CN105112463A - 通过在发酵罐中高密度培养真核微生物来增加含有多烯脂肪酸的脂质的产生 - Google Patents
通过在发酵罐中高密度培养真核微生物来增加含有多烯脂肪酸的脂质的产生 Download PDFInfo
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Abstract
本发明涉及通过在发酵罐中高密度培养真核微生物来增加含有多烯脂肪酸的脂质的产生。本发明提供了培养真核微生物的方法,所述微生物可以生产脂质,具体是含有多烯脂肪酸的脂质。本发明还提供了生产真核微生物脂质类的方法。
Description
本发明申请是基于申请日为2001年1月26日、申请号为200910133079.4、名称为“通过在发酵罐中高密度培养真核微生物来增加含有多烯脂肪酸的脂质的产生”的发明专利申请的分案申请。
技术领域
本发明涉及培养微生物和回收微生物脂质的新方法。具体地,本发明涉及生产微生物多不饱和脂。
背景技术
在真核微生物中生产多烯脂肪酸(含有2个或更多个不饱和碳碳键的脂肪酸)一般认为需要分子氧的参与(即需氧条件)。这是因为据认为在所有非寄生性真核微生物的脂肪酸中形成的顺式(cis)双键参与直接的氧依赖型去饱和反应(氧化微生物去饱和酶系统)。其它已知需要分子氧的真核微生物脂质包括真菌甾醇和植物甾醇,羟基类胡萝卜素(oxycarotenoids)(即叶黄素),泛醌,和从任一种这类脂质制备的化合物(如次级代谢产物)。
已证实某些真核微生物(如藻类;真菌,包括酵母;和原生生物)在发酵罐中可以很好地生产多烯脂肪酸。但是,极高密度培养(微生物的生物量大于100g/L,特别是商业规模的)会降低多烯脂肪酸的含量,这样会降低多烯脂肪酸的生产力(productivity)。这可能部分是由于几种因素,包括由于微生物的高浓度造成对氧的高需求,而难于维持发酵液中的溶氧水平。保持较高溶氧水平的方法包括提高通气速率和/或采用纯氧替代空气通气和/或提高发酵罐的搅拌速度。这些解决方法一般提高脂质生产的成本和发酵设备的资金成本,而且会产生其它的问题。例如,在高细胞密度时增加通气容易在发酵罐中产生严重的起泡问题,加强搅拌会由于发酵液中剪切力增加而导致微生物细胞破碎(这会导致脂质释放到发酵液中,从而被氧化和/或被酶降解)。对于正处于氮受限或耗尽以诱导产生脂质从而细胞壁较弱的细胞,细胞破碎问题更为突出。
结果,当以极高细胞密度培养生产脂质的真核微生物时,它们的脂质通常都只含有极少量的多烯脂肪酸。例如,以醇为碳源培养斯达氏油脂质酵母(Lipomycesstarkeyi)在140小时到153g/L的密度,产生的脂质浓度为83g/L。但是在浓度大于100g/L时酵母的多烯脂肪酸含量平均只有总脂肪酸的4.2%(在细胞密度为20-30g/L时其含量从占总脂肪酸的11.5%开始减少)。Yamauchi等,J.Ferment.Technol.,1983,61,275-280。这样产生的多烯脂肪酸浓度只有约3.5g/L,平均多烯脂肪酸生产力只有约0.025g/L/hr。此外,在酵母脂质中唯一报导的多烯脂肪酸是C18:2。
已证实另一酵母,Rhodotorulaglutinus,具有的平均脂质生产力约为0.49g/L/hr,但其脂质中多烯脂肪酸含量也较低(占全部脂肪酸的15.8%,14.7%C18:2和1.2%C18:3),导致在补料分批培养中多烯脂肪酸生产力只有约0.047g/L/hr,在连续培养中是0.077g/L/hr。
本发明人之一以前已证实破囊壶菌目(Thraustochytriales)的某些海洋微藻类在发酵罐中是极好的多烯脂肪酸生产者,特别是在低盐,特别是极低氯化物水平培养时。其它有人描述了Thraustochytrids在培养120小时,细胞密度为59g/L时的平均多烯脂肪酸(DHA,C22:6n-3;和DHA,C22:5n-6)生产力约为0.158g/L/hr。但是这样的生产力只能在约50%的海水盐度下达到,这样的浓度会严重腐蚀传统的不锈钢发酵罐。
生产含多烯脂肪酸的微生物脂质,特别是高度不饱和脂肪酸,如C18:4n-3,C20:4n-6,C20:5n3,C22:5n-3,C22:5n-6和C22:6n-3,的费用一直较高,部分原因是含高水平多烯脂肪酸的真核微生物培养密度的限制和在这样的高细胞浓度下的氧限制以及获到高生产力所需的较高温度的限制。
因此,需要高浓度培养微生物,并同时利于提高含多烯脂肪酸的脂质的产量。
发明内容
本发明提供了培养真核微生物的方法,所述微生物能产生至少约20%的生物量的脂质,本发明还提供生产这样的脂质的方法。优选这些脂质包含一或多种多烯脂肪酸。此方法包括向含有真核微生物的发酵培养基加入碳源,优选是非醇碳源,和限制性营养源。优选地,所述碳源和营养源的添加速度足以提高发酵培养基的生物量密度到至少约100g/L。
本发明的一方面,发酵条件包括生物量密度提高阶段和脂质生产阶段,其中所述生物量密度提高阶段包括加入碳源和限制性营养源,所述脂质生产阶段包括添加碳源但不加入限制性营养源,以形成诱导脂质产生的条件。
本发明的另一方面,在脂质生产阶段的发酵培养基中的溶氧量低于在生物量密度提高阶段的发酵培养基中的溶氧量。
本发明的另一方面,微生物选自藻类,真菌(包括酵母),原生生物,细菌或其混合物,其中所述微生物能产生多烯脂肪酸或其它一般被认为其合成需要氧的脂质。本发明特别有用的微生物是能在发酵培养基中氧水平低于约3%的饱和度的情况下生产脂质的真核微生物。
本发明的另一方面,以补料分批培养方式培养微生物。
本发明的另一方面还提供了在此发酵工艺的后半部分保持发酵培养基中氧水平低于约3%饱和度。
本发明的另一方面提供了生产真核微生物脂质的方法,包括:
