ODDD区域的保守脯氨酸残基的共价修饰对HIF-1α蛋白的稳定性起决定性作用。常氧下,HIF-1α亚基半衰期很短,在细胞中不断地被合成又被快速降解,这是由于α亚基ODDD结构域中的两个脯氨酸残基(pro402和pro564)能够被脯氨酰羟化酶(PHDs)羟基化,羟基化的脯氨酸残基与肿瘤抑制基因蛋白(pVHL)发生相互作用,并通过泛素–蛋白酶体途径降解 [5] [6]。PHDs的活性取决于氧、抗坏血酸和辅酶Fe2+的含量 [7],低氧下,PHDs活性丧失,HIF-1α不被降解并向细胞核内转移,与HIF-1β亚基形成HIF-1二聚体,再与靶基因表达调控区域的HRE结合,参与调节靶基因的表达。

受HIF-1调控的靶基因的启动子或增强子内含有一个或多个低氧反应元件(HRE),通过对HRE的鉴定,迄今发现的能够与HIF-1直接作用的基因有60多个,这些靶基因与细胞内的多种生理活动密切相关,包括血管生成 [8]、血管舒张 [9] 和糖代谢 [2] 等。

3. 谷氨酰胺代谢

3.1. 谷氨酰胺

大多数细胞在增殖过程中都会消耗大量的葡萄糖和谷氨酰胺 [10] [11] [12]。葡萄糖和谷氨酰胺分别作为碳源和氮源,能够促进肿瘤细胞的生长 [11] [12] [13]。Gln在生物体内被认为是一种非必需氨基酸,肌肉和其他器官能够合成谷氨酰胺并可通过其他氨基酸代谢来清除多余的氨。肾脏通过释放谷氨酰胺中的氨来维持酸碱平衡 [10],肝脏和肾脏通过尿素循环消除谷氨酰胺中以尿素形式存在的过量氮。根据细胞代谢状态的不同,Gln可以作为蛋白质、核苷酸、谷胱甘肽生物合成的前体或产生ATP为驱动线粒体提供动力 [14]。由于这种双重功能,Gln对许多细胞的增殖是必不可少的,如肠粘膜细胞、活化淋巴细胞、肾小管细胞和癌细胞等。谷氨酰胺可通过转运蛋白(如SLC1A5)进入细胞 [15] [16],也可利用L型氨基酸转运体1 (LAT1,SLC7A5和SLC3A2的异质二聚体) [17] 将其他氨基酸(如亮氨酸)交换到细胞外的。除了转运外,癌细胞还能在营养缺乏的情况下通过大分子的分解获得谷氨酰胺 [18] [19]。

3.2. 谷氨酰胺的胞内代谢

Glu进入细胞后,可促进核苷酸的生物合成 [20];也能促进尿苷二磷酸N-乙酰葡萄糖胺(UDP-GlcNAc)合成,促进蛋白质折叠和运输;还能通过谷氨酰胺酶转化成谷氨酸,被转运蛋白转入线粒体中。进入线粒体的谷氨酸可通过氧化或还原途径 [21] (图2)被利用:谷氨酸脱氢酶(GLUD)或转氨酶将谷氨酸转化为α-酮戊二酸(α-KG),α-KG可以被α-酮戊二酸脱氢酶(αKGDH)氧化为琥珀酸,参与TCA循环,为细胞提供能量;TCA循环衍生的草酰乙酸(OAA)或苹果酸被输出到细胞质中,苹果酸通过苹果酸酶产生NADPH和丙酮酸,OAA可以转化为天冬氨酸,以支持核苷酸的合成;α-KG也可以被异柠檬酸脱氢酶(IDH2)还原羧化为柠檬酸。谷氨酸衍生的柠檬酸可被运输到细胞质中,以生成乙酰辅酶A (Ac-CoA),用于脂肪酸合成等 [22] [23]。因此,谷氨酰胺可以作为仅次于葡萄糖的碳源。

谷氨酰胺还能够作为氮源,谷氨酰胺-氮对细胞的生存是必不可少的,细胞对谷氨酰胺–氮的利用主要从以下几个方面。谷氨酸通过GLUD或转氨酶转化为α-KG,GLUD反应的副产物是 NH 4 + /NH3,对细胞有毒性,而转氨酶反应的副产物是其他氨基酸(如脯氨酸、天冬氨酸等) [24],不产生 NH 4 + /NH3。示踪实验证明,体外培养的癌细胞中至少50%用于蛋白质合成的非必需氨基酸可以直接通过谷氨酰胺代谢获取 [15] [25]。例如谷氨酸作为氨基转移反应的氮供体,通过谷氨酸草酰乙酸转氨酶(GOT)、谷氨酸丙酮酸转氨酶(GPT) [26] 和磷酸丝氨酸转氨酶1 (PSAT1)的作用,参与合成丙氨酸、天冬氨酸和丝氨酸 [27];TCA循环中衍生的天冬氨酸还可通过一系列的酶将氮转移到嘧啶前体;同时,谷氨酰胺还可以直接提供酰胺氮和间接提供胺氮以进行核苷酸生物合成。缺乏谷氨酰胺的癌细胞会发生细胞周期停滞,但这种停滞可以被外源核苷酸挽救(但不能被草酰乙酸等TCA循环中间产物挽救) [20] [28]。事实上,在体外培养的人类原发性肺癌细胞中,人们已经观察到外源性谷氨酰胺合成核苷酸的现象 [29]。

