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. 2024 Mar 28;49(3):467–475. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2024.230199

Hb构象变化对氧转运生理功能的影响

Effect of Hb conformational changes on oxygen transport physiology

YIN Ziyue 1,2,2, LI Doudou 1,2, GUO Qianwen 1,2, WANG Rong 2, LI Wenbin 2,✉
Editors: 林 依琳, 郭 征
PMCID: PMC11208409  PMID: 38970521

Abstract

Red blood cells (RBCs) are the primary mediators of oxygen transport in the human body, and their function is mainly achieved through conformational changes of hemoglobin (Hb). Hb is a tetramer composed of four subunits, with HbA being the predominant Hb in healthy adults, existing in two forms: tense state (T state) and relaxed state (R state). Endogenous regulators of Hb conformation include 2,3-diphosphoglyceric acid, carbon dioxide, protons, and chloride ions, while exogenous regulators include inositol hexaphosphate, inositol tripyrophosphate, benzabate, urea derivative L35, and vanillin, each with different mechanisms of action. The application of Hb conformational regulators provides new insights into the study of hypoxia oxygen supply issues and the treatment of sickle cell disease.

Keywords: hemoglobin, conformational regulators, oxygen affinity, anti-hypoxia

血红蛋白(hemoglobin，Hb)是一种高等生物体内负责运载氧的蛋白质。Hb是由4个亚单位组成的四聚体，可分为6种：胚胎型HbGowerⅠ(ζ2ε2)、HbGowerⅡ(α2ε2)、HbPortland(ζ2γ2)，胎儿型HbF(α2γ2)，成人型HbA(α2β2)、HbA2(α2δ2)；其中，HbA为健康成人中主要的Hb，包括4条球蛋白链(2条α链、2条β链)和4个血红素基团，每条球蛋白链结合1个血红素基团成为1个Hb亚基，4个Hb亚基共同构成异四聚体。α亚基、β亚基分别折叠形成7个、8个螺旋区段，分别称为A-H，由非螺旋段(称为角)连接。在折叠的多肽蛋白区段之间形成含有氨基酸残基的中心空腔[1-3]，它的入口容纳带正电的β链基团，形成阴离子变构效应物的结合位点。血红素基团就被包围在这个疏水空腔，由4个吡咯环上的氮原子与1个Fe2+配位结合，由此得到具有轴向咪唑碱基的5配体结构，可以与氧气可逆性结合(氧合Hb、去氧Hb)，引起HbA构象的改变[4]。

氧转运是Hb的基本功能[5]，这一功能主要取决于Hb结合和解离氧的能力[6-7]。Hb氧解离曲线(oxygen dissociation curve，ODC)中的半饱和氧分压可直观反映红细胞的氧亲和力，即在37 ℃、pH值7.4及动脉血二氧化碳分压为40 mmHg(1 mmHg=0.133 kPa)时，Hb的50%氧饱和度时的氧分压，半饱和氧分压是决定Hb供氧效率的关键参数之一[8]。半饱和氧分压数值越高表明HbA更倾向于释放氧气，而数值越低表明HbA更倾向于携带氧气。氧气供应效率作为HbA的关键指标，与适应缺氧环境(如高原)密切相关。