(a)在发酵培养基中培养真核微生物,以便将该发酵培养基的生物量密度提高到至少约100g/L;
(b)提供足以使所述微生物生产所述脂质的发酵条件;和
(c)回收所述脂质,
其中所述脂质的多于15%是多不饱和脂。
本发明的另一方面提供了回收脂质的方法,包括
(d)除去所述发酵培养基中的水,得到干的微生物;和
(e)从所述干的微生物分离所述脂质。
优选地,所述除去水的步骤包括将所述发酵培养基不经预先离心而直接与转鼓式干燥机接触。
本发明的另一方面提供了回收脂质的步骤,包括:
(d)处理发酵液以透化,溶解,或破裂微生物细胞;和
(e)在有或没有水溶性试剂帮助裂解脂质/水乳剂的情况下,通过重力分离,优选离心,回收发酵液中的脂质。
优选地,步骤(c)中是在发酵罐或类似容器中处理微生物细胞。
本发明的另一方面提供了富集微生物的多烯脂肪酸含量的方法。所述方法包括在溶氧水平低于10%的生长培养基中发酵微生物。
本发明的又一方面是生产产品和微生物的异养方法。该方法包括在生长培养基中培养含有聚酮化合物合成酶基因的微生物并保持培养液中的溶氧水平低于10%。
具体地,本发明涉及如下各项:
1.一种从真核微生物生产含有多烯脂肪酸的脂质的方法,所述微生物能产生至少占其生物量约20%的脂质,该方法包括向含有所述微生物的发酵培养基中以足以提高该发酵培养基生物量密度到至少约100g/L的速率加入非醇碳源和限制性营养源。
2.培养能生产占其生物量的20%为脂质的真核微生物的方法,包括向包含所述微生物的发酵培养基中添加碳源和限制性营养源,添加的速率足以提高该发酵培养基的生物量密度到至少约100g/L,其中该方法生产脂质的速度至少平均约为0.5g/L/hr,所述微生物产生的总脂质中至少约15%是多不饱和脂。
3.培养真核微生物的方法,包括向包含所述微生物的发酵培养基中添加碳源和限制性营养源,添加的速率足以提高该发酵培养基的生物量密度到至少约100g/L,其中所述微生物选自藻类,真菌(包括酵母),原生生物,细菌或其混合物,其中所述微生物能生产占其生物量至少约20%的包含多烯脂肪酸的脂质。
4.一种生产真核微生物脂质的方法,包括:
(a)在发酵培养基中培养真核微生物以便将该发酵培养基的生物量密度提高到100g/L;
(b)提供足以使所述微生物生产所述脂质的发酵条件;和
(c)回收所述脂质,其中所述脂质的多于约15%是多不饱和脂。
5.一种生产真核微生物脂质的方法,包括:
(a)向包含所述微生物的发酵培养基中加入非醇碳源和限制性营养源;
(b)提供足以使所述微生物生产所述微生物脂质的条件;和
(c)回收所述微生物脂质,其中所述微生物脂质的至少约15%为多不饱和脂。
6.一种生产真核微生物脂质的方法,包括:
(a)在含有真核微生物的发醇培养基中添加碳源和限制性营养源,并提供足以将该发醇培养基中溶氧水平维持在至少约4%的条件,以便产生至少约100g/L的生物量密度;
(b)提供足以将该发醇培养基中溶氧水平维持在约1%或更低水平的条件,并提供足以使所述微生物生产所述脂质的发酵条件;和
(c)回收所述脂质,其中所述微生物脂质的至少约15%是多不饱和脂。
7.一种富集微生物的多烯脂肪酸含量的方法,包括在溶氧水平低于10%的生长培养基中发酵所述微生物。
8.一种生产产物和微生物的异养方法,包括:
a.在生长培养基中培养所述微生物,所述微生物中包含聚酮化合物合成酶基因;和
b.保持溶氧水平低于10%。
附图说明
图1是微生物的各种脂质生产参数对发酵培养基中溶氧量的表和图。
发明详述
本发明提供了培养微生物,例如藻类,真菌(包括酵母),原生生物,和细菌的方法。优选地,微生物选自藻类,原生生物,细菌或其混合物。更优选地,微生物是藻类。而且,本发明方法可用于生产各种脂质化合物,尤其是不饱和脂质,优选多不饱和脂(即含有至少2个不饱和碳-碳键,例如双键,的脂质),更优选高度不饱和脂(即含有4个或更多个不饱和碳-碳键的脂质)如ω-3和/或ω-6多不饱和脂肪酸,包括二十二碳六烯酸(即DHA);和其它天然的不饱和,多不饱和及高度不饱和化合物。本文中术语“脂质”包括磷脂;游离脂肪酸;脂肪酸的酯;三酰基甘油;甾醇和甾醇酯;类胡罗卜素;叶黄素(例如羟基类胡萝卜素);烃;类异戊二烯衍生的化合物和本领域技术人员所知的其它脂质。
更具体地,本发明方法可用于生产真核微生物多烯脂肪酸,类胡萝卜素,真菌甾醇,植物甾醇,叶黄素,泛醌,和通常认为需要氧来产生不饱和碳-碳键(即通气条件)的其它类异戊二烯衍生的化合物,和其次级代谢产物。具体地,本发明方法可用于培养生产多烯脂肪酸的微生物,并用于生产微生物多烯脂肪酸(类)。
本发明的方法可用于培养许多微生物并得到由其产生的包含多不饱和脂的化合物,但为了简洁,便利和说明,此发明详述将讨论培养能产生含有ω-3和/或ω-6多不饱和脂肪酸的脂质的微生物,尤其能产生DHA(或密切相关的化合物如DPA,EPA或ARA)的微生物的方法。优选的微生物包括微藻类,真菌(包括酵母),原生生物和细菌。优选的一组微生物是称为Stramenopiles的成员,包括微藻类和类藻微生物。Stramenopiles包括下列微生物:Hamatores,Proteromonads,Opalines,Developayelle,Diplophrys,Labrinthulids,Thraustochytrids,Biosecids,卵菌纲(Oomycetes),Hypochytridiomycetes,Commation,Reticulosphaera,Pelagomonas,Pelagococcus,Ollicola,Aureococcus,Parmales,硅藻属(Diatoms),黄藻(Xanthophytes),Phaeophytes(褐藻),Eustigmatophytes,Raphidophytes,Synurids,Axodines(包括Rhizochromulinaales,Pedinellales,Dictyochales),Chrysomeridales,Sarcinochrysidales,Hydrurales,Hibberdiales,和Chromulinales。