动物营养学报    2019, Vol. 31 Issue (10): 4481-4487    PDF    
D-天冬氨酸生理功能及其在畜禽生产中的应用
夏嗣廷1,2 , 胡睿智1 , 贺建华1 , 李铁军2     
1. 湖南农业大学动物科学技术学院, 长沙 410128;
2. 中国科学院亚热带农业生态研究所, 亚热带农业生态过程重点实验室, 湖南省畜禽健康养殖工程技术研究中心, 农业部中南动物营养与饲料科学观测实验站, 湖南畜禽安全生产协同创新中心, 长沙 410125
摘要: D-天冬氨酸(D-Asp)主要为一种具有多种生理功能的神经递质,同时也参与动物体内的激素调节、保护神经、调控生殖,还具有一定的营养潜力,可以应用到医药、食品及畜禽生产等行业中。本文综述了D-Asp的生理功能及其在实际畜禽生产中的应用。
关键词: D-天冬氨酸    生理功能    畜禽    应用    
Physiological Function of D-Aspartate and Its Application in Animal Production
XIA Siting1,2 , HU Ruizhi1 , HE Jianhua1 , LI Tiejun2     
1. College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China;
2. Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences; National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production; Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production; Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture; Hunan Co-Innovation Center of Animal Production Safety, Changsha 410125, China
Abstract: D-aspartic acid (D-Asp) is mainly a neurotransmitter with many physiological functions. It also participates in hormone regulation in animals, protects nerves, regulates reproduction, and has certain nutritional potential, and applied to industries such as medicine, food and livestock production. This paper reviews the physiological functions of D-Asp and its application prospects in livestock and poultry production.
Key words: D-aspartic acid    physiological function    livestock and poultry    application    

D-天冬氨酸(D-aspartic acid,D-Asp)是在自然界中存在的与L-天冬氨酸(L-aspartic acid,L-Asp)互成镜像的对映体,是一种广泛存在于无脊椎动物和脊椎动物组织器官中的内源性氨基酸,其衍生物N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)天然存在于动物机体中。D-Asp在1965年首次被提出,随后发现它存在于普通头足类软体动物章鱼的大脑和视叶中[1-2],进而在很多动物的神经和内分泌组织中找到了D-Asp。1986—1990年,Neidle等[3]和Dunlop等[4]通过试验发现了D-Asp促进参与神经系统发育的蛋白质的合成,在突触处起着神经递质或神经调节剂的作用。2000年,D’Aniello等[5]发现D-Asp和NMDA存在于大鼠神经内分泌组织中,并对黄体生成素和生长激素释放具有调节作用。2011年,Errico等[6]通过增加大脑D-Asp含量挽救了小鼠海马年龄相关性突触(hippocampal age-related synaptic)可塑性的恶化。2018年,Li等[7]通过试验发现了D-Asp对断奶仔猪生产性能的影响。D-Asp作为一种具有多种生理功能的氨基酸可以广泛应用于食品、药品、畜禽养殖等领域,其市场开发方面具有较大的潜力。本文综述了D-Asp的生理功能及其在畜禽生产中的应用,旨在为其开发利用提供参考。

1 D-Asp的理化特性

氨基酸的α-碳原子的立体化学构型是所有生命系统的基础。除甘氨酸外,目前蛋白质中发现的所有氨基酸都具有光学活性,并且具有与α-碳原子相同的立体化学构型。这些氨基酸的前缀L可以追溯到19世纪前,1851年Louis Pasteur观察到天然氨基酸天冬氨酸是“左旋”,即能够将偏振光分散到左侧;此外,前缀D的氨基酸可以使偏振光向右旋转。除去甘氨酸,人体内的其他基本氨基酸,包括天冬氨酸都有2种对映体互成镜像,即D-型与L-型(图 1)。D-Asp为无色结晶体,溶于热水和稀盐酸,微溶于冷水,不溶于乙醇和乙醚,其分子式与L-Asp同为C4H7O4N,熔点269~271 ℃,相对分子质量133.10,比旋光度[α]D25-25.4°(5 mol/L盐酸中)。

