组氨酸二肽是一类水溶性二肽，广泛存在于多种脊椎动物的骨骼肌和脑组织中，主要包括肌肽、鹅肌肽、鲸肌肽、高肌肽等。其中肌肽在生物体内分布最广、含量最大，俄国科学家Gulewitsch等[1]在李比希氏牛肉提取液中分离发现，后被分析证实肌肽的结构为β-丙氨酰-L-组氨酸，是由β-丙氨酸和L-组氨酸通过肌肽合成酶合成的。纯肌肽为白色针状结晶体，熔点为246℃～250℃（分解），旋光度+24.1°（1.5%，水中）[2]。肌肽的甲基化衍生物鹅肌肽（β-丙氨酰-1-甲基-L-组氨酸）于1929年被Ackermann等[3]分离出。随后，肌肽的另一个甲基化衍生物鲸肌肽，也称蛇肌肽（β-丙氨酰-3-甲基-L-组氨酸）[4]以及高肌肽（γ-氨基丁酰基-L-组氨酸）也被发现。组氨酸二肽具有相似的结构和生物学功能，都具有较强的抗氧化性，在食品工业中可作为天然的抗氧化剂，具有保健作用。
1 组氨酸二肽的分布
组氨酸二肽主要存在于脊椎动物的骨骼肌中，大脑、心脏、肝脏、肾脏等组织中也含有一定量的组氨酸二肽，在某些动物的神经系统和嗅觉感受器中也有发现。组氨酸二肽的含量与动物的种类、性别、年龄和肌肉部位等因素相关。
1.1 动物种类
几种常见动物中组氨酸二肽含量由高到低排序禽类包括鸟类为火鸡＞鸡＞马＞猪＞兔＞牛[5]。对于陆地哺乳动物（牛、猪、马、狗等）其肌肉中肌肽含量高于鹅肌肽含量，人类仅含有肌肽。禽类中鹅肌肽含量高于肌肽含量。鲸肌肽是蛇和海洋哺乳动物（如鲸、海豚）中存在的唯一一种组氨酸二肽。某些鱼类（如鲣鱼、鲔鱼、海鳗）中也含有丰富的鹅肌肽和肌肽，且鹅肌肽含量高于肌肽含量。不同物种的组氨酸二肽含量和比例不同，故可通过测定组氨酸二肽的含量和不同二肽间的比例来鉴定肉制品的原料肉[6]。
1.2 性别及年龄
母鸡的胸肉和腿肉中肌肽含量显著高于公鸡，而鹅肌肽含量在母鸡和公鸡间无显著差异[7]。雄性成年小鼠骨骼肌中组氨酸二肽含量显著高于雌性成年小鼠，在成年前，雄性小鼠骨骼肌中肌肽和鹅肌肽含量都随日龄的增加而增长，但雌性小鼠的肌肽无明显提高，鹅肌肽含量增加了2倍～3倍[8]。
1.3 肌肉部位
组氨酸二肽在白肌纤维中的含量比红肌纤维高，在禽类胸肉中的含量比腿肉高[9]，在猪的腿肉中含量比肩胛肉高[10]，鲣鱼的背腹肉中含量比暗色肉和头部肉高[11]。
2 组氨酸二肽的生理功能
组氨酸二肽的生理功能如图1所示，组氨酸二肽具有多种生理功能，主要涉及抗氧化、抗衰老、神经保护、治疗糖尿病、肝保护、降尿酸等功能。
图1 组氨酸二肽的生理功能
Fig.1 Physiological function of histidine dipeptide
2.1 抗氧化
组氨酸二肽具有的抗氧化性主要基于其结构中的咪唑环。咪唑环上的活泼氢易以氢离子形式离去，且同时具有酸性和碱性，还具有金属离子结合位点。组氨酸二肽的抗氧化机理也反映了咪唑环的性质。
2.1.1 清除自由基
