TWI715088B - 新穎的破囊壼菌屬微藻菌株及使用該微藻菌株製造多元不飽和脂肪酸的方法 - Google Patents
新穎的破囊壼菌屬微藻菌株及使用該微藻菌株製造多元不飽和脂肪酸的方法 Download PDFInfo
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本揭露係關於一種包含高含量的多元不飽和脂肪酸的破囊壼菌屬菌株,以及使用該破囊壼菌屬菌株製造生物量的方法。依據本揭露之新穎的破囊壼菌屬CJM01微藻,由於生物量中脂質的含量及生物量中不飽和脂肪酸(例如二十二碳六烯酸)的含量高,該微藻本身、藉由微藻的培養及發酵而製造的生物量、該生物量的凝縮物及該生物量的乾燥產物皆非常適合作為飼料組成物。
Description
本揭露係關於一種包含高含量的多元不飽和脂肪酸的破囊壼菌屬菌株、由該菌株產生的生物量、包含該菌株的脂質,以及製造多元不飽和脂肪酸的方法。
二十二碳六烯酸(DHA)係一種多元不飽和脂肪酸,係大腦、眼睛組織及神經系統必需的脂肪酸,且已知在嬰兒的視敏度及運動神經元能力的發展中扮演著重要的角色。據報導,失智症患者腦中DHA的含量顯著減少,且新發現DHA具有各種抗衰老的功能,例如抑制老花眼中的黃斑部退化。此外,據報導,DHA亦可用作魚類的飼料添加劑(韓國專利申請公開號10-2007-0040751)。由於大多數高等動物(包括人類)無法順利合成正常生物功能所需的多元不飽和脂肪酸,因此必須攝取多元不飽和脂肪酸作為必需營養素,且世界衛生組織建議穩定食用至少1g/天的含DHA的多元不飽和脂肪酸。傳統上,DHA多元不飽和
脂肪酸的供應源為佔據海洋生態系統頂層的深海魚類,例如鮪及鮭魚。然而,隨著海洋環境污染加劇,由於深海魚體內汞、重金屬、環境荷爾蒙及放射性物質等污染物的積累,故攝入深海魚類的風險正在增加。因此,作為安全可靠地供應DHA多元不飽和脂肪酸油的新手段,破囊壼菌屬微藻乃具有非常重要的工業價值。
已建議了破囊壼菌屬微藻中各種基因過量表現的方法。由於使用乙醯乳酸合酶作為選擇標識的破囊壼菌屬微藻的基因轉形方法首先係由Martec Corporation導入,因此報導了使用各種抗生素抗性基因作為選擇標識的破囊壼菌屬微藻的轉形技術。具體而言,韓國專利申請公開號2015-0084148揭露“一種用於提高微藻生物量及脂質的生產率的重組載體及其用途”。
然而,迄今從破囊壼菌屬微藻開發的基因轉形技術係一種染色體整合方法,其中共同導入的基因插入染色體DNA中,並具有插入基因穩定維持的優點,惟與使用具有自我複製能力的中節質體或附加型質體的基因表現方法相比,基因套數及表現調控有限。
據此,本案發明者已發展出藉由使破囊壼菌屬KC01微藻突變以提高二十二碳六烯酸的含量與生產率之微藻,且已建立了包含含二十二碳六烯酸的脂質的生物量,以及藉由培養該等微藻而製造生物油的方法。依據該發展及建立從而完成本揭露。
本揭露之一目的為提供一種破囊壼菌屬CJM01微藻(國內寄存號:BCRC930212),與野生微藻相比,藉由該微藻產生的二十二碳六烯酸(DHA)的生產量增加且胺基酸的生產量減少。
本揭露之另一目的為提供一種製造生物量的方法,係包括下述步驟:培養破囊壼菌屬CJM01微藻;及從該微藻、其培養產物、其乾燥產物、或其粉狀產物中回收含二十二碳六烯酸(DHA)的生物量。