Figure 2. Glutamine metabolism and its products

图2. 谷氨酰胺代谢过程及其产物

4. 低氧与HIF-1对谷氨酰胺代谢的影响

4.1. 低氧促进谷氨酰胺–碳的利用

氧气在细胞呼吸中承担着重要的角色,一方面,氧气是线粒体电子传递链中电子的最终受体,低氧导致电子传递异常;另一方面,缺乏氧气还会导致烟酰胺腺嘌呤二核苷酸(NAD+)被破坏,影响柠檬酸循环。低氧细胞虽然增加了对葡萄糖的摄取,但低氧导致TCA循环被抑制,葡萄糖无法通过有氧呼吸为细胞提供足够的能源和碳源,只能转化成乳酸,排出细胞外 [30] [31]。导致细胞缺乏碳源,特别是细胞增殖所必需的脂质。

Gln可通过氧化途径参与TCA循环,也可以通过还原途径生成柠檬酸,合成脂肪酸前体Ac-CoA [22] [32],为细胞提供碳源。还原途径在HIF-1α稳定的细胞中更受青睐 [33] [34]。研究发现,在低氧的肿瘤细胞中,谷氨酰胺被用作的主要的碳源,尤其是用于脂质生物合成 [34] [35]。Ac-CoA是合成脂质的前体,柠檬酸又是Ac-CoA的前体物质。在常氧下,葡萄糖和谷氨酰胺都对细胞柠檬酸库有贡献,谷氨酰胺是草酰乙酸的主要来源 [13],葡萄糖是Ac-CoA [36] 的主要来源,柠檬酸合成酶将Ac-CoA的乙基与草酰乙酸的酮基缩合生成柠檬酸。丙酮酸脱氢酶(PDH)将葡萄糖衍生的丙酮酸转化为Ac-CoA,以及通过TCA循环将谷氨酰胺转化为草酰乙酸都依赖于NAD+,然而,NAD+在低氧条件下可被破坏,柠檬酸的合成受到抑制。谷氨酰胺成为低氧细胞柠檬酸盐的主要来源已被证实 [35]。谷氨酰胺衍生的α-酮戊二酸能够被线粒体异柠檬酸脱氢酶(IDH2)还原羧化形成异柠檬酸,然后异构化为柠檬酸。最近的研究发现,低氧条件下的肺癌细胞中异柠檬酸脱氢酶IDH2的依赖性羧化增加 [11],谷氨酰胺成为柠檬酸盐的主要来源,当缺少谷氨酰胺或RNAi使IDH2沉默时,低氧细胞将无法增殖。低氧条件下谷氨酰胺衍生的Ac-CoA比例也显著提高 [37]。此外,低氧下葡萄糖产生的乳酸也可以诱导谷氨酰胺摄取和代谢 [38]。

4.2. 低氧促进谷氨酰胺–氮的排泄

低氧细胞在摄取和利用谷氨酰胺时,如果谷氨酰胺–氮代谢同化不能与谷氨酰胺–碳同步,细胞就需要清除多余的氨基氮,因为游离的氨对细胞有毒性 [39] [40]。游离的氨可在谷氨酰胺合成酶的作用下与谷氨酸逆合成谷氨酰胺,但这一过程可以看作谷氨酰胺脱氨的逆转,对谷氨酰胺衍生氨的清除并没有实际上的作用。常氧下,氨在氨甲酰磷酸合成酶I (CPSI)的作用下合成尿素,或者被GLUD催化将α-酮戊二酸和氨转化成谷氨酸,并转移胺基使其他氨基酸(如脯氨酸和天冬氨酸)直接获得氨中的氮,还能与丙酮酸结合生成丙氨酸排出体外。然而,Wang等人 [37] 发现低氧下体外培养的肿瘤细胞中尿素和丙氨酸等的合成并未增加。低氧实质上导致了细胞核苷酸前体特别是嘧啶前体的积累,包括氨甲酰天冬氨酸、二氢乳清酸和乳清酸,其中二氢乳清酸是细胞主要的分泌产物 [37]。游离的氨可以被二氢乳清酸酶(CAD)转化成氨基甲酰磷酸或者被谷草转氨酶1 (GOD1)将氨并入天冬氨酸中,氨基甲酰磷酸和天冬氨酸在CAD的作用下生成氨甲酰天冬氨酸,最后生成二氢乳清酸,分泌到细胞外。