组氨酸二肽可作为氢供体捕捉羟基自由基、超氧阴离子自由基等，通过清除自由基抑制活性氧的产生，保护细胞免受氧化应激造成的损伤[12]。肌肽和鹅肌肽可通过清除羟基自由基有效抑制内源性神经毒素1-甲基-6，7-二羟基-1，2，3，4-四氢异喹啉（salsolinol，Sal）/铁蛋白系统介导的DNA链断裂[13]。
2.1.2 金属离子螯合作用
组氨酸二肽含有较多金属结合位点，包括咪唑基上的两个N原子、氨基、羧基和肽键，能够结合Cu2+、Fe2+、Fe3+、Zn2+、Co2+等金属离子形成络合物。体内的 Cu2+等金属离子会造成脂质氧化，过多的Fe2+会导致活性氧增加，引起过氧化反应，组氨酸二肽与这些金属离子螯合可减少由金属离子引起的脂肪氧化反应。肌肽还可与非血红素铁、血红蛋白铁、肌红蛋白铁等结合，减少细胞膜损伤，因此可用作肉类及其制品的抗氧化剂，保持肉类制品的品质并延缓色泽变化[14-16]。
利用组氨酸二肽的金属离子螯合能力可开发其在工业生产、医疗等领域的应用。利用固定有Cu2+的化学修饰葡聚糖或树脂络合组氨酸二肽，可在混合溶液中选择性回收组氨酸二肽[17-18]。组氨酸二肽与金属离子结合后还能促进金属离子的吸收和转运以及发挥生理功能，如肌肽螯合Zn2+可有效治疗放射性食管炎[19]。
2.1.3 缓冲生理pH值
肌肽的解离常数pK值为6.9，鹅肌肽的pK值为7.1，组氨酸二肽的pK值使其非常适合作为骨骼肌细胞中的pH值缓冲剂，组氨酸二肽的缓冲能力在pH值为6.5～7.5之间较高，在5℃～40℃范围内受温度影响较小。当动物进行无氧运动时，依靠糖酵解提供能量会产生大量三磷酸腺苷（adenosine triphosphate，ATP）和乳酸，使肌肉中H+急剧增加，组氨酸二肽的生理缓冲功能可抑制pH值下降，维持肌肉内部的酸碱平衡。对不同物种的研究表明，依赖无氧形式产生能量的物种中组氨酸二肽的含量很高，并且快收缩无氧酵解型纤维比例较高的肌肉中组氨酸二肽含量也较高[20]。
2.2 抗衰老
组氨酸二肽通过恢复衰老细胞活力、抑制端粒缩短、抗氧化、清除羰基、抑制糖酵解、上调线粒体活性等机制起到抗衰老的作用[21]。研究表明，老年人每日补充鹅肌肽和肌肽可对其记忆力、认知功能和身体活动机能产生有益影响[22-23]。补充肌肽可减少老年大鼠血清和肝脏中的糖、脂质和蛋白质氧化产物，减轻氧化应激导致的衰老[24]。肌肽可通过降低皮质酮的循环水平和激活PI3K/Akt信号促进衰老皮肤伤口的愈合，提高皮肤中胶原蛋白的含量，预防皮肤衰老[25]。
2.3 神经保护作用
组氨酸二肽可减少神经元细胞死亡，具有神经保护作用，可预防和治疗神经退行性疾病[26]。肌肽可抑制蛋白质的交联和β-淀粉样蛋白的聚集，还可抑制自由基的产生，降低一氧化氮和丙烯醛的毒性，具有抗炎活性，因此可以预防和治疗阿尔兹海默症等神经退行性疾病[27-28]。帕金森病也是一种主要的神经退行性疾病，会造成运动障碍和α-突触核蛋白沉积导致的嗅觉功能障碍，摄入肌肽治疗可增强帕金森患者线粒体功能，对帕金森病的症状有显著缓解作用[29-30]。
组氨酸二肽的神经保护作用可减少脑部缺血及出血性损伤，可预防和治疗脑卒中。肌肽的神经保护作用可减轻脑出血后的脑水肿、血脑屏障破坏、氧化应激以及神经细胞凋亡[31]，可改善缺血缺氧性脑损伤患者的脑功能，减轻脑损伤[32]。