本揭露之又另一目的為提供一種製造生物油的方法,係包括下述步驟:培養破囊壼菌屬CJM01微藻;及從該微藻、其培養產物、其乾燥產物、或其粉狀產物中回收含二十二碳六烯酸(DHA)的脂質。
依據本揭露之新穎的破囊壼菌屬CJM01微藻,由於胺基酸的生產量顯著地減少,且生物量中的脂肪含量及不飽和脂肪酸(例如二十二碳六烯酸)的含量高,該微藻本身、藉由微藻的培養及發酵而製造的生物量、該生物量的凝縮物及該生物量的乾燥產物皆非常適合作為飼料組成物。
第1圖係顯示藉由光學顯微鏡觀察破囊壼菌屬KC01菌株的照片。
第2圖係顯示破囊壼菌屬KC01菌株、破囊壼菌屬菌株、橙黃壺菌(Aurantiochytrium)屬菌株及裂殖壺菌(Schizochytrium)屬菌株之間的系統樹。
在下文中,將詳細說明本揭露。
另一方面,本文揭露的具體實施例的特定結構與功能描述僅用於其他具體實施例的說明性目的。在不悖離本揭露的精神與顯著特徵的情況下,本揭露可以許多不同的形式體現。因此,本揭露的實施方式僅出於說明性目的而揭露者,且不應將其解釋為限制本揭露。
為了完成上述目的,本揭露之一態樣為提供一種破囊壼菌屬CJM01微藻,與野生微藻相比,藉由該微藻產生的二十二碳六烯酸(DHA)的生產量增加且胺基酸的生產量減少。
本文使用之“破囊壼菌屬”的術語係意指有機異營的微藻,係作為含有各種多元不飽和脂肪酸(包括高濃度的二十二碳六烯酸(DHA))之三酸甘油酯的供應源而扮演著重要的角色。再者,該“微藻”係意指只能通過顯微鏡才能看見的生物,因肉眼無法看到且在水中自由漂浮,故亦稱為浮游植物。
本文中使用,例如用伽瑪射線照射破囊壼菌屬野生KC01菌株以產生突變菌株,從該突變菌株中選擇具有提高含多元不飽和酸之油的生產率的菌株,且此等菌株係命名為破囊壼菌屬CJM01菌株,於2018年5月30日寄存於Korean Collection for Type Cultures(KCTC)(即,一所布達佩斯條約下的國際寄存機構),並獲得國內寄存號BCRC930212。
再者,本揭露之破囊壼菌屬CJM01微藻可具有SEQ ID NO.1之18s rRNA,惟本揭露並非限於此。
本文使用之“二十二碳六烯酸(DHA)”的術語係由式C22H32O2所示之多元不飽和脂肪酸之一者,且係從鮪魚或沙丁魚等鰺魚中大量萃取的物質。再者,二十二碳六烯酸(DHA)與二十碳五烯酸(EPA)及α-次亞麻油酸(ALA)均屬於
ω-3脂肪酸。
本揭露之破囊壼菌屬CJM01微藻,相較於作為親代菌株的破囊壼菌屬KC01菌株,可包括高含量的二十二碳六烯酸(DHA)。具體而言,基於包括於該微藻的脂肪酸的總重量,該CJM01微藻可包括含量為30重量%至65重量%、30重量%至60重量%、40重量%至65重量%或40重量%至60重量%的二十二碳六烯酸(DHA),惟本揭露並非限於此。
再者,本揭露之破囊壼菌屬CJM01微藻,相較於作為親代菌株的破囊壼菌屬KC01菌株,可具有提高的二十二碳六烯酸(DHA)的生產率。二十二碳六烯酸(DHA)的生產率可藉由1小時內所產生的二十二碳六烯酸(DHA)的濃度(g/L)而測量。本揭露之微藻可具有0.4至0.8(g/l/小時)、0.4至0.7(g/l/小時)、0.5至0.8(g/l/小時)或0.5至0.7(g/l/小時)之二十二碳六烯酸(DHA)的生產率,惟本揭露並非限於此。
