CN113480552B - 一种化合物及其在改善动物瘤胃微生物发酵中的用途 - Google Patents
一种化合物及其在改善动物瘤胃微生物发酵中的用途 Download PDFInfo
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Abstract
本发明发现式I化合物能够有效改善反刍动物瘤胃微生物代谢，因此提供了一种式I所示的化合物或其生理学上可接受的盐在制备改善动物瘤胃微生态环境的制剂中的用途。该化合物的安全性好，几乎无毒副作用，可以广泛应用于动物药物制剂、营养制剂或饲料制剂中。
Description
技术领域
本发明属于动物营养和药物领域，具体涉及一种化合物及其生理学上可接受的盐在改善动物瘤胃微生物发酵中的用途。
背景技术
反刍动物瘤胃微生物代谢对于氮利用具有重要作用，其中微生物代谢产生的氨被瘤胃微生物利用进而合成微生物蛋白，为动物自身的生长提供氮源。然而，氨生成过快则与能量释放不同步，会降低微生物对氨的利用率，影响生产性能。过量氨氮的产生易导致高尿氮排放引起的环境污染，同时过量的氨通过瘤胃壁进入血液，极易引起动物机体氨应激，甚至氨中毒，危害动物健康。尿素是瘤胃氨氮产生的重要来源。因此，改善反刍动物瘤胃微生态环境，能改善瘤胃的发酵，提高饲料利用率，同时有利于调理动物身体营养与健康，降低瘤胃微生物代谢不平衡对动物生产性能造成的负面影响。
天然生物碱类化合物及其衍生物与传统的兽用药物制剂、动物营养添加剂相比，具有天然性、多功能性、可持续性等优势，具有多成分、多功能的特点，更能符合动物机体功能相互协调和整体统一的规律，作用更具有全面性，同时它多成分协同作用，使得其中某种特定成分含量较低，经炮制和加工后使其毒性(代谢毒性、致畸性、致癌和突变能力)进一步减弱或消除，对动物不会产生明显的副作用，不易产生抗药性，适合长期使用。
发明内容
为改善现有技术中存在的问题，本发明提供一种下式I所示的化合物，或其生理学上可接受的盐：
其中，R1、R2、R3、R4相同或不同，彼此独立地选自氢、羟基、C1-6烷基、C1-6烷氧基；或者R1、R2与其相邻的碳形成4-8元环状结构，R3、R4与其相邻的碳形成4-8元环状结构。
根据本发明的实施方案，R1、R2、R3、R4相同或不同，彼此独立地选自氢、羟基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基；
根据本发明的实施方案，所述4-8元环状结构可以与相邻苯环并接的4-8元环烷基、4-8元杂环基，例如为
根据本发明的实施方案，式I所示化合物具有以下结构：
根据本发明的实施方案，所述生理学上可接受的盐可以是酸加成盐，例如式I化合物与如下无机酸形成的酸加成盐：例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸，或硫酸氢盐、或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
优选的，所述生理学上可接受的盐选自以下结构：
本发明还提供式I所示化合物，或其生理学上可接受的盐在制备改善动物瘤胃微生态环境的制剂中的用途。
根据本发明的实施方案，所述动物可以为反刍动物。
根据本发明的实施方案，所述制剂可以调节动物体内氮代谢。
根据本发明的实施方案，所述氮代谢可以为尿素氮代谢。
根据本发明的实施方案，所述氮代谢可以为尿素的分解速率和/或氨的合成速率。
根据本发明的实施方案，所述制剂可以调节动物体内瘤胃微生物活性。
根据本发明的实施方案，所述制剂包括药物制剂或营养制剂或饲料中的添加剂。
本发明还提供一种组合物，包含式I所示化合物或其生理学上可接受的盐。
根据本发明的实施方案，所述组合物中，式I所示化合物或其生理学上可接受的盐的质量分数为1-99％，优选为10-90％，还优选为20-80％。
根据本发明的实施方案，所述组合物还包括一种或多种生理学上具有相容性的辅料。
有益效果
本发明发现式I所示化合物能够有效改善反刍动物瘤胃微生物代谢，安全性好，几乎无毒副作用，可以广泛应用于动物药物制剂、营养制剂或饲料制剂中。