在药物的合成中,D-Asp主要作为合成的前体或中间体,例如作为前体合成D-天冬氨酸-β-羟胺(D-aspartate-β-hydroxylamine,DAH)[8],作为中间体合成阿扑西林(aspoxicillin,ASPC)[9]。由于不易被细菌所降解而产生抗药性,D-Asp被作为酶抑制剂的重要合成前体,其代替L-Asp生产的多肽类药物半衰期得到有效的延长,同时降低了药物的副作用[10]

图 1 D-天冬氨酸和L-天冬氨酸构型 Fig. 1 Configuration of D-aspartic acid and L-aspartic acid
2 D-Asp的生理功能 2.1 对动物体神经调节的功能

D-Asp可参与不同的神经活动,包括视觉生理学[11-12]、神经发生[12-14]以及学习和记忆过程[6, 15-16]。事实上,D-Asp早已经在突触体和突触泡中被检测到,在化学(钾离子、离子霉素)或电刺激后释放[1]

自从在大鼠垂体和视网膜中发现D-Asp[11]后,许多研究表明D-Asp参与视网膜中许多重要生理事件,包括指导细胞分化和突触形成等[12-13]。当动物处于黑暗时,D-Asp的浓度在视网膜中减少,表明其在视觉中具有重要作用[12]。在胚胎中还观察到高浓度的D-Asp,分娩后其在神经组织中消失,但在内分泌腺中暂时增加,例如在特定阶段的垂体、松果体和肾上腺,这意味着D-Asp可能在神经系统的发育中发挥重要作用[14]。此外,D-Asp浓度在出生前和成熟期间的睾丸中增加,其中在曲精小管内产生的D-Asp通过激活类固醇源性急性调节蛋白(steroidogenic acute regulatory protein,StAR)的表达,在睾酮合成增强后作用于间质细胞。

关于D-Asp在学习和记忆中的作用,已经发现在阿尔茨海默病患者的脑组织和脑室脑脊液中,D-Asp的浓度与健康对照相比显著降低[15]D-Asp可增加小鼠的长期电位[16],防止长期抑郁,减轻精神分裂症样症状[17],并挽救海马年龄相关的突触可塑性的老化[6],这意味着它可以改善年龄相关的NMDA受体信号传导的减少[6]。另外,D-Asp增加大鼠的空间记忆[18],而成年小鼠海马新生神经元中天冬氨酸消旋酶的消耗,导致神经元中D-Asp的浓度减少以及树突发育的缺陷,这意味着D-Asp是一种神经发生的调节剂[19]。通过口服摄入D-Asp(40 mmol/L)可以明显改善大鼠的认知能力,其表现为在Morris水迷宫测试中找到一个隐藏的平台[18],这意味着口服摄入D-Asp会通过与海马神经元的相互作用对记忆功能产生影响,而L-Asp的胃内给药不会激活海马[20]

综上,我们可以推断D-Asp是神经系统中新的内源性神经递质。值得注意的是,D-Asp符合一系列限制性标准,足以将其置于与其他经典神经递质氨基酸如L-谷氨酸(L-Glu)相同的类别中[21]

2.2 对动物体激素调节的功能

D-Asp在内分泌系统中参与调节激素的合成和释放。在大鼠的下丘脑中,它能促进促性腺激素释放激素(gonadotropin releasing hormone,GnRH)的释放,诱导催产素和加压素mRNA的合成[22]。可刺激分泌催乳素(prolactin,PRL)、促黄体生成素(luteinizing hormone,LH)与生长激素(growth hormone,GH)的分泌[23]。此外,在睾丸中,它存在于间质细胞中,参与睾酮和孕酮的释放。在新生儿和成年大鼠中,D-Asp主要分布于内分泌腺,如肾上腺[24]和睾丸[25],其次是大脑和周围组织[26]。这些器官中D-Asp的含量在出生后增加,随着组织的成熟达到最大值。