另一方面,在本揭露之破囊壼菌屬CJM01微藻中,相較於作為親代菌株的破囊壼菌屬KC01菌株,胺基酸的生產量可減少。具體而言,本揭露之破囊壼菌屬CJM01微藻或其培養液可不包括選自由天冬胺酸、絲胺酸、麩胺酸、甘胺酸、丙胺酸、纈胺酸、甲硫胺酸、異白胺酸、白胺酸、酪胺酸、苯丙胺酸、離胺酸及精胺酸所組之群組的至少一個胺基酸。例如從實施例2可知,可能無法從本揭露之破囊壼菌屬CJM01微藻的培養液中檢測出天冬胺酸、絲胺酸、麩胺酸、甘胺酸、丙胺酸、纈胺酸、甲硫胺酸、異白胺酸、白胺酸、酪胺酸、苯丙胺酸、離胺酸及精胺酸。
例如,本揭露之破囊壼菌屬CJM01微藻之胺基酸總產量,相較於作為親代菌株的破囊壼菌屬KC01菌株,可減少90%或更多、95%或更多、97%
或更多,或者99%或更多。此乃表明與KC01親代菌株相比,該CJM01菌株係更有效地用於二十二碳六烯酸生物合成的途徑。具體而言,由於本揭露之破囊壼菌屬CJM01微藻很少產生胺基酸,該菌屬培養液僅可包括含量為0.1至20mg/L、0.1至15mg/L、0.1至10mg/L、0.1至7mg/L或0.1至5mg/L的胺基酸。
本揭露之另一態樣為提供一種製造生物量的方法,係包括:培養破囊壼菌屬CJM01微藻;及從該微藻、其培養產物、其乾燥產物、或其粉狀產物中回收含二十二碳六烯酸(DHA)的生物量。再者,該生物量可以乾燥真菌體的形式製成,惟本揭露並非限於此。
本揭露提供一種藉由該方法製造的生物量。該生物量基於其總重量可包括含量為15至40重量%、20至35重量%或25至30重量%的二十二碳六烯酸(DHA),惟本揭露並非限於此。
本揭露之又另一態樣為提供一種製造生物油的方法,係包括:培養破囊壼菌屬CJM01微藻;及從該微藻、其培養產物、其乾燥產物、或其粉狀產物中回收含二十二碳六烯酸(DHA)的脂質。
本揭露提供一種藉由該方法製造的生物油。該生物油基於脂肪酸的總重量,可包括含量為30至65重量%、30至60重量%、40至65重量%或40至60重量%的二十二碳六烯酸(DHA)。
具體而言,依據本揭露之製造生物油的方法可包括下述步驟:培養該破囊壼菌屬CJM01微藻;從該微藻、其培養產物、其乾燥產物、或其粉狀產物中製造含二十二碳六烯酸(DHA)的生物量;及從該產生的生物量回收含二十二碳六烯酸(DHA)的脂質。惟本揭露並非限定於此。
該“破囊壼菌屬”及“二十二碳六烯酸”係如上所述。
本文使用之“生物油”係藉由生物學、熱化學或生理化學萃取程序從生物量而得者。依據本揭露而製造的生物油可包括多元不飽和脂肪酸,具體而言,係二十二碳六烯酸,惟本揭露並非限於此。
此外,該“生物量”係意指可用作化學能的生物,例如植物、動物及微生物,亦即,生物能源。此外,該生物量在生態學上亦指在單位時間與空間內存在的特定生物的重量或能量。再者,儘管生物量包括由細胞分泌的化合物,其亦可包括細胞外材料以及細胞及/或細胞內內容物。本文使用之生物量可為破囊壼菌屬CJM01微藻本身、其培養產物、其乾燥產物、其粉狀產物、藉由培養或發酵該微藻而產生的產物,或者可為該生物量的凝縮物或該生物量的乾燥產物。惟該生物量並非限定於此。