1. T态到R态过渡的多状态

依据MWC/Perutz模型，HbA作为一种典型的变构蛋白质，以2种形式存在，紧张态(T态)和松弛态(R态)，即去氧Hb态和氧合Hb态(附图1，https://doi.org/10.57760/sciencedb.17753)。T态的结构变化使得Hb在氧结合方面表现为低亲和力，而R态的结构变化使得Hb表现为高亲和力。研究[9-13]揭示了不同的Hb松弛状态，这些状态不能用经典的T态→R态跃迁解释，这表明松弛态并非经典R态所独有，而是表现为不同四级构象的完全配体态的集合，这些状态包括R2、RR2、R3和RR3态。从结构上确定这些状态取决于不同的关键参数，如α1β1二聚体相对于α2β2二聚体的刚体螺钉旋转(根据螺钉旋转角度、螺钉旋转平动、螺钉旋转轴方向和旋转轴上的一个点来定义)、中间二聚体盐桥/氢键相互作用、血红素-血红素距离、远端血红素袋的大小、中央水腔的大小及α-裂和β-裂的大小[14-15]。此外，T态→R2态最初被认为是沿着T态→R态跃迁，以R态作为最终状态，而进一步的分析发现T态→R2态跃迁和T态→RR2态跃迁大致沿T态→R态跃迁的螺杆旋转轴的相同方向发生，顺序为T态→R态→RR2态→R2态[16]。在R2态和RR2态结构中，β2FG从R态结构位置进一步垂直旋转，使β2His97和α1Thr38之间的氢键相互作用分离，导致2个结构的中央水腔变宽，并使βHis146的2个C端残基能够进行更紧密的相互作用，与R态结构中高度无序的βHis146相比，位置更明确。由于βHis146对玻尔效应的关键贡献，这一观察结果是重要的[17]。另一种独特的配体结构，RR3态位于R态→R3态跃迁之间，顺序为T态→R态→RR3态→R3态[3, 13, 15]。RR3态显示βHis63(E7)从远端囊腔中显著旋转，形成了被称为His(E7)配体通道到本体溶剂 ，在R3态中也观察到His(E7)的较小旋转。βHis63在R3态或RR3态上的旋转位置通过咪唑侧链和β-丙酸血红素之间的盐桥作用而稳定[13, 15]。综上所述，T态和R态的平衡有2种过渡轨道理论，第1种轨道理论表明R2态是一种终端状态，R态和RR2态都位于T态→R2态的跃迁上；第2种轨道理论表明R3态是另一种末端状态，R态和RR3态位于T态→R3态的跃迁位置(附图2，https://doi.org/10.57760/sciencedb.17753)。

2. Hb构象的内源性调节器

2.1. 2,3-双磷酸甘油酸

2,3-双磷酸甘油酸(2,3-bisphosphoglycerate，2,3-BPG)是红细胞糖酵解的代谢产物[18-19]，不能透过红细胞膜屏障。缺氧时增加红细胞中2,3-BPG的含量可有效地增加氧气向组织的释放，从而缓解机体缺氧，影响Hb构象的改变。每个Hb分子都存在2,3-BPG的结合位点，在Hb的4个亚基的对称中心腔内，组成孔穴壁的2个β亚基处的Lys β82(EF6)、His β2(NA2)、His β143(H21)和氨基末端Val β1(NA1)残基的正电荷与2,3-BPG的负电荷基团通过静电结合形成盐，使T态更加稳定，从而降低Hb与氧分子的亲和力(附图3，https://doi.org/10.57760/sciencedb.17753)。

糖酵解旁路的2,3-双磷酸甘油酸变位酶(bisphosphoglycerate mutase，BPGM)对2,3-BPG的浓度起着决定性的作用，BPGM是直接影响2,3-BPG生成的酶，除此之外，已糖激酶(hexokinase，HK)、磷酸果糖激酶(phosphofructokinase，PFK)和丙酮酸激酶(pyruvate kinase，PK)这3个限速酶均对2,3-BPG具有调节作用(附图4，https://doi.org/10.57760/sciencedb. 17753)。增加HK的活性，能够将更多的碳通量重新进行分配，HK可以参与能量生长和分解代谢[20]，维持机体稳态。当细胞缺氧时，可以通过调控HK活性提升腺苷三磷酸(adenosine triphosphate，ATP)及2,3-BPG的浓度[21]。PK是糖酵解中的3种调节酶之一，使用K+和Mg2+耦合磷酸烯醇丙酮酸水解的自由能作为产生ATP和丙酮酸的辅助因子[22]，PK基因中存在丝氨酸/苏氨酸蛋白激酶位点可以调节PK的活性，从而控制生物体内丙酮酸的水平[23]。并且糖酵解途径中PK活性水平会影响2,3-BPG的浓度[24]。PFK是催化糖酵解的第一步，催化6-磷酸果糖(fructose 6-phosphate，F6P)生成1, 6-二磷酸果糖(fructose-1,6-bisphosphate，F-1, 6-P)的过程需要ATP与Mg2+参与。有研究[25]指出低2,3-BPG的纯化红细胞与高2,3-BPG纯化红细胞相比，PFK在生理水平上受到了更显著的抑制，表明PFK在高2,3-BPG纯化红细胞中具有更高的体内活性。通过改变限速酶的活性可以使糖酵解通路更加活跃，有利于抗氧自由基应激损伤和代偿性地增加葡萄糖的分解，对于糖酵解合成2,3-BPG有十分重要的影响。糖酵解途径相关底物(丙酮酸钠、磷酸盐、肌苷)都会转化为2,3-BPG，且可以增加2,3-BPG浓度，降低Hb对氧气的亲和力，使缺氧组织的氧释放增加[26-28]。