其它优选的微藻类包括绿藻和腰鞭毛目(dinoflagellates),包括Crypthecodium属的成员。更具体地,本发明的优选实施方案参照培养海洋微生物的方法进行讨论,所述海洋微生物尤其是藻类,例如破囊壶菌目的Thraustochytrids,更尤其是破囊壶菌属(Thraustochytrium)的破囊壶菌(Thraustochytriales)以及Schizochytrium属,包括在共同转让的美国专利5340594和5340742(两者授权于Barclay,都全文引入作为参考)中公开的破囊壶菌。应注意,许多专家同意Ulkenia不是一个单独的属,实际是Schizochytrium属的一部分。在本文中,Schizochytrium属包括Ulkenia。
优选的微生物是那些可通过聚酮化合物合成酶系统产生目的化合物的微生物。这样的微生物包括具有内源的聚酮化合物合成酶系统的微生物以及已通过基因工程导入聚酮化合物合成酶系统的微生物。聚酮化合物是结构多样的天然产物,具有多种生物活性,包括抗生素和药物学特性。聚酮化合物合成酶催化聚酮化合物碳链骨架的生物合成。象结构和机理相关的脂肪酸合成酶,聚酮化合物合成酶催化酰基硫代酸酯之间的重复的脱羧缩合,一次可以使碳链延长两个碳原子。但是,与脂肪酸合成酶不同,聚酮化合物合成酶能产生结构具有很大差异的终产物。单个聚酮化合物合成酶系统可如下实现这一点:利用非乙酸酯的起始单元,利用甲基或乙基丙二酸酯作为延伸单位,和改变每次缩合所得β-酮基的酮还原、脱水和烯酰基还原反应的还原周期(cycle)。本文特别感兴趣的是脱水步骤导入的碳-碳双键在终产物中可保持。此外,尽管这些双键开始是反式构型,通过酶促异构化作用在DHA(和其它目的多烯脂肪酸)中可转变为顺式。脱水酶和异构化反应都可在缺乏分子氧的情况下出现。
优选地,本发明提供了异养方法用于产生产品和微生物。此方法优选包括在生长培养基中培养微生物,所述微生物中包含了聚酮化合物合成酶系统。优选地,保持溶氧水平低于约8%,更优选低于约4%,更优选低于约3%,更优选低于约1%。
但是应理解地是,本发明作为一个整体并非要进行这样的限制,本领域技术人员会认识到根据本发明的方法可用于其它微生物生产多种其它化合物,包括其它脂质化合物。
假定某种藻类有相对恒定的生产脂质的速度,显然较高的生物量密度能使单位体积生产的脂质总量更多。当今传统的培养藻类的发酵方法产生的生物量密度为约50到约80g/L或更少。本发明人已经发现通过采用本发明方法,可以得到比现有已知生物量密度显著提高的生物量密度。优选地,本发明生产的生物量密度为至少约100g/L,更优选至少约130g/L,还优选至少约150g/L,还优选至少约170g/L,最优选至少约200g/L。因此,有了这样高的生物量,即使藻类的脂质生产率稍稍降低,单位体积的脂质总产量也会显著高于现有方法。
本发明培养破囊壶菌目微生物的方法包括向包含微生物的发酵培养基中加入碳源和限制性营养源,其加入速度足以提高发酵培养基的生物量密度到上述水平。此处,“限制性营养源”指微生物生长所必需的营养来源(包括营养物本身),当生长培养基中限制性营养耗尽时,它的缺乏会大大抑制微生物的进一步生长或复制。但是,由于其它营养物质还很丰富,所述生物会继续制造和累积胞内和/或胞外产物。通过选择特异性的限制性营养物,可以控制积累产物的类型。因此,以一定的速度提供限制性营养源,可以控制微生物的生长速度和所需产物(例如脂质)的生产或积累。这种发酵过程由于将一或多种底物(例如碳源和限制性营养源)增量加入,而通常称为补料分批发酵过程。已发现在分批发酵过程中加入底物时,大量的碳源(例如每60g/L生物量约200g/L或更高密度)对微生物有不利影响。不受任何理论的限制,认为这样大量的碳源会对微生物产生有害影响,包括渗透压,并抑制微生物的初始生产力。本发明方法避免了这种不需要的有害影响,同时提供了足以使所述微生物达到上述生物量密度的底物量。
本发明的培养微生物的方法包括生物量密度的提高阶段。在此阶段,发酵过程的主要目的是提高发酵培养基中的生物量密度以得到上述的生物量密度。加入碳源的速度一般保持在不对微生物的生产力,或微生物的活力产生显著有害影响的特定水平或范围,所述有害影响是由于发酵设备除热和对培养液输入或输出气体的能力不足而导致的。具体微生物在发酵过程所需的碳源量的合适范围为本领域技术人员所熟知。优选地,本发明的碳源是非醇碳源,即不包含醇的碳源。此处,“醇”指具有4个或更少的带有一个羟基的碳原子,例如甲醇,乙醇和异丙醇,但是为了本发明的目的不包括羟基有机酸如乳酸和类似的化合物。更优选地,本发明的碳源是碳水化合物,包括,但不限于果糖,葡萄糖,蔗糖,糖蜜,和淀粉。其它合适的单纯和复合碳源和氮源公开在上述参考的专利中。但是典型地,碳水化合物,优选玉米糖浆用作主要的碳源。脂肪酸,羟基形式的脂肪酸,三酸甘油酯,和双-和单-酸甘油酯也可用作碳源。
特别优选的氮源是尿素,硝酸盐,亚硝酸盐,大豆蛋白,氨基酸,蛋白质,玉米浆,酵母提取物,动物性副产物,无机铵盐,更优选硫酸铵,氢氧化铵,最优选氢氧化铵。其它限制性营养源包括碳源(如上定义),磷酸盐源,维生素源(如维生素B12源,泛酸盐源,硫胺素源),痕量金属源(如锌源,铜源,钴源,镍源,铁源,锰源,钼源),主要金属源(如镁源,钙源,钠源,钾源,和二氧化硅源等)。痕量金属源和主要金属源选自这些金属的硫酸盐或氯化物(例如MgSO4·7H2O;MnCl2·4H2O;ZnSO4·7H2O;CoCl2·6H2O;Na2MoO4·2H2O;CuSO4·5H2O;NiSO4·6H2O;FeSO4·7H2O;CaCl2;K2SO4;KCl;和Na2SO4)。