本文使用之該破囊壼菌屬CJM01微藻的培養產物係意指藉由培養該微藻而得的產物,且具體而言,可為包含該微藻的培養液或不包含該微藻的培養液,惟本揭露並非限於此。本文使用之該破囊壼菌屬CJM01微藻的培養產物係意指藉由從該微藻去除水分而得的產物,且具體而言,可以乾燥真菌體的形式製成,惟本揭露並非限於此。本文使用之該破囊壼菌屬CJM01微藻的粉狀產物統稱地意指藉由粉化該微藻而得的產物,且可以上澄液或團塊的形式製成,惟本揭露並非限於此。
該破囊壼菌屬CJM01微藻本身、其培養產物、其乾燥產物或其粉狀產物包括二十二碳六烯酸,且可用於製造生物量或生物油。
本文使用之“培養”的術語係意指該微藻係在適度控制的環境條件下生長。依據本揭露之培養程序可因應適當的培養基及培養條件下進行。發明所屬技術領域中具有通常知識者可依據所選擇的微藻輕易地調整此培養程序。
具體而言,依據本揭露之破囊壼菌屬CJM01微藻的培養可在異營條件下進行,惟本揭露並非限於此。
本文使用之“異營營養(heterotrophic nutrition)”係依賴於從體外能量(營養)來源獲得的有機物質的營養形式,且係對應於獨立營養的術語。依據本揭露之破囊壼菌屬CJM01微藻可藉由在異營條件下最佳化碳源或氮源的培養基的組成以改善二十二碳六烯酸的含量及生產率。再者,本文使用之“異營營養”的術語可與“黑暗培養(dark culture)”互換使用。
此外,該培養微藻之步驟並無特別限定,且可藉由已知的批式培養方法、已知的連續式培養方法、饋料批式培養方法等來進行。用於培養本揭露之微藻的培養基及其他培養條件可無限制地使用,只要此等通常可用於培養微藻者即可。具體而言,本揭露之微藻可在含有碳源、氮源、磷源、無機化合物、胺基酸及/或維生素的一般培養基中培養,同時在有氧狀態下調整溫度、pH等。
具體而言,可藉由鹼性化合物(例如氫氧化鈉、氫氧化鉀或氨)或酸性化合物(例如磷酸或硫酸)調整最適pH(例如pH 5至9,具體而言pH 6至8,且更具體而言pH 6.8),惟本揭露並非限於此。
再者,可將氧或含氧氣體注入培養物中以維持培養物的有氧狀態,或者可將氮氣、氫氣或二氧化碳氣體注入培養物中而不注入氧氣或含氧氣體,以維持培養物的厭氧或非有氧狀態,惟本揭露並非限於此。
再者,該培養溫度可保持在20℃至45℃,具體而言,25℃至40℃,且該培養可進行約10至160小時,惟本揭露並非限於此。此外,可藉由使用例如脂肪酸聚乙二醇酯的消泡劑來抑制氣泡的形成,惟本揭露並非限於此。
依據本揭露之破囊壼菌屬CJM01微藻的培養可藉由使用含有碳
源及氮源的培養基來進行。
本文使用之“培養基”的術語係意指用於培養本揭露之微藻的培養基及/或培養該微藻後而得的產物。該培養基可具有兩種形式,即包含該微藻的形式,以及通過離心、過濾等從包含該微藻的培養液去除微藻而得的形式。
再者,在本揭露所使用的培養基中,作為碳源、糖及醣(例如葡萄糖、蔗糖、乳糖、果糖、半乳糖、甘露糖、麥芽糖、阿拉伯糖、木糖、糖蜜、澱粉及纖維素),脂肪與油(豆油、葵花籽油、花生油及椰子油),脂肪酸(例如棕櫚酸、硬脂酸及亞麻油酸),醇(例如甘油及乙醇)及有機酸(例如乙酸)可單獨或組合使用。具體而言,該碳源可選自由葡萄糖、果糖、麥芽糖、半乳糖、甘露糖、蔗糖、阿拉伯糖、木糖及甘油所組成之群組的至少一者,惟只要可用於培養微藻則無特別限定。再者,在本揭露所使用的培養基中,作為該碳源可使用具有濃度為10至50g/L、10至40g/L、20至50g/L、20至40g/L或25至35g/L的葡萄糖,惟本揭露並非限於此。