附图说明
图1为化合物2抑制UreG的GTP酶活性的IC50值曲线。
图2为化合物2对UreG与Ni结合的影响。A图为未添加化合物2时UreG蛋白与Ni的结合能力曲线，B图为添加化合物2时UreG蛋白与Ni的结合能力曲线。
图3为化合物2对UreG二级结构的影响。A图为化合物2对UreG的CD谱图的影响，B图为化合物2对UreG各二级结构比例的影响。
具体实施方式
下文将结合具体实施例对本发明的通式化合物及其制备方法和应用做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
1、实验仪器
酶标仪(Thermo Electron Varioskan Flash G-282)
微等温滴定量热仪(General Electric Company Auto-iTC200)
圆二色光谱仪(Chirascan Plus spectrometer)
2、主要试剂
(1)GTP酶缓冲液：2mM MgSO4、300μM GTP、200mM NaCl、1mM三(2-羧乙基)膦、10mMKHCO3、20mM HEPES，20μM NiSO4，调节pH至7.5，4℃保存。
(2)Ni-UreG结合缓冲液：2mM MgSO4、200μM GTP、200mM NaCl、1000μM三(2-羧乙基)膦、40mM HEPES，调节pH至7.5，4℃保存。
(3)酚-硝普钠溶液：称取10g苯酚和50mg硝普钠(又名亚硝基铁氰化钠)，用去离子水溶解并定容至1L，放入棕色瓶中，4℃可保存一个月。
(4)碱性次氯酸钠溶液：将5g NaOH和8.4mL NaClO溶液，用去离子水溶解并定容至1L，放入棕色瓶内，4℃可保存一个月。
(5)UreG蛋白：制备瘤胃微生物UreG蛋白，包括以下步骤a)-c)：
a)UreG基因的合成
利用基因合成仪，合成从牛瘤胃微生物中获得的UreG基因，并在该基因5’端加入内切酶EcoRI序列5'GAATTC 3'(其核苷酸序列为SEQ ID NO:1)，基因3’端加入内切酶SalI序列5'GTCGAC 3'(其核苷酸序列为SEQ ID NO:2)。
UreG核苷酸序列为SEQ ID NO:3：
‘5-ATGAAAGGCAATCCGCTTCGTGTCGGTGTCGGCGGGCCTGTGGGATCAGGCAAGACCGCGCTGATTGAGAAGCTCTGCAAGGCGATGCGCGACAGATGGAGCATCGGGGTCGTTACTAACGACATCTACACCAAGGAGGATCAGCGCATCCTGACCGAGGCCGGCGCGCTTCCCGCGGAGCGCATCATCGGAATCGAGACCGGAGGCTGCCCGCATACCGCGATAAGGGAGGATGCCTCCATGAACCTCGCGGCAATCGATGATCTGCTGCAGAAGTTCCCGGATCTCGACCTCATCTTCATTGAGAGCGGCGGTGACAACCTGAGCGCGACGTTCAGCCCGGAGCTTGCCGACATAACCATCTATGTCATCGATGTCGCGGAGGGCGAGAAGATTCCGAGAAAGGGCGGGCCCGGCATCACGAAATCCTCGTTCTTCGTGATAAACAAGACCGATCTCGCGCAGTATGTCGGCGCAAGCCTCGAGGTCATGGAGCGCGACACCAGGAGAATGCGCCCGACGAAGCCCTGGTGCTTCACCAACCTCAAGAAGGAGGAGGGACTGCCAAATGTCATCTCCTTCATCGAGGACTATCTTAAGATCGGGAACTGA-3’
b)克隆
首先将目的基因和对应的质粒用同样的两个内切酶进行酶切，按照表1的双酶切体系进行混合，然后置于37℃恒温水浴锅内，孵育2h。酶切后的目的基因和质粒进行琼脂糖凝胶电泳，用胶回收试剂盒回收目的基因和质粒。
表1双酶切体系(NEB公司)