当铵用作氮源时,如不加碱或不用缓冲液控制,发酵培养基会变酸。当氢氧化铵用作主要的氮源时,它也可用于控制pH。破囊壶菌目微生物,尤其破囊壶菌属的破囊壶菌和Schizochytrium属可在较宽pH范围内生长,例如从约pH5到约pH11。本领域技术人员了解具体微生物发酵的合适pH范围。
本发明培养微生物的方法还包括生产阶段。在此阶段,微生物利用底物的主要用途不是提高生物量密度,而是利用该底物生产脂质。应理解地是在生物量密度提高阶段微生物也产生脂质;但是,如上所述,在生物量密度提高阶段的主要目的是提高生物量密度。一般地,在生产阶段,减少或优选停止添加限制性营养底物。
以前一般认为在利用真核微生物生产多不饱和化合物,包括ω-3和/或ω-6多不饱和脂肪酸时,发酵培养基中的溶氧的存在是至关重要的。因此,通常认为发酵培养基中优选溶氧水平相对较高。但是,本发明人惊奇地发现在生产阶段当溶氧水平降低时脂质的生产速率显著提高。因此,在生物量密度提高阶段发酵培养基中的溶氧水平优选至少约8%的饱和度,优选至少4%的饱和度,而在产生阶段发酵培养基中的溶氧水平减少到约3%的饱和度或更少,优选约1%饱和度或更少,更优选0%饱和度。在发酵开始时,DO值可以为或接近饱和,当微生物生长时可使DO值降低至这些低DO设定值。在本发明的一个具体实施方案中,发酵期间发酵培养基中的溶氧量有变化。例如,对于总发酵时间为从约90小时到约100小时的一个发酵过程,发酵培养基中的溶氧水平在前24小时保持在约8%,在约第24小时到约第40小时约为4%,从第40小时到发酵过程终止约为0.5%或更少。
可通过控制发酵罐顶部空间中的氧量来控制发酵培养基中的溶氧量,或优选通过控制发酵培养基的摇动(或搅拌)速度来控制。例如,高的摇动(或搅拌)速度会比低摇动速度在发醇培养基中产生相对更高的溶氧水平。例如,在约14,000加仑容量的发酵罐中,摇动速度设定为前12小时约50rpm到约70rpm,约第12小时到18小时约55rpm到约80rpm,约第18小时到发酵过程终止为约70rpm到约90rpm,以获得上述总发酵时间约90到约100小时的发酵过程所具有的溶氧水平。获得发醇培养基中特定溶氧量所需搅拌速度的特定范围是本领域技术人员能够决定的。
本发明方法的优选温度是至少约20℃,更优选约25℃,最优选至少约30℃。应理解地是,冷水比热水更能保持较高的溶氧量。因此,较高的发酵培养基温度具有降低溶氧量的额外的好处,这是如上所述特别需要的。
某些微生物可能需要在发酵培养基中有一定量的矿物盐。这些矿物盐,特别是氯离子,能腐蚀发酵罐和其它下游处理设备。为防止或降低在发酵培养基中相对大量氯离子的存在的这些不需要的影响,本发明方法还包括使用不含氯的钠盐,优选硫酸钠,作为发酵培养基中的钠源。更具体地,发酵中绝大部分钠需求以不含氯的钠盐形式提供。例如,在发酵培养基中少于约75%的钠盐以氯化钠的形式提供,更优选少于约50%,更优选少于25%。本发明的微生物可在氯浓度低于约3g/L时生长,优选少于约500mg/L,更优选低于250mg/L,更优选在约60mg/L到约120mg/L之间。
不含氯的钠盐可包括苏打灰(碳酸钠和氧化钠的混合物),碳酸钠,碳酸氢钠,硫酸钠及其混合物,优选包括硫酸钠。苏打灰,碳酸钠,碳酸氢钠将会提高发酵培养基的pH,因此需要控制步骤以维持培养基的正确的pH。硫酸钠的浓度有效地符合微生物的盐度要求,优选钠浓度(表示为g/L的钠)至少约为1g/L,更优选为1g/L到约50g/L,更优选为约2g/L到约25g/L。
接种,培养,和回收微生物的各种发酵参数,详述于美国专利5130242,其全文引入作为参考。任何现今分离方法可用于从发酵培养基分离微生物,包括离心,过滤,超滤,倾析,和溶剂蒸发。本发明人发现,由于本发明的方法产生如此高的生物量密度,当采用离心回收微生物时,优选加入水稀释发酵培养基以降低生物量密度,从而能更有效的从发酵培养基分离微生物。
本发明中获得的极高生物量密度也便于回收微生物脂质的“无溶剂”方法。2000年1月19日提交的题为“无溶剂提取方法”的美国临时专利申请60/177,125、2001年1月19日提交的题为“无溶剂提取方法”的美国专利申请09/766,500(现为U.S.LettersPatentNo.6,750,048,2004年6月15日授 权)和2001年1月19日提交的题为“无溶剂提取方法”的PCT专利申请PCT/US01/001806(皆全文引入作为参考),都记述了在发酵罐中裂解细胞的优选方法。优选的在细胞于发酵罐中透化,破碎或裂解后回收脂质的方法(它可使脂质乳剂裂解,并回收富含脂质的级分),包括WO96/05278公开的脱油方法,其全文引入作为参考。在此方法中,在油/水乳液中加入水溶性化合物,例如醇或丙酮,以裂解乳液,所得混合物通过重力分离技术,例如离心来分离。此方法经改良后也可以用其它试剂(水和/或脂溶性的试剂)裂解乳液。
备选地,通过使发酵培养基的水分蒸发,例如使发酵培养基直接接触干燥设备如转鼓式干燥机(即没有,例如通过离心来预先浓缩),而从培养基回收干(dry)的微生物,即一种直接的转鼓式干燥机回收方法。当采用直接转鼓式干燥机回收方法分离微生物时,一般采用蒸汽加热式转鼓式干燥机。此外当采用直接转鼓式干燥机回收方法时,所述发酵培养基的生物量密度优选至少约130g/L,更优选至少约150g/L,最优选至少约180g/L。这种高生物量密度通常是直接转鼓式干燥机回收方法所希望的,因为生物量密度低时所述发酵培养基含有的水分足以使转鼓明显冷却,使微生物不能彻底干燥。其它干燥细胞的方法,包括喷雾干燥,已为本领域技术人员所熟知。