另外，有研究[29]指出内源性H2S通过抑制膜锚定的BPGM从膜释放到细胞质来抑制红细胞2,3-BPG的产生，且通过H2S供体GYY4137处理可逆转缺氧诱导的红细胞2,3-BPG和半饱和氧分压升高。该研究揭示了一种调节红细胞携氧能力的新信号通路。此外，Bertrand[30]指出NO能通过调控甘油醛-3-磷酸脱氢酶(glyceraldehyde-3-phosphate dehydrogenase，G3PDH)间接抑制2,3-BPG，该研究可应用于镰状细胞病(sickle cell disease，SCD)的治疗。SCD是一种常染色体显性遗传的Hb分子病，由Hb β亚基的氨基酸突变引起。其特征是在较低氧分压的血管中红细胞呈异常的“镰状”，畸形红细胞对狭窄血管形成阻塞，在某种情况下，调控NO可改善“镰状”现象。

2.2. 玻尔效应——二氧化碳、质子和氯化物

对于哺乳动物Hb而言，氧亲和力取决于环境的pH值，以及T态和R态之间的平衡 [31-33]。在组织中，二氧化碳浓度高，其转化为氨基甲酸酯或碳酸氢盐释放离子，降低pH值，从而使Hb的氧亲和力降低。这种质子依赖性的分子基础涉及α链αArg141和β链βHis146的C端残基[34-35]，在高pH值的脱氧Hb中，βHis146与βAsp94和αLys40发生亚基内和亚基间的盐桥相互作用，而αArg141也与αLys127和αAsp126参与单独的亚基间盐桥相互作用，这些相互作用稳定了低亲和力的T态，从而增加氧气的释放；在低pH值的脱氧Hb中，特别是在组织中，这些搭建的盐桥被破坏，增加了αArg141和βHis146的迁移率，促进T态→R态跃迁，从而增加Hb的氧亲和力。其他残基，如αVal1、αHis122、βHis2、βLys82、βHis143，也通过脱氧连接的质子结合促进玻尔效应[36-37]。中央水腔过量的带正电荷残基会增加Hb的自由能[38]，而Cl离子通过中和这些正电荷稳定Hb，从而促进玻尔效应，并且较大的水腔中会发现更多的Cl离子，导致T态更加稳定，同时增加氧气的释放[39]。另外，双重玻尔效应可见于胎儿：在胎儿侧，血液中二氧化碳含量降低，ODC向左移动，有利于胎儿的Hb吸氧；胎儿血液中的二氧化碳扩散到母体，使母体释放更多的氧气。双重玻尔效应的临床意义在于促进氧气从母体转移到胎儿的胎盘，从而增加胎儿的氧合指数[40]。

鞘氨醇-1-磷酸(sphingosine-1-phosphate，S1P)是一种重要的生物活性信号分子，富集在红细胞中。机体通过激活细胞表面的S1P受体，S1P受体与细胞内的关键调节蛋白相互作用来调节多种生物过程[41-42]。Yang等[43]首次指出了S1P与Hb之间的相互作用。研究[44]表明：鞘氨醇激酶(sphingosine kinase 1，SPHK1)是红细胞中鞘氨醇生成S1P的鞘脂代谢途径中的主要酶，而敲低SPHK1可以纠正致病性代谢重编程，促进葡萄糖的戊糖磷酸途径代谢，抑制2,3-BPG的产生，起到有效的抗镰状细胞和抗溶血作用。与之相反，S1P可通过增加2,3-BPG的生成来促进氧气的输送，从而抵抗组织缺氧[45]。这些研究为红细胞病理学和生理学提供了重要的新见解，为SCD的治疗提供了新思路。