目的基因与质粒连接时的摩尔质量比在3:1-10:1之间，两者的总质量在0.02-0.2μg之间。按照表2体系进行混合，然后室温孵育30min，转入大肠杆菌JM109感受态细胞。取1mL不含抗生素的LB培养液放入离心管中，轻轻混匀后，置于37℃恒温水浴锅中，复苏1h。最后置于离心机中，5 000r/min离心1min，吸走上清，留取约100μL的菌体沉淀，轻轻重悬沉淀后均匀涂布至含有对应抗生素的LB固体培养基上。将培养板倒放入37℃振荡培养箱中，培养约18h，挑取单克隆提取质粒后，进行测序鉴定。
表2 DNA与质粒连接体系(NEB公司)
c)UreG蛋白的表达和纯化
将含有UreG基因的重组质粒转入高效表达的BL21(DE3)感受态细胞中，加入含有氯霉素(终浓度30μg/mL)的LB培养液中，当培养至OD 600在0.5-0.6(约需3-4h)时，加入诱导剂无水四环素，使其终浓度为0.2μg/mL，然后置于18℃振荡培养箱中，250r/min过夜培养。置于4℃离心机，12 000r/min、离心5min进行收集。利用Strep-TagП磁珠蛋白质纯化试剂盒(海狸公司)对UreG蛋白进行纯化，获得UreG蛋白。
实施例1.化合物2抑制瘤胃微生物UreG蛋白的GTP酶活性测试
本实施例参照Malachite Green Phosphate Assay Kit(Sigma-aldrich)说明书采用如下步骤：
步骤一，标准工作曲线的制备：
表1
步骤二，工作液的制备：将试剂盒中的A液和B液按照100：1的比例混合，现用现配。
步骤三，化合物2的制备：溶剂为DMSO，800μM的化合物2用DMSO进行倍比稀释至400μM、200μM、100μM、50μM，例如800μM的化合物2与DMSO按照1：1比例稀释即为400μM，然后400μM的化合物2与DMSO按照1：1比例稀释即为200μM，以此类推。
步骤四，在96孔酶标板中，按照表2添加溶液，置于恒温混匀仪上混匀，然后室温孵育40min。
表2
步骤五，加入工作液20μL，置于恒温混匀仪上混匀，室温孵育30min，用分光光度计在620nm处测定吸光度。
步骤六，结果分析：GTP酶活性的定义为每毫克蛋白每分钟产生的磷酸盐的纳摩尔数[nmol/(min·mg)]。化合物2作用下的UreG GTP酶活性＝S1组GTP酶活性-S2组GTP酶活性。
步骤七，IC50值计算：UreG的半抑制率(IC50)是指UreG的GTP酶活性被抑制一半时所需的天然化合物的浓度。对不同浓度化合物2作用下的UreG GTP酶活性用GraphPadPrism 6.0软件进行拟合曲线，以C1组减去C2组的GTP酶活性为100％，根据拟合曲线计算IC50值。图1结果表明，UreG终浓度为3μM时，化合物2抑制UreG的GTP酶活性的IC50值为19.62μM。
实施例2.化合物2抑制UreG与镍的结合测试
步骤一，实验材料准备：UreG用3kDa的超滤浓缩管浓缩，并置换入Ni-UreG结合缓冲液中。化合物2和NiSO4分别用Ni-UreG结合缓冲液溶解。
步骤二，滴定样品的准备：抑制剂组：化合物2和NiSO4混合，化合物2的终浓度为238μM,NiSO4的终浓度为1 500μM。UreG组：化合物2用Ni-UreG结合缓冲液代替。
步骤三，被滴定样品的准备：抑制剂组：化合物2和UreG混合，化合物2的终浓度为238μM,UreG的终浓度为27μM。UreG组：化合物2用Ni-UreG结合缓冲液代替。背景参照组：被滴定样品中的UreG用Ni-UreG结合缓冲液代替。
步骤四，滴定时，每滴2μL，第一滴0.5μL，但不计入计算，共计20滴，每滴持续时间4s，两滴间隔120s，搅拌速度为750r/min。
步骤五，滴定结束后，用仪器自带的Origin软件拟合分析，实际滴定结果为试验组滴定曲线减去背景参照组滴定曲线，然后选择One-site binding model进行最终曲线拟合。根据曲线，可以进一步得到镍与UreG的结合摩尔比N、亲和力KD、焓变ΔH。
由图2可以看出，化合物2降低了镍与UreG的结合摩尔比N、焓变ΔH的绝对值，增加了KD值。KD值越大代表两者亲和力越小，即化合物2降低了镍与UreG的亲和力。
实施例3.化合物2改变UreG蛋白二级结构的测试