本发明的方法提供至少约0.5g/L/hr的平均脂质生产速度,优选至少约0.7g/L/hr,更优选至少约0.9g/L/hr,最优选1.0g/L/hr。而且,本发明方法生产的脂质包含约15%以上的多不饱和脂,优选约20%以上,更优选约25%以上,还优选约30%以上,最优选约35%以上。可从干微生物或发酵培养基中的微生物回收脂质。通常,本发明方法中由微生物产生的脂质至少约20%是ω-3和/或ω-6多不饱和脂肪酸,优选至少约30%的脂质是ω-3和/或ω-6多不饱和脂肪酸,更优选至少约40%的脂质是ω-3和/或ω-6多不饱和脂肪酸,最优选至少约50%的脂质是ω-3和/或ω-6多不饱和脂肪酸。或者,本发明方法的ω-3脂肪酸(例如DHA)平均产生速度为至少约0.2gω-3脂肪酸(例如DHA)/L/hr,优选至少约0.3gω-3脂肪酸(例如DHA)/L/hr,更优选至少约0.4gω-3脂肪酸(例如DHA)/L/hr,最优选至少约0.5gω-3脂肪酸(例如DHA)/L/hr。或者,本发明方法的ω-6脂肪酸(例如DPAn-6)平均产生速度为至少约0.07gω-6脂肪酸(例如DPAn-6)/L/hr,优选至少约0.1gω-6脂肪酸(例如DPAn-6)/L/hr,更优选至少约0.13gω-6脂肪酸(例如DPAn-6)/L/hr,最优选至少约0.17gω-6脂肪酸(例如DPAn-6)/L/hr。还备选地,至少约25%的脂质是DHA(基于总脂肪酸甲基酯),优选至少约30%,更优选至少约35%,最优选至少约40%。
从中提取了脂质的微生物,在提取脂质之后所剩的生物量或其混合物可直接用作食品成分,例如饮料,调味汁,乳制品(例如乳,酸乳酪,干酪和冰淇淋)和烤制的食品的成分;营养添加剂(胶囊或片剂形式中);其肉或产品为人所消费的任何动物的饲料或饲料添加剂;食品添加剂,包括幼儿食品和婴儿乳粉;药品(在直接或附属的治疗应用中)。术语“动物”指属于动物界的任何生物,包括但不限于可得到家禽肉,海产食品,牛肉,猪肉或羊肉的任何动物。海产食品得自但不限于鱼,虾,甲壳类动物。术语“产品”包括除了这类动物的肉以外的任何产品,包括但不限于蛋,乳或其它产品。当饲喂这样的动物时,多不饱和脂能被引入到这些动物的肉,乳,蛋或其它产品中以提高它们中这些脂质的含量。
在了解了下面的实施例后,本发明的其它目的,优势和新的特点对本领域一般技术人员是显而易见的,这些实施例并不构成对本发明的限制。
实施例
在较宽范围的各种发酵条件下,这些实施例所用的Schizochytrium菌株产生两种主要的多烯酸,DHAn-3和DPAn-6,比例一般为3:1,还有少量的其它多烯酸,如EPA和C20:3。因此,当下列实施例仅列出了DHA的量时,可以采用上述的比例容易地计算出产生的DPA(n-6)的量。
实施例1
本实施例举例说明发酵培养基中氧含量对脂质生产力的影响。
检测了在各种溶氧水平下Schizochytrium菌株ATCC20888的发酵结果。该结果见图1,其中RCS是蔗糖的残余浓度,DCW是细胞干重。
实施例2
本实施例也举例说明发酵培养基中低溶氧水平对最终生物量产物中DHA含量(%干重)的影响。
在250ml的Erlenmeyer烧瓶中进行“按比例缩小(scale-down)”实验以模拟在大规模发酵罐中培养Schizochytrium细胞时低氧量对DHA含量的影响。在O4-4培养基中培养Schizochytrium菌株(ATCC20888)。该培养基由每升去离子水中溶解的如下物质组成:Na2SO412.61g;MgSO4·7H2O1.2g;KCl0.25g;CaCl20.05g;谷氨酸单钠7.0g;葡萄糖10g;KH2PO40.5g;NaHCO30.1g;酵母提取物0.1g;混合维生素1.0mL;PII金属1.00mL。PII金属混合物含有(每升):6.0gNa2EDTA,0.29gFeCl3·6H2O,6.84gH3BO3,0.86gMnCl2·4H2O,0.06gZnCl2,0.026gCoCl2·6H2O,0.052gNiSO4·H2O,0.002gCuSO4·H2O,和0.005gNa2MoO4·2H2O。混合维生素含有(每升):100mg硫胺素,0.5mg生物素,0.5mg维生素B12。调培养液的pH为7.0,然后过滤除菌。
此按比例缩小实验的构想是,在有不同体积培养液的摇瓶中培养细胞–摇瓶中几乎装满(例如在250mL摇瓶中装200mL),在摇床上不能充分混合,这样在细胞生长时就会产生低溶氧条件。为此,在本实验中建立4种处理,每一种都双份:(1)250mL摇瓶中装50mL培养基;(2)250mL摇瓶中装100mL培养基;(3)250mL摇瓶中装150mL培养基;(4)250mL摇瓶中装200mL培养基。这8个摇瓶的每一个都接种已经培养了48小时的Schizochytrium细胞,所述细胞已经在O4-4培养基中按照第1种处理所述条件,在28℃以220rpm在摇床上培养。将所有这8个摇瓶置于培育箱(28℃)中的摇床(220rpm)上,避光培养48小时。在实验结束时,用YSI溶氧计检测每个摇瓶中的溶氧(DO)水平,也测定培养基中的pH,以及细胞干重和脂肪酸含量。实验结果列于表1中。
表1:观察低溶氧浓度对Schizochytrium菌株的长链高度不饱和脂肪酸含量(DHA%干重)的影响的按比例缩小实验结果。
该结果显示在低溶氧水平下培养的细胞的脂质含量(以%FAME计)和DHA含量(%干重)较高,溶氧水平越低,脂质和DHA量越高。这是令人意外的,因为一般认为氧是形成不饱和(双)键所必需的。令人惊异的是在低溶氧水平下形成如此多的DHA,因为DHA是最不饱和的脂肪酸之一。尽管随着溶氧水平降低,生物量产量降低,DHA含量却提高了。因此,较为有利地是使生长阶段的溶氧水平较高以形成最多的生物量,然后降低溶氧水平以产生最多的长链脂肪酸。