2.4 治疗糖尿病
肌肽可通过调节葡萄糖代谢通路上的酶，包括抑制葡萄糖-6-磷酸脱氢酶表达，增加糖原合酶、葡萄糖激酶和葡萄糖转运蛋白2的表达，起到降低血糖的作用[33]，还可降低血清甘油三酯和糖基化终产物含量[34]。肌肽可通过增加红细胞的变形能力来改善微血管循环障碍，可减少脂质过氧化来保护细胞和组织免受损伤，增加一氧化氮水平从而改善血管内皮的功能紊乱。因此，肌肽在糖尿病治疗中可有效阻止糖尿病并发症的发生[35]。肌肽可通过抗氧化应激、抑制蛋白质非酶糖基化、改善糖脂代谢以及抑制肾素-血管紧张素系统活性等机制[36]，调节细胞周期进程抑制肾小球膜细胞增殖，预防和治疗糖尿病肾病；肌肽还能加速糖尿病患者伤口愈合[37]，改善患者的学习和认知障碍[38]。
2.5 肝保护作用
肌肽治疗可抑制由四氯化碳导致的血清谷丙转氨酶、谷草转氨酶、谷氨酰转肽酶活性升高和肝脏中丙二醛水平升高，减少肝脏脂质过氧化，可改善与保护四氯化碳引起的肝损伤[39-40]。肌肽还可减轻肝硬化患者的肝损伤，并预防肝硬化和肝功能衰竭导致的高氨血症等并发症[41]。
2.6 降尿酸作用
摄入鹅肌肽可降低血尿酸含量，提高尿酸清除率，缓解高尿酸血症[42]。鹅肌肽可使次黄嘌呤磷酸核糖基转移酶和乳酸脱氢酶的表达增加，从而抑制尿酸的合成。鹅肌肽可被完整吸收进人体血液，在进入尿液中可稳定尿液的pH值，提高尿酸的溶解度并加速排出[43]。
2.7 治疗眼病
组氨酸二肽可治疗白内障等由于氧化损伤造成的眼科疾病。组氨酸二肽眼部给药可减少老年白内障患者晶状体的浑浊区域，提高晶状体的清晰度以改善视力[44]。肌肽可抑制由视神经压迫造成的视网膜神经节细胞死亡，从而预防和治疗青光眼等视神经病变[45]。
2.8 其他
除上述生理功能外，组氨酸二肽还具有抗抑郁[46]、抗癌症[47-49]、抗炎[50]、抗疲劳[51]、脾保护作用[52]和肾保护作用[53]等生理功能。
3 组氨酸二肽的提取
动物体内的肌肽是通过存在于骨骼肌和大脑中的肌肽合成酶利用β-丙氨酸和L-组氨酸合成的，体外获取组氨酸二肽主要有3种方法：化学合成、细胞培养[54]、动物肌肉中提取。目前，采用化学合成法工业化生产的组氨酸二肽已被广泛应用于其生理活性的研究，但在化学合成组氨酸二肽时会产生一种强还原剂——肼，会影响脂质氧化及其产物的检测，因此采用化学合成的组氨酸二肽需经过纯化，并重新评估其生理活性。此外，化学合成组氨酸二肽需消耗大量化学试剂，易造成环境污染，产品中也存在有害物质残留的隐患，且对设备要求较高，操作较繁琐。因此，从天然动物组织中提取组氨酸二肽以及对其生理功能性的评估是目前的主要研究方向。
由于组氨酸二肽是一类水溶性的二肽，因此可采用水提取法对肉类中的组氨酸二肽进行提取。将肌肉组织样品绞碎后加入一定比例的去离子水，进行匀浆处理，离心，将上清液通过Whatman 4号滤纸过滤，将滤液在沸水浴中加热10 min后冰浴冷却，离心去除蛋白质沉淀，上清液通过Whatman 4号滤纸过滤后进行超滤，滤液冷冻干燥即得到组氨酸二肽提取物[55]。为提高组氨酸二肽的得率，采用酶解法提取可显著提高肉类中肌肽的得率[56]。