步骤一，实验材料准备：UreG组：UreG用3kDa的超滤浓缩管浓缩，并置换入双蒸水中，浓度为233μg/mL，其中双蒸水为背景参照。抑制剂组：化合物2添加入UreG蛋白溶液中，并使化合物2终浓度为238μM，蛋白终浓度为233μg/mL，其中化合物2溶解入双蒸水中至终浓度为238μM作为此组的背景参照。
步骤二，圆二色光谱仪参数设置：比色皿光径规格为1mm，光谱测量范围设置为190-260nm，步进为1nm，每个样品采集数据3次。
步骤三，结果分析：每组扣除背景参照值后，用仪器自带的软件进行平滑处理得到CD谱图。并用CDNN软件估算α螺旋、β-折叠、β-转角和无规卷曲的含量。
由图3可以看出，化合物2明显改变了UreG的CD谱图，主要体现在α螺旋和β-折叠上。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
SEQUENCE LISTING
<110> 中国农业科学院北京畜牧兽医研究所
<120> 一种化合物及其在改善动物瘤胃微生物发酵中的用途
<130> CPCN21410409
<160> 3
<170> PatentIn version 3.3
<210> 1
<211> 6
<212> DNA
<213> 人工序列
<400> 1
gaattc 6
<210> 2
<211> 6
<212> DNA
<213> 人工序列
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gtcgac 6
<210> 3
<211> 612
<212> DNA
<213> 人工序列
<400> 3
atgaaaggca atccgcttcg tgtcggtgtc ggcgggcctg tgggatcagg caagaccgcg 60
ctgattgaga agctctgcaa ggcgatgcgc gacagatgga gcatcggggt cgttactaac 120
gacatctaca ccaaggagga tcagcgcatc ctgaccgagg ccggcgcgct tcccgcggag 180
cgcatcatcg gaatcgagac cggaggctgc ccgcataccg cgataaggga ggatgcctcc 240
atgaacctcg cggcaatcga tgatctgctg cagaagttcc cggatctcga cctcatcttc 300
attgagagcg gcggtgacaa cctgagcgcg acgttcagcc cggagcttgc cgacataacc 360
atctatgtca tcgatgtcgc ggagggcgag aagattccga gaaagggcgg gcccggcatc 420
acgaaatcct cgttcttcgt gataaacaag accgatctcg cgcagtatgt cggcgcaagc 480
ctcgaggtca tggagcgcga caccaggaga atgcgcccga cgaagccctg gtgcttcacc 540
aacctcaaga aggaggaggg actgccaaat gtcatctcct tcatcgagga ctatcttaag 600
atcgggaact ga 612
Claims (6)
1.化合物1所示白屈菜红碱，或其生理学上可接受的盐在制备改善动物瘤胃微生态环境的制剂中的用途；所述制剂调节反刍动物体内胃瘤微生物活性；且所述制剂调节反刍动物体内尿素氮代谢；
2.根据权利要求1所述的用途，其特征在于，所述生理学上可接受的盐是酸加成盐。
3.根据权利要求2所述的用途，其特征在于，所述酸加成盐具有以下结构：
4.根据权利要求1所述的用途，其特征在于，所述氮代谢为尿素的分解速率和/或氨的合成速率。
5.根据权利要求1或2所述的用途，其特征在于，所述制剂为药物制剂或营养制剂。
6.根据权利要求1或2所述的用途，其特征在于，所述制剂为饲料中的添加剂。
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