实施例3
本实施例阐明本发明方法的再现性。
采用正常工作体积为1200加仑的发酵罐生产微生物。浓缩所得发酵液,采用转鼓式干燥机干燥微生物。提取所得微生物等分试样的脂质,并纯化产生精炼的,脱色的,除臭的油。在分析脂质前加入约3000ppmd-l-α-生育酚醋酸酯作为营养添加剂。
对Schizochytrium菌株ATCC20888进行九次发酵,所得结果表示于表2中。在前24小时溶氧水平为约8%,其后为约4%。
表2:Schizochytrium菌株生产DHA的补料分批发醇结果
批次 | 菌龄(Hrs) | 产量1(g/L) | DHA2(%) | FAME3(%) | 生产力4 |
1 | 100.3 | 160.7 | 17.8 | 49.5 | 0.285 |
2 | 99.8 | 172.4 | 19.4 | 51.3 | 0.335 |
3 | 84.7 | 148.7 | 14.4 | 41.4 | 0.253 |
4 | 90.2 | 169.5 | 19.7 | 53.9 | 0.370 |
5 | 99.0 | 164.1 | 12.5 | 38.9 | 0.207 |
6 | 113.0 | 187.1 | 19.7 | 47.2 | 0.326 |
7 | 97.0 | 153.5 | 13.7 | 41.0 | 0.217 |
8 | 92.8 | 174.8 | 16.4 | 48.6 | 0.309 |
Aver.5 | 97.1 | 166.4 | 16.7 | 46.5 | 0.288 |
Std.6 | 8.4 | 12.3 | 2.9 | 5.4 | 0.058 |
CV7(%) | 8.7 | 7.4 | 17.3 | 11.7 | 20.2 |
1.生物量密度实际产量,
2.以%细胞干重计的DHA含量,
3.以%细胞干重计的总脂肪酸含量(以甲基酯形式测定),
4.(gDHA)/L/Hr,
5.平均值,
6.标准差
7.变异系数。变异系数值低于5%指示具有极佳再现性的方法,在5%到10%之间指示具有良好再现性的方法,在10%到20%之间指示具有合理再现性的方法。
补加玉米糖浆使发酵罐中的体积达到约1200加仑,此时停止加入玉米糖浆。在残余糖浓度低于5g/L时停止发酵过程。从接种到终点的典型菌龄为约100小时。
发酵液,即发酵培养基用水稀释至接近2:1的比例以减少终产品中灰分含量并帮助改进离心步骤时的相分离。将浓缩的细胞加热到160。F(约71℃),在BlawKnow双-转鼓式干燥机(42”×36”)上干燥。但是优选微生物不经离心而直接在转鼓式干燥机上干燥。
从表2中每一实体的等分试样提取的脂质的分析结果总结在表3中。
表3:表2所列补料分批发酵中产生的微生物生物量的分析。
批次 | DHA相对于FAME的% | 以重量计算的总脂质% |
1 | 36.0 | 72.3 |
2 | 37.8 | 70.3 |
3 | 34.8 | 61.5 |
4 | 36.5 | 74.8 |
5 | 32.1 | 52.8 |
6 | 41.7 | 67.7 |
7 | 33.4 | 49.9 |
8 | 33.7 | 61.4 |
平均值 | 35.8 | 63.8 |
Std.Deviation3 | 3.0 | 9.1 |
CV4(%) | 8.5 | 14.2 |
1.参见表2。
2.参见上述讨论。
3.标准差
4.变异系数。变异系数值低于5%指示具有极佳再现性的方法,在5%到10%之间指示具有良好再现性的方法,在10%到20%之间指示具有合理再现性的方法。
除非特别指出,在本文实施例部分所用的发酵培养基包括如下成分,其中第一个数字指出正常的目标浓度,括号中的数字表示可接受的范围:硫酸钠12g/L(11-13);KCl0.5g/L(0.45-0.55);MgSO4·7H2O2g/L(1.8-2.2);HodagK-60消泡剂0.35g/L(0.3-0.4);K2SO40.65g/L(0.60-0.70);KH2PO41g/L(0.9-1.1);(NH4)2SO41g/L(0.95-1.1);CaCl2·2H2O0.17g/L(0.15-0.19);95DE玉米糖浆(以固体计)4.5g/L(2-10);MnCl2·4H2O3mg/L(2.7-3.3);ZnSO4·7H2O3mg/L(2.7-3.3);CoCl2·6H2O0.04mg/L(0.035-0.045);Na2MoO4·2H2O0.04mg/L(0-0.045);CuSO4·5H2O2mg/L(1.8-2.2);NiSO4·6H2O2mg/L(1.8-2.2);FeSO4·7H2O10mg/L(9-11);硫胺素9.5mg/L(4-15);维生素B120.15mg/L(0.05-0.25)和泛酸钙3.2mg/L(1.3-5.1)。此外,28%NH4OH溶液用作氮源。
干微生物的灰分量约为6%重量份。
实施例4
本实施例用于阐明14000加仑规模的发酵培养基中溶氧水平降低对微生物生产力的影响。
采用实施例3所述方法,利用Schizochytrium野生型菌株进行标称体积为14000加仑的发酵,所述菌株是用上述美国专利5340594和5340742公开的分离方法得到的。在前24小时发酵培养基中的溶氧水平为约8%,在第24到40小时约为4%,从第40小时到发酵过程终止约为0.5%。表4显示了发醇过程中此低溶氧水平的结果。
表4:在降低的溶氧浓度下14000加仑规模的Schizochytrium补料分批发酵的结果。
实施例5
本实施例阐明41000加仑规模的发酵培养基中低溶氧水平对微生物生产力的影响。
除了发酵在41000加仑的发醇罐中进行外,采用与实施例4相同的方法。增加培养液体积以在此规模下维持目标化合物的浓度。实验结果显示于表5。