总的来说,低氧下谷氨酰胺转化为Ac-CoA,用于低氧条件下的脂肪生成,同时通过TCA循环和GOT1将谷氨酰胺和谷氨酰胺基团并入分泌型二氢乳清酸中,从而为细胞增殖提供碳源,并排出细胞中多余的氮。

4.3. HIF-1对谷氨酰胺代谢的调控

HIF-1是低氧调控的关键因子,近20% (12/65)的HIF-1靶基因(如GLUT-1、丙酮酸激酶(PKM)、乳酸脱氢酶(LDHA)、己糖激酶1和2 (HK1和HK2)或葡萄糖激酶(GCK))直接或间接参与葡萄糖代谢。低氧促进谷氨酰胺代谢,主要是通过激活HIF-1调控糖代谢和TCA循环相关的酶,来抑制葡萄糖源柠檬酸的合成,促进谷氨酰胺源柠檬酸参与TCA循环和脂质的合成,补偿低氧细胞的能量需求,为细胞提供碳源。

已知的HIF-1对谷氨酰胺代谢的调控,主要是通过激活几种关键酶(如图3所示)来进行的。首先,HIF-1能够直接激活其靶基因丙酮酸脱氢酶激酶1 (PDK1)基因,使得TCA循环酶—丙酮酸脱氢酶(PDH)失活 [40]。由于PDH的作用是将丙酮酸转化为Ac-CoA,这会导致丙酮酸不再进入TCA循环,而是被还原成乳酸排出细胞外,造成葡萄糖源柠檬酸盐的缺乏。同时,HIF-1的激活促进α-KG脱氢酶(αKGDH)复合物(OGDH2) E1亚单位48kDa剪接变异体的SIAH2靶向泛素化和蛋白水解 [35]。aKGDH由E1 (oxogluterate dehydrogase, OGDH)、E2 (dihydrelopamide S-琥珀酰转移酶,DLST)和E3 (dihydrelopamide dehydrogase, DLD)组成,它们共同将aKG转化为琥珀酰辅酶a和烟酰胺腺嘌呤二核苷酸 [41]。SIAH2的泛素化和蛋白水解使得αKGDH活性降低,α-KG水平升高,推动了异柠檬酸脱氢酶的逆反应,谷氨酰胺类柠檬酸盐增加,促进谷氨酰胺类脂质的合成。除此之外,在肺癌细胞中 [42],HIF-1还能够通过上调谷氨酸脱氢酶(GDH)的表达,增加了肺癌细胞对谷氨酸的吸收、谷氨酸到酮戊二酸的代谢通量和ATP的生成。HIF1a结合GDH的启动子,促进肺癌细胞中GDH基因的转录。

Figure 3. Effect of HIF-1 on glutamine metabolism

图3. HIF-1对谷氨酰胺代谢的影响

5. 总结与展望

综上所述,谷氨酰胺对低氧细胞的增殖是必不可少的,低氧下的谷氨酰胺承担了重要的生理作用,如合成核苷酸、氨基酸和脂质,代替葡萄糖成为低氧细胞中主要的碳源。而低氧诱导因子HIF-1对谷氨酰胺代谢中的许多重要基因都有调节作用。如,HIF-1能够激活丙酮酸脱氢酶激酶1 (PDK1)基因的表达,使TCA循环酶—丙酮酸脱氢酶(PDH)失活,造成葡萄糖源柠檬酸盐的缺乏。还能促进α-酮戊二酸脱氢酶(α-KGDH)泛素化和蛋白水解,使得α-KGDH活性降低,α-KG水平升高,推动了异柠檬酸脱氢酶的逆反应,为细胞的生长和增殖提供脂质。谷氨酰胺代谢过程中产生的游离的氨,通过GOD1被并入分泌型二氢乳清酸中,排出细胞外。

大多数肿瘤生活在低氧环境中,HIF-1通过促进肿瘤细胞的谷氨酰胺代谢、促进细胞能量代谢对肿瘤发生、转移及肿瘤抗药性等方面发挥了重要作用,因此,HIF-1是肿瘤治疗的靶点。目前已有抑制HIF-1的药物进入临床试验,但还应考虑HIF-1与谷氨酰胺代谢之间的作用。通过控制谷氨酰胺及其代谢产物的含量以及相关酶的表达,从而达到抗肿瘤的效果,具有重要的应用前景。

NOTES

*通讯作者。

文章引用: 刘梦琦 , 王冬杨 , 邬超越 , 曹诣斌 (2021) 低氧与HIF-1对谷氨酰胺代谢的影响。 生物过程, 11, 1-8. doi: 10.12677/BP.2021.111001

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