3. Hb构象的外源性调节器

3.1. 低氧亲和力的变构调节剂

3.1.1. 肌醇六磷酸、肌醇三焦磷酸

多种聚阴离子可作为变构的Hb效应物，特别是多聚磷酸盐能够降低人类Hb对氧气的亲和力，其中肌醇六磷酸(myo-inositol hexakisphosphate，IHP)与脱氧Hb的结合[46]，在与BPG相同的带正电荷的变构口袋中，形成非常紧密的化合物，解离常数为6×10-8，但该效应物可能不会通过红细胞膜，所以用于治疗时吸收有限[47]。IHP的类似物肌醇三焦磷酸(myo-inositol trispyrophosphate，ITPP)，由红细胞膜上的阴离子转运蛋白介导进入红细胞，增加红细胞对缺氧组织的氧释放能力[48]。

3.1.2. 苯扎贝特、尿素衍生物L35

除了上述IHP、ITPP与脱氧Hb相互作用，抗脂药物苯扎贝特(bezafibrate，BZF)和尿素衍生物(urea derivatives)L35[49-50]被证明与靠近α-血红素的配体Hb的中央水腔和/或表面结合，可在空间上阻止配体与血红素的结合[51-53]，降低Hb的氧亲和力。

3.1.3. RSR-13

RSR-13(Efaproxiral)及其几个衍生物(KDD3-138、RSR-40、RSR-4、TB-27等)[54-55]与IHP或2,3-BPG不同，这些化合物部分通过与脱氧Hb的中央水腔中间结合来影响其变构活性。RSR-13最初是为了模拟BZF的变构效应而合成[56-57]，X射线晶体结构表明，RSR-13分子与蛋白质的2个α亚基和1个β亚基产生氢键和疏水相互作用，使Hb稳定为T构象，降低Hb-O2亲和力[58]。有研究[59]在缺氧和缺血条件下进行了诱导RSR-13的临床测试，指出该化合物可以增加O2的供应，并且可以作为辅助手段用于后期人体试验。另外，Safo等[60]通过亚硝基氧乙基、亚硝基丙基等分别连接到RSR-13的羧酸盐上，开发了RSR-13衍生物的新型NO释放前体药物。晶体学研究表明，这些化合物能降低Hb对氧的亲和力。

3.1.4. 合成肽IRL-2500

通过高通量实验从多种化合物中筛选出种合成肽——IRL-2500。IRL-2500以1꞉1的比例与Hb的β链非共价结合。化合物与2,3-BPG结合位点重叠，其可以与β-Lys82、β-Asn139发生水介导的直接氢键作用[61]；与蛋白残基β-His2、β-Asn139和β-His143之间存在疏水相互作用，这些提供了脱氧Hb的2个β亚基界面额外的相互作用，导致T态进一步稳定，并像IHP和RSR-13一样降低Hb对O2的亲和力。

3.1.5. 苯酞类化合物

来自中药当归的主要活性成分苯酞类化合物能够很好地干预全身血液循环，抑制氧合Hb(oxyhemoglobin，oxyHb)转化为高氧亲和力的R态。通过建立分子对接模型，Chen等[62]发现活性区域位于α1/α2界面，苯酞类化合物与Hb上的2个重要残基α1Arg141和α2Val1发生相互作用，并且提出通过搭建α1Tyr140-α2His87盐桥，强化α1/α2界面以稳定T态，降低Hb对氧气的亲和力，增强其释放氧的能力；该学者还提出2种苯酞衍生物——z-亚丁基苯酞和z-川芎内酯作为新型胎儿Hb(fetal Hb，HbF)调节剂，通过γ1/γ2界面周围的间隙与HbF相互作用，提高HbF的诱导治疗作用，以减轻β-Hb病(包括SCD和β地中海贫血)，且在降低HbF对氧气的亲和力方面要远优于2,3-BPG，是更为有效的Hb变构调节剂[63]。