表5:Schizochytrium的41000加仑规模发酵
实施例6
本实施例阐明额外的氮对本发明的发酵过程的影响
采用与实施例4近似的方法进行4组250L规模的补料分批培养实验。进行两组对照实验和两组含有额外的氨(1.15×和1.25×标称量)的实验。实验结果显示于表6中。
表6:额外的氨对Schizochytrium发酵的影响
通常,额外的氮对发酵效能有负面影响,在加入了额外的氨的两批中DHA生产力显著降低。如表6所示,对照批次的最终DHA水平占总细胞干重的18.4%和22.1%,额外供应了氨的批次为9.2%(1.15×氨)和12.6%(1.25×氨)。
实施例7
本实施例显示本发明发酵方法的动力学特征(profile)。
采用与实施例4近似的方法进行1000加仑规模的补料分批培养实验。表7表示了发酵过程的动力学特征。
表7:1000加仑规模的Schizochytrium补料分批发酵的动力学特征
*在48小时的时候分析了两个不同的样品。
**这是洗过的细胞干重(DCW)样品。其它的值是未洗过的样品的。
实施例8
本实施例阐明了碳源的量对生产力的影响。
采用实施例4的方法以不同的碳源的量进行了三批不同发酵实验。结果如表8所示。
表8:不同碳源量对Schizochytrium发酵的影响。
菌龄(hrs) | 产量(g/L) | 碳源量 | 转化效率 | %DHA含量 | %FAME含量 | 生产力(g/L/hr) |
90 | 171 | 51.3% | 33.3% | 22.2 | 61.6 | 0.42 |
94 | 122 | 40.5% | 30.1% | 19.1 | 57.3 | 0.25 |
59 | 73 | 20.0% | 36.5% | 11.9 | 40.8 | 0.15 |
实施例9
本实施例阐明营养限制对碳转化为生物量,脂质并特别是DHA的转化效率的影响。
为了研究营养限制的影响,在2升Applikon发酵罐中对Schizochytrium菌株ATCC20888进行连续培养实验,基本生长培养基(ICM-2)由下列化合物组成(标定浓度):I组成分:Na2SO4(18.54g/L),MgSO4·7H2O(2.0g/L)和KCl(0.572g/L);II组成分(每一个单独制备):葡萄糖(43.81g/L),KH2PO4(1.28g/L),CaCl2·6H2O(0.025g/L)和(NH4)2SO4(6.538g/L);III组成分:Na2EDTA(6.0mg/L),FeCl3·6H2O(0.29mg/L),H3BO3(6.84mg/L),MnCl2·4H2O(0.86mg/L),ZnSO4·7H2O(0.237mg/L),CoCl2·2H2O(0.026mg/L),Na2MoO4·2H2O(0.005mg/L),CuSO4·5H2O(0.002mg/L)和NiSO4·6H2O(0.052mg/L);和IV组成分:盐酸硫胺素(0.2mg/L),维生素B12(0.005mg/L),泛酸钙(0.2mg/L)。加入到发酵罐之前,I和II组高压灭菌,III和IV组过滤除菌。用Schizochytrium接种生长培养基,在30℃,pH5.5,溶氧为20%饱和度的控制条件下生长直到达到最大细胞密度。
通过以足以维持稀释速率为0.06hr-1的流量泵入无菌ICM-2进料培养基到发酵罐并同时移出含Schizochytrium细胞的培养液进行连续模式操作,直到达到稳定状态。为观察营养限制的影响,减少ICM-2进料培养基中的含有特定所需营养的化合物,使该营养成分在含细胞的出口培养液中耗尽,这样由于该特定所需营养的缺乏,细胞生长受到限制。一旦确立每一条件的稳定状态的操作,就测定最终培养液的干生物量,残余葡萄糖,限制性营养浓度,细胞脂质含量和细胞DHA含量。用葡萄糖总耗量除以所得干生物量的总量,计算出葡萄糖转化为生物量的转化效率,以百分比表示。
对列于下表中的每一营养成分重复进行此实验,研究每一营养成分限制生长的效应。最终结果列于下表中。
表9:营养限制对Schizochytrium菌株的生物量产量,转化效率(葡萄糖→生物量),脂质含量和DHA含量的影响。
限制性营养 | 生物量1(g/l) | Yx/s 2 | RCS3(g/l) | 脂含量4(%) | DHA含量5(%) |
葡萄糖 | 18.7 | 46.8 | 0.0 | 19.8 | 7.3 |
氮 | 14.5 | 36.3 | 0.6 | 47.5 | 10.3 |
磷酸盐 | 17.8 | 44.5 | 0.8 | 37.0 | 8.2 |
硫胺素 | 7.5 | 18.8 | 7.7 | 11.1 | 4.0 |
锌 | 16.0 | 40.0 | 1.3 | 27.8 | 7.2 |
铜 | 14.0 | 35.0 | 10.4 | 13.8 | 5.3 |
钴 | 14.5 | 36.3 | 0.0 | 22.2 | 6.9 |
镍 | 17.8 | 44.5 | 0.0 | 21.9 | 8.0 |
铁 | 15.9 | 39.8 | 3.5 | 18.5 | 7.2 |
锰 | 12.5 | 31.3 | 3.4 | 26.1 | 8.0 |
镁 | 13.9 | 34.8 | 5.3 | 18.7 | 6.4 |
钙 | 16.7 | 41.8 | 4.3 | 18.7 | 6.4 |
维生素B12 | 19.6 | 49.0 | 0.0 | 17.5 | 6.3 |
钼 | 18.9 | 47.3 | 0.0 | 19.3 | 7.0 |
泛酸盐 | 19.2 | 48.0 | 0.0 | 20.4 | 6.7 |
钠 | 17.9 | 44.8 | 1.8 | 21.8 | 8.2 |