4 组氨酸二肽的分离检测
4.1 高效液相色谱法
高效液相色谱法（high performance liquid chromatography，HPLC）是近年来检测组氨酸二肽使用最广泛的方法，该法可快速、灵敏检测样品中的目标物，准确度高。由于不同组氨酸二肽间的结构相似，差异较小，所以众多学者开发了不同的HPLC检测方法。
由于组氨酸二肽的紫外吸收和疏水性较弱，检测灵敏度较低，可采用柱前或柱后衍生提高HPLC的检测效果。朱俊颖等[57]使用ODS-C18色谱柱采用OPA柱前衍生法对动物肌肉中肌肽和鹅肌肽进行了测定。Aristoy等[58]采用阳离子交换HPLC结合OPA柱后衍生法测定了动物饲料和肌肉组织中肌肽、鹅肌肽和鲸肌肽的含量。
在液相色谱后串联质谱可更加准确地鉴定组氨酸二肽化合物。Pucciarini等[59]使用高效液相色谱-紫外检测器串联质谱法同时分离检测组氨酸二肽混合样品中的肌肽、鹅肌肽、鲸肌肽，准确性和精密度高，且不需柱前衍生。Maciá等[60]使用超高效液相色谱串联三重四极杆质谱法检测了鸡汤中的肌肽和鹅肌肽，分析时间短且可检测含盐样品。王雨晴等[61]采用超高效液相色谱-电喷雾串联三重四极杆质谱法可对动物源食物提取物中的肌肽和鹅肌肽进行同时快速检测。Uenoyama等[62]开发了一种使用液相色谱-电喷雾串联三重四极杆质谱对肉类样品中的肌肽、鹅肌肽、鲸肌肽3种组氨酸二肽进行定量的方法。
4.2 离子色谱法
离子色谱-电化学检测法是一种高效分离的检测技术，广泛应用于无机阴阳离子、糖类、醛醇类、氨基酸和含硫化合物等的检测。朱作艺等[63]采用离子色谱-积分脉冲安培法测定肉类样品中肌肽、鹅肌肽和高肌肽，3种化合物可在短时间内完全分离且灵敏度高。
4.3 毛细管电泳法
在一定的电压下，利用解离样品中各组分在毛细管中的淌度不同，可对组氨酸二肽进行分离和检测。Jozanovi
等[64]开发了一种微芯片毛细管电泳-非接触电导法，可良好分离定量家禽肌肉中的肌肽和鹅肌肽。Zinellu等[65]采用场放大样品进样毛细管电泳紫外检测法分离和检测了肌肽、鹅肌肽、高肌肽，已应用于动物组织和人脑脊髓液的分析。
5 结语
动物体内天然存在的组氨酸二肽由于具备多种生理活性，越来越受到重视并吸引了众多学者的研究。不同组氨酸二肽间的差异很小，改进的高效液相色谱法、离子色谱法和毛细管电泳法可对它们进行良好的分离检测。组氨酸二肽具有的抗氧化功能使其近年来被广泛应用，在食品行业作为天然安全的抗氧化剂，在化妆品行业作为一种抗衰老成分添加至美容护肤产品，组氨酸二肽具备的多种其他生理功能近年来也逐渐引起了医药界的重视，但其对许多疾病的治疗作用机制仍未被阐明，而且可能还有生物学活性未被发现，仍有待进一步的探究。
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