D-Asp所调控的神经类固醇除了有助于突触的形成、突触可塑性和认知活动外,还对髓鞘破坏有保护作用[27-29]。例如,由适应性和先天免疫反应介导的试验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)导致炎性脱髓鞘和轴突损伤,而在饮水中添加D-Asp可以显著降低EAE小鼠小脑炎症因子的表达水平[30]。此外,D-Asp可以调控孕酮的表达水平,保护大鼠的脊髓运动神经元[27, 31],也可以通过对17β-雌二醇的调控保护少突胶质细胞,使其免受细胞毒性死亡[28]D-Asp影响下丘脑-垂体-性腺轴,从而影响血浆类固醇水平[32-33]。类固醇生成途径始于类固醇激素合成StAR介导的胆固醇在线粒体膜上的易位,其中胆固醇通过P450侧链裂解酶(P450scc)转化为孕烯醇酮,孕烯醇酮扩散到胞质溶胶中并在光滑的内质网中转化为孕酮,然后通过3β-羟基类固醇脱氢酶(3β-hydroxysteroid dehydrogenase,3β-HSD)转化为雄烯二酮,随后17β-羟基类固醇脱氢酶催化雄烯二酮转化为睾酮,最终通过细胞色素P450芳香化酶(P450-aro)转化为17β-雌二醇[34-36]D-Asp激活N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptors,NMDAR),经由腺苷-3′, 5′-环化一磷酸(cAMP)和激活丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)途径增加StAR表达,StAR通过调节线粒体内胆固醇的转移影响血浆类固醇水平[33]。此外,D-Asp还可诱导大脑中性激素水平的提高,但不排除提高的水平可能是由于循环激素的增加[37]

3 D-Asp在畜禽生产中的作用效应 3.1 对繁殖系统的作用效应

D-Asp可以增加睾酮水平,这在精子发生中起关键作用,这对于睾酮浓度较低的畜禽来说尤为重要。在没有睾酮或其活性受体的情况下,精子发生很少的减数分裂[38]。在小鼠体内,D-Asp通过刺激睾丸中NMDAR、雄激素受体以及胞外信号调节激酶(extracellular signal-regulated kinase,ERK)信号通路,能够提高睾酮的合成[32]。在雄性生殖道和精浆中选择性储存D-Asp,可引起生殖细胞的级联存活,或调节精子的成熟和排出后的活性[39]

与NMDAR相结合,D-Asp通过cAMP激活MAPK和蛋白激酶B(AKT)信号通路途径,增加StAR表达,刺激雄性激素受体的表达和精原细胞的增殖[32, 40-42]。同时,17β-雌二醇与雌激素受体β(estrogen receptor β,ESR2)相互作用且激活P450-aro/ESR2通路,可进一步刺激精原细胞增殖[32, 43]D-Asp还可以改善线粒体活性,通过提供细胞ATP,在精子运动参数及其膜功能中发挥关键作用[44]

补充锌、D-Asp和辅酶Q10的精子培养基可以保护公牛精子免受外源性氧化应激的影响,并提高其支持胚胎发育的能力[45]。在畜禽饲粮中添加适宜浓度的D-Asp可以对其精子质量参数、生育力和禽类孵化率产生积极影响[44],过量添加则会对精子质量和生育结果产生不利影响。在Di Fiore等[37]研究中,D-Asp浓度高于200 mg/(kg BW·d)时,大多数评估性状中观察到下降趋势。适宜浓度的D-Asp可以有效地保护公鸡精子免受冻融过程中发生的低温伤害。通过口服200 mg/(kg BW·d) D-Asp可以改善公鸡新鲜精子(总体和前向运动和质膜功能)和解冻后精子(总体和前向运动、质膜功能、线粒体活性以及生育力和孵化率)的品质。