3.1.6. 芳氧基链烷酸

芳氧基链烷酸是另一类特殊的右移化合物，其对Hb的作用取决于结合位点。在中央水腔和蛋白质表面与αTrp14或CD角位点非共价结合[64]，可以有效增强Hb对氧气的亲和力；在大多数情况下，仅与中央水腔结合的芳氧基链烷酸稳定T态，表现出低氧亲和力的抗镰状活性[65]。

3.2. 高氧亲和力的变构调节剂

3.2.1. 香兰素

香兰素(vanillin)是一种食品添加剂，已被作为治疗SCD的潜在药物[66]。HbA-vanillin的X射线晶体学研究[67]表明：香兰素在中央水腔的αHis103、αCys104和βGln131附近结合，在βHis116和βHis117之间存在二级结合位点。红细胞的流变性评价结果显示香兰素可能对镰刀状HbS聚合物的形成有直接的抑制作用，同时氧平衡曲线测定、分光光度法和X射线研究[67]结果表明：香兰素可能通过双重作用机制(R态HbS分子的变构调节和T态HbS聚合的立体特异性)抑制HbS聚合物的形成。

3.2.2. SAJ-310、INN-312、INN-298和TD-7

Safo团队[68-70]发现一些苯甲醛的吡啶基衍生物显示出比香兰素高数倍的使ODC左移的效力，其中SAJ-310、INN-312、INN-298和TD-7与Hb的复合物已被阐明，表现出与R2态类似的结合特点。INN-312、INN-298和TD-7与Hb α-亚基的N端形成加合物，以限制R态向T态转变，增强Hb对氧气的亲和力，起到双重抗镰状作用[71]。SAJ-310的2个分子醛基分别与αVal1残基的2个N-末端胺产生席夫碱相互作用，在较低浓度下抑制红细胞的镰状反应，表现出较高的稳定性[68]。αF-螺旋已被证明在聚合物稳定中起重要作用，其扰动会破坏聚合物的稳定性[68]。根据这一假设，Hb的变体Stanleyville(αAsn78→αLsy78)抑制HbS聚合，这些化合物的代表包括VZHE-039、PP-6、PP-10、PP-14，目前正在进行临床前体内研究[72]。

3.2.3. 羟甲基糠醛

羟甲基糠醛(5-hydroxymethyl-2-furfural，5-HMF)是一种化学活性很高的小分子无机物。5-HMF来源于含碳水化合物的食物中氨基酸和还原糖发生的美拉德(Maillard)反应，以及糖的受热分解[73]，可与2,3-DPG竞争性地结合Hb的位点，从而增强Hb对氧气的亲和力。该物质很容易通过胃肠道吸收进入血液循环，可以通过红细胞膜，与细胞内HbS共价结合，并与HbS的N端αVal1氮对称形成高亲和力席夫碱HbS加合物，将ODC转移到更易溶的氧-HbS构象[74]，并在缺氧条件下抑制HbS细胞的镰状反应。Lucas等[75]对缺氧期间麻醉的黄金仓鼠进行了冠状动脉血流和心肌代谢分析，结果证实了天然存在的芳香醛5-HMF可对Hb的结构进行修饰，增强Hb对氧气的亲和力，提高肺中的血氧浓度，并增加了缺氧期间氧气在全身的输送。

3.2.4. Voxelotor

香兰素的合成醛类似物Voxelotor(GBT440)通过与Hb α链的N端αVal2可逆性结合，以稳定R态来增强Hb对氧气的亲和力和抗镰状作用[76]。此外，魏铭等[77]研究发现GBT440能够增强Hb对氧气的亲和力，提高急性“严重”缺氧条件下动物的生存能力及急性“中度”缺氧条件下动物的作业能力，显著改善缺氧引起的组织损伤。

3.2.5. TD-1、TD-3

Nakagawa等[78]开发一种可评估小分子TD-1调节Hb对氧气亲和力的高通量测定方法。Hb与TD-1复合物的三维结构表明，TD-1单体与β-Cys93和β-Cys112共价结合，与Hb四聚体中心水腔非共价结合。TD-1与Hb的结合稳定了Hb的R态。此外，Nakagawa等[79]指出TD-1与Hb共价结合的高反应性可能是由于其含有的三唑环结构稳定了从TD-1分离的MU分子。与其结构相似的还有化合物TD-3，TD-3与HbA的βCys93形成二硫键，从而抑制βAsp94和βHis146之间的盐桥形成，降低玻尔效应并增强Hb对氧气的亲和力，减少体外缺氧诱导的人类镰状红细胞的产生。