钾 | 13.0 | 32.5 | 8.8 | 14.1 | 5.3 |
1.干生物量浓度(g/L)
2.产量系数(%产生的生物量/消耗的葡萄糖)
3.培养液中的残余葡萄糖浓度(g/L)
4.干生物量中的脂质含量(g脂质(以FAME计)/g干生物量)
5.干生物量中的DHA含量(gDHA/g干生物量)
表中清楚地显示,氮限制导致DHA在细胞中的积累最多,然后是磷酸盐,钠,镍,锰,葡萄糖(碳源),锌和铁。该信息可用于商业,即将这些营养成分中一种或多种以足以限制细胞生长的速度加入到分批发酵中。在最优选的情况下,将氮以限制性方式加入到分批发酵中,以使细胞中的DHA量达到最高水平。其它营养成分(或其混合物)可以限制性方式加入以最大化生物量或其它有价值产物的产量。其它没有评价的生物学必需成分,如硫,也可用作这种发酵控制策略中的限制性营养。
本发明,在各种实施方案中,包括基本如本文记述的组分,方法,工艺过程,系统和/或装置,它们包括各种实施方案,其进一步组合与集合。本领域技术人员在了解本发明后能理解如何实施和应用本发明。本发明,在各种实施方案中,包括提供没有在此或各实施方案中记述的项的装置和方法,包括那些可能已在以前的装置或方法中采用的项,例如为改进效果,减轻劳动和/或降低实施成本而采用的项。
出于阐述和说明的目的提供本发明的上述讨论。上述内容不打算限制本发明于本文所公开的形式。尽管本发明的说明已经包括一种或多种实施方式和某些变化与修饰的说明,不过其他变化与修饰也在本发明的范围内,例如在理解了目前的公开内容后,可以在本领域的技术与知识范围内作出这些变化和修饰。本发明打算获得包括替代实施方式的权利至这样一种程度,包括与所要求保护的那些可交替、互换和/或等价的结构、功能、范围或步骤,无论本文是否公开这类可交替、互换和/或等价的结构、功能、范围或步骤,并且不打算以公众名义贡献任何可授予专利权的主题。
保藏材料
以下材料保藏于美国典型培养物保藏中心(AmericanTypeCultureCollection,ATCC)。
名称保藏号保藏日
Schizochytriumsp.(裂殖壶菌属菌种)S31ATCC208881988-8-5
Claims (22)
1.一种含高度不饱和脂肪酸的微生物生物量,其中所述生物量通过在包含碳源和限制性营养源的发酵培养基中进行所述微生物的发酵的方法来产生,所述方法包括:
a)提供包含碳源和限制性营养源的发酵培养基;
b)向所述发酵培养基中添加所述微生物;
c)向所述发酵培养基中添加额外量的所述碳源和限制性营养源以将该发酵培养基的生物量密度提高以按细胞干重计至少约100g/L。
d)向所述发酵培养基中添加额外量的所述碳源同时限制添加的限制性营养源的量以诱导所述微生物产生脂质;且
其中所述微生物是破囊壶菌目的微生物,并产生以所述生物量的细胞干重计至少15%的脂质。
2.权利要求1的生物量,其中所述方法进一步包括:
e)从所述微生物中回收至少一些所述脂质。
3.权利要求1的生物量,其中当发酵培养基的生物量密度以细胞干重计为至少150g/L时,所述微生物的发酵产生含有高度不饱和脂肪酸的脂质。
4.权利要求1的生物量,其中所述方法以每小时发酵每升发酵培养基至少0.5克脂质的平均速率产生脂质。
5.权利要求1的生物量,其中所述微生物选自破囊壶菌属(Thraustochytrium),裂殖壶菌属(Schizochytrium)及其混合物。
6.权利要求1的生物量,其中所述方法平均产生每小时发酵每升发酵培养基至少0.2克的二十二碳六烯酸。
7.权利要求1的生物量,其中当所述生物量密度为以细胞干重计至少100g/L时所述微生物产生含有高度不饱和脂肪酸的脂质。
8.权利要求1的生物量,其中所述高度不饱和脂肪酸选自下组:二十二碳六烯酸,二十二碳五烯酸,二十碳五烯酸,花生四烯酸及其混合物。
9.权利要求8的生物量,其中所述高度不饱和脂肪酸为二十碳五烯酸。
10.权利要求1的生物量,其中所述脂质的至少约25%是二十二碳六烯酸。
11.权利要求1的生物量,其中所述方法以至少0.5g/L/hr的平均速率产生脂质且其中所述脂质的至少约25%是二十二碳六烯酸。
12.权利要求1的生物量,其中所述碳源包括碳水化合物。
13.权利要求1的生物量,其中所述限制性营养源包括氮源。
14.权利要求1的生物量,其中所述发酵培养基的pH从约pH5到约pH11。
15.权利要求1的生物量,其中所述发酵培养基的温度为至少20℃。
16.权利要求1的生物量,其中所述微生物在需氧条件下产生高度不饱和脂肪酸。
17.从权利要求1-16中任一项的生物量中提取的油。
18.如权利要求17所述的油,其中所述油是从所述生物质中提取的没有进一步加工的粗制油。
19.一种含有权利要求1-16中任一项的生物质或权利要求17-18中任一项的油的饲料产品。
20.权利要求19的饲料产品,其中所述饲料产品为饲料或饲料添加剂。
21.权利要求20的饲料,其中所述饲料为动物饲料。
22.权利要求20的饲料,其中所述饲料为水产养殖饲料。
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CN106359930A (zh) * | 2016-08-29 | 2017-02-01 | 界首市任寨乡天佑家庭农场 | 一种用于生产epa、dpa含量高的功能性牛肉饲料 |
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CN109022284B (zh) * | 2018-09-03 | 2021-05-21 | 杭州园泰生物科技有限公司 | 提高球等鞭金藻生物量以及dha产量的方法 |
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