Chandrashekar等[46]研究了过量D-Asp摄入对睾丸生理的影响,研究发现,过量的外源性D-Asp主要由于D-Asp氧化酶(D-Asp oxidase,D-AspO)的代谢而提高氧化应激。在正常生理条件下,D-Asp被D-AspO代谢成草酰乙酸、氨和过氧化氢。过氧化氢通过过氧化氢酶或谷胱甘肽过氧化物酶立即水解,从而使过氧化损伤最小化。当超过细胞的抗氧化能力时,将不可避免的发生线粒体功能障碍。在存在钙离子(Ca2+)的情况下,膜电位的显著降低和膜转换孔的增加是破坏线粒体膜完整性的潜在机制。因此,高浓度D-Asp的促氧化作用可能导致线粒体功能受损和精子质量降低。

3.2 对营养调控的作用效应

在Li等[47]的研究中发现,低浓度的D-Asp可以改善动物的生长性能和抗逆性。另一项研究中发现,D-Asp可能改变仔猪肠道菌群同时影响其新陈代谢,从而进一步调控机体生理功能[7],具体体现在D-Asp调控仔猪肠道微生物的数量和种类,例如其在属的水平上显著增加志贺氏大肠杆菌(Escherichia shigella)、森氏梭状芽孢杆菌1(Clostridium sensu stricto 1)以及链球菌(Streptococcus)等的物种丰富度。在饲粮中混合添加D-Asp与L-Asp可以使小鼠的生长性能得到有效提高,但是过量添加D-氨基酸则会抑制其生长[48]。例如口服D-Asp(0、3.75、7.50和15.00 mmol/kg BW)会导致鸡采食量的线性下降[49]。口服D-Asp后采食量减少的原因可能是:1)由于过量的D-Asp浓度会通过不平衡的氨基酸比例抑制雏鸡的食物摄入量;2)可能是由于D-Asp给药引起消化道蠕动作用下降的结果[50];3)可能是由于机体内部存在的D-氨基酸与摄入D-Asp之间拮抗作用造成的[51-52]。所以可以推断,在饲粮中添加适宜浓度的D-Asp具有潜在的营养价值,但是过高添加浓度则会阻碍动物机体中其他重要生物活性物质的合成与代谢。

3.3 对热应激的作用效应

在环境温度偏高[(40±1) ℃,3 h]的情况下,长期口服含有可以产生D-Asp的活细菌的培养基可以有效降低雏鸡的直肠温度[52]。给药含有活菌的培养基会引起小鸡肠道菌群的变化,从而影响能量合成。同时观察到长期给药导致鸡解耦联蛋白(avian uncoupling protein,avUCP)的基因表达下调,鸡腺嘌呤核苷酸转运体(avian adenine nucleotide translocator,avANT)在鸡骨骼肌中的基因表达上调[53]avUCP基因表达的变化可能导致线粒体产热的减少,并且可能使ATP的合成代谢功能增加,从而降低了雏鸡的体温。D-Asp还可以诱导雏鸡产生镇静作用,从而有效减少新生雏鸡的应激诱导行为,口服D-Asp可以显著提高间脑中D-Asp的浓度[54]。因此,在雏鸡饲粮中添加适量的产生D-Asp的活性菌可以起到减少其发生热应激的几率,从而提高采食量,提升饲料转化率,加快其生长发育。

4 小结

综上所述,D-Asp具有调节动物神经、调控激素分泌的生理功能;在畜禽生产中能通过调节睾酮分泌,提高精子活力;能通过神经调节,起到镇静作用,减轻应激诱导行为。此外,D-Asp还能减轻精子的冷冻损伤和氧化损伤,提高畜禽生长性能,因此在畜禽生产中具有良好的应用前景。目前,国内外关于D-Asp在畜禽养殖应用方面的研究还十分稀少,其对于不同动物的适宜添加量、吸收和代谢机理等方面都尚不明确。随着我们更加深入的研究,D-Asp将更好地应用于畜禽生产领域。

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