3.2.6. 双(3,5-二溴水杨基)富马酸酯

双(3,5-二溴水杨基)富马酸酯通过将β1-Lys82交联到β2-Lys82，封闭Hb与2,3-BPG的结合位点，增强Hb对氧气的亲和力。虽然双(3,5-二溴水杨酰基)富马酸酯对溶液中的Hb反应性强，但它在修饰红细胞内的Hb方面效果较差。与细胞内Hb的反应被证明受到在红细胞膜外表面催化试剂的竞争性水解的限制[80]。

3.2.7. 白藜芦醇

白藜芦醇(resveratrol，RSV)是一种天然存在的多酚，具有抗糖酵解作用。最近的研究[81]表明RSV通过与HbA结合，提高供氧效率，改善对急性重度缺氧的适应。RSV与HbA的作用模式通过软件模拟发现，RSV的酚环与HbA的V63氨基酸形成一种Π-氢键，且与周围带正电荷的氨基酸Y43、H46、H59等发生氢键相互作用[81]。

3.3. 针对同一位点但诱导相反平衡位移的变构效应子

前述的几种芳香醛通过在α裂处与Hb αVal1氮形成席夫碱相互作用来增强Hb对氧气的亲和力。然而，并非所有含有芳香醛的αVal1氮席夫碱加合物都会增强Hb对氧气的亲和力。Abraham等[82]测试了几种Hb的单醛酸效应物，如5-FSA，2-BF和2-PEF，与这些化合物的结合会降低Hb对氧气的亲和力，由于苯环上的羧酸盐取代基，这些化合物优先与脱氧Hb的α链结合，它们与αVal1氮形成席夫碱相互作用，以及羧酸与Hb的相反αArg141的胍基之间的亚基间盐桥相互作用，为T态提供了额外的约束。R2态在正确位置没有发生αArg141与化合物的羧酸盐的这种盐桥相互作用，而R态、RR2态和R3态空间位阻在其各自的α裂处结合，从化合物中去除羧酸盐消除了脱氧T态中的αArg141相互作用，导致这些分子优先以R2态的形式与配体Hb结合[70]。尽管缺乏强烈的亚基间相互作用，这些非羧酸芳香醛仍然与脱氧Hb结合。低氧亲和力芳香醛的化学结构见附图5(https://doi.org/10.57760/sciencedb.17753)。

4. 结 语

Hb的携氧功能涉及一系列状态，它们的具体功能还未被完全了解。各种Hb变构效应物通过不同的分子机制调节Hb的氧结合特性。这些变构效应物通过与T态或R态的相互作用模式，可以降低或增强Hb对氧气的亲和力，前者用于缺氧和缺血诱导的疾病，后者用于治疗SCD。虽然目前有很多化合物可以调节Hb构象以改善Hb的氧转运能力，但临床上往往会出现不能透过红细胞膜及可利用率低的情况，因此，是否具有很好的可吸收利用度和临床疗效是评价化合物的重要标准。总之，我们可以依据现有的化合物寻找配体结构的共同点，并结合发展迅速的计算机网络技术以寻求突破。

基金资助

国家自然科学基金(82173738)；医院科研计划立项项目(2021yxky005)；医学科技青年培育计划拔尖项目(20QNPY070)。This work was supported by the National Natural Science Foundation (82173738), the Hospital Scientific Research Plan Project (2021yxky005), and the Medical Science and Technology Youth Training Program Excellence Project (20QNPY070), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

尹紫悦 论文撰写与修改；李豆豆、郭茜文、王荣 论文修改；李文斌 论文指导与修改。所有作者阅读并同意最终的文本。

Footnotes

http://dx.chinadoi.cn/10.11817/j.issn.1672-7347.2024.230199

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202403467.pdf

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