用於本揭露之培養基的氮源可分類成有機氮源及無機氮源,惟此等有機氮源及無機氮源可單獨或組合使用。具體而言,該氮源可為選自由酵母萃取物、牛肉萃取物、蛋白腖及胰化蛋白所組成之群組的有機氮源,或者選自由醋酸銨、硝酸銨、氯化銨、硫酸銨、硝酸鈉、尿素及麩胺酸單鈉(MSG)所組成之群組的無機氮源。
再者,在本揭露所使用的培養基中,作為氮源之實例可包括酵母萃取物、硫酸銨、硝酸鈉及MSG,惟只要可用於培養微藻則無限於此。
具體而言,該酵母萃取物可以0.1至10g/L、0.5至10g/L、0.5至7g/L、0.5至5g/L、0.5至3g/L、0.5至2g/L或0.5至1.5g/L的濃度包括在培養
基中,該硫酸銨可以1至5g/L、1至4g/L、2至5g/L或2至4g/L的濃度包括在培養基中,該硝酸鈉可以0.1至10g/L、0.5至9g/L、1至9g/L、2至9g/L、3至9g/L、5至9g/L或7至9g/L的濃度包括在培養基中,以及該MSG可以0.1至2g/L、0.1至1.5g/L、0.5至2g/L或0.5至1.5g/L的濃度包括在培養基中。惟本揭露並非限定於此。
為了本揭露之目的,由於CJM01菌株的特徵在於不具有氨抑制且可在寬廣鹽濃度下生長,因此考慮到此等特性可適當地調整碳源及氮源。
在本揭露所使用的培養基中,作為磷源,磷酸二氫鉀、磷酸氫二鉀及與其對應的含鈉鹽可單獨或組合使用,惟本揭露並非限於此。該培養基可包括其他金屬鹽(例如硫酸鎂及硫酸鐵)、胺基酸及必需的促生長材料例如維生素。
在從培養步驟中培養的微藻中回收生物量之步驟中,可藉由使用發明所屬領域中已知的合適方法收集、其培養產物、乾燥產物、其粉狀產物或所需的生物量。
在回收於培養步驟中所產生的二十二碳六烯酸之步驟中,可藉由使用發明所屬領域中已知的合適方法從該微藻本身或其培養產物中收集所需的二十二碳六烯酸。例如,可從藉由發明所屬領域中已知的合適方法培養的微藻、其培養產物、其乾燥產物或其粉狀產物,且在這種情況下可使用離心、過濾、陰離子交換層析法、結晶作用、HPLC等回收所需的生物量或所需的二十二碳六烯酸。回收該生物量或二十二碳六烯酸的步驟可更包括分離步驟及/或純化步驟。
例如,脂質及脂質衍生物例如脂肪醛、脂肪醇及烴(例如烷類)可藉由疏水性溶劑例如己烷萃取(Frenz et al.1989,Enzyme Microb.Technol.,11:717)。脂質及脂質衍生物亦可藉由使用液化萃取(Sawayama et al.1999,
Biomass and Bioenergy 17:33-39和Inoue et al.1993,Biomass Bioenergy 6(4):269-274);油液化(Minowa et al.1995,Fuel 74(12):1735-1738);以及超臨界二氧化碳萃取(Mendes et al.2003,Inorganica Chimica Acta 356:328-334)。再者,已知的微藻脂質回收方案揭露了一種方法,係包括步驟i)使用離心收集細胞,使用蒸餾水洗滌收集的細胞,然後冷凍乾燥洗過的細胞,以獲得細胞粉末;以及步驟ii)將獲得的細胞粉末在研鉢中粉碎,然後使用正己烷萃取脂質[Miao and Wu,Biosource Technology(2006)97:841-846]。
本揭露之又另一態樣為提供包含破囊壼菌屬CJM01微藻、其培養產物、其乾燥產物或其粉狀產物的組成物。該組成物可包括使用該微藻製造的生物量或生物油。
該破囊壼菌屬CJM01微藻、其培養產物、其乾燥產物及其粉狀產物係如上所述。使用該微藻製造的生物量或生物油亦如上所述。為了製備一種包含高含量二十二碳六烯酸的組成物,可使用本揭露的微藻。該組成物可以溶液、粉末或懸浮液的形式製成,惟本揭露並非限於此。更具體而言,可提供一種食物組成物、飼料組成物或飼料添加物,係包括破囊壼菌屬CJM01微藻、其培養產物、其乾燥產物或其粉狀產物。
本文使用之“飼料”的術語係意指用於進食、攝取與消化的動物食物,或指任何合適的天然或人工飲食,一餐或一餐的成分。依據本揭露之飼料,其包括用於預防或治療作為活性成分之代謝疾病的組成物,可製成本發明領域中習知的各種飼料,且其實例可包括濃縮飼料、粗飼料及/或特殊飼料。
本文使用之“飼料添加物”的術語係意指為了各種效果例如營養補充、預防重量損失、改善飼料中纖維素的消化利用、改善油質、預防生殖障礙、
提高受胎率及預防夏季時的高溫脅迫,而添加到飼料中的材料。本揭露之飼料添加物對應於飼料管理法下的補充飼料,且可更包括礦物質製劑,例如碳酸氫鈉、膨土、氧化鎂或複合礦物質;為微量礦物質的礦物質製劑,例如鋅、銅、鈷或硒;維生素製劑,例如胡蘿蔔素、維生素E、維生素A、維生素D、維生素E、菸酸或複合維生素B;保護性胺基酸製劑,例如甲硫胺酸或離胺酸;保護性脂肪酸製劑,例如脂肪酸鈣鹽;活細菌製劑,例如益生菌(乳酸菌)、酵母培養或黴菌發酵產物;以及酵母製劑。
本文使用之“食物組成物”的術語包括各類食品,例如功能性食品、營養補充劑、保健食品及食品添加劑。上述食物組成物可依據本發明領域中習知的方法以各種形式製成。
本揭露提供一種製造包含生物量或生物油之組成物的方法。該生物量、生物油及組成物係如上所述。
在上述製造生物油的方法中,包含高含量二十二碳六烯酸的生物油可藉由下述步驟製得:在異營條件下,於包含特定組成之碳源與特定成分之氮源的培養基中,培養具有高生產率之二十二碳六烯酸的破囊壼菌屬CJM01微藻。
在下文中,將參考實施例更詳細地說明本揭露。惟此等實施例僅係用於說明本揭露,且本揭露之範圍並非限於此等實施例。
本揭露之CJM01微藻係屬於破囊壺菌科的微藻,並具有製造包含高含量二十二碳六烯酸之多元不飽和脂肪酸的能力。本揭露之CJM01微藻具有SEQ ID NO.1所示的18S rRNA基因的DNA核苷酸序列,且在異營條件下具有高含量的生物量,而非於光培養的生長條件下。
在以下實施例中,將更詳細地說明實驗方法。
為了分離破囊壺菌科的微藻菌株,係進行下述實驗。
具體而言,從韓國慶尚南道的巨濟與統營地區的20個沿海地區採集海水、土壤及葉子環境樣本。然後,將樣本儲存在10℃的冰箱中,並運送到實驗室。該樣本在2至3天內用於細菌分離工作。將這些樣本直接塗抹在瓊脂培養基上,然後使用液體松粉施用方法分離破囊壺菌菌株。將各自包含藉由顯微鏡觀察到的微藻樣形式的樣本塗抹在用於微生物分離的IYP培養基(1g/L的酵母萃取物、1g/L的蛋白腖、2g/L的MgSO4‧7H2O、20g/L的海鹽、5.0mg/L的H3BO3、3.0mg/L的MnCl2、0.2mg/L的CuSO4、0.05mg/L的NaMo4‧2H2O、0.05mg/L的CoSO4、0.7mg/L的ZnSO4‧7H2O及15g/L的瓊脂)上以獲得菌落。將獲得的菌落進行數次的繼代培養以進行純化與分離,然後僅選擇並分離形成作為破囊壺菌屬微藻典型特徵的游動孢子囊的菌株。使用鹽度為1.5%的無菌海水稀釋與洗滌無法通過顯微鏡觀察確認的環境樣本,然後使用松粉噴霧這些樣本並培養。將藉由在與每個收集環境相似的溫度與pH條件下培養獲得的微生物菌落塗抹在用於微生物分離的IYP培養基上,並進行繼代培養以進行純化與分離。在這種情況下,在調整其濃度的同時引入抗生素什錦混合溶液(0至500mg/L的硫酸鏈黴素、0至500mg/L的胺苄青黴素、0至500mg/L的青黴素G及0至500mg/L的硫酸康黴素),從而調控其他微生物的生長與污染。
使用IGGYP培養基(甘油10g/L、葡萄糖10g/L、酵母萃取物1g/L、蛋白腖1g/L、MgSO4‧7H2O 2g/L、曬製鹽20g/L、H3BO3 5.0mg/L、MnCl2 3.0mg/L、CuSO4 0.2mg/L、NaMo4.2H2O 0.05mg/L、CoSO4 0.05mg/L、ZnSO4‧
7H2O 0.7mg/L及混合維生素溶液10ml/L)將分離的菌落於500mL燒瓶中在15℃至28℃的溫度及50至200rpm的轉速下培養約7天。最終選擇了一種生長率快且培養條件不複雜的微藻,並回收了真菌體。使用光學顯微鏡觀察所選擇的菌株的形式(如第1圖所示)。使用磷酸鹽緩衝溶液(PBS,pH7.5)洗滌所選擇的菌體,然後在55℃的烘箱中乾燥16小時,以獲得乾燥菌體。
分析18s rRNA基因序列的最終選擇的微藻的菌株的分子鑑定。將DNA從所選擇的菌株的純分離菌落中分離,然後使用用於基因擴增的引子在18s rRNA區域中藉由聚合酶鏈鎖反應(PCR)擴增18s rRNA。用於基因擴增的引子係總結於下表1中。
在這種情況下,於95℃變性5分鐘後,在下列條件下進行PCR總共25個循環:在95℃變性30秒;在52℃黏合30秒;及在72℃聚合1分鐘30秒。此後,聚合反應在72℃進行7分鐘。
作為使用擴增的反應溶液分析核苷酸序列的結果,係獲得大小約1792bp的核苷酸序列1(SEQ ID NO.1)。作為NCBIBLAST搜索的結果,係發現核苷酸序列1與先前報導的破囊壼菌屬菌株具有約99%的同源性,且與橙黃壺菌屬及裂殖壺菌屬的菌株具有約84%的同源性。
因此,表達菌株之間的系統樹,並將其結果顯示於第2圖。相應
的菌株被鑑定為破囊壺菌科的破囊壼菌屬微藻,因此命名為破囊壼菌屬KC01。
實施例2:突變體微藻的發展
實施例2-1:藉由人工突變方法選擇突變體微藻
在本揭露中,藉由實施例1中分離的破囊壼菌屬KC01菌株的伽瑪射線照射突變,進行如下實驗以分離具有提高二十二碳六烯酸(DHA)生產率的菌株。
具體而言,該破囊壼菌屬KC01菌株係培養在GYEP培養基(葡萄糖2%、蛋白腖1%、酵母萃取物0.5%及曬製鹽2%)24小時以活化菌株。將該活化菌株接種到經在121℃滅菌15分鐘並培養14小時的繼代培養基(葡萄糖5%、蛋白腖1%,、酵母萃取物0.5%及曬製鹽2%)中,然後回收真菌體。將該回收的菌體懸浮於50mL的PBS緩衝液中,以1至5kGy的劑量用伽瑪射線照射1小時,然後使用500mL的燒瓶在50mL的基礎培養基(葡萄糖5%、蛋白腖1%、酵母萃取物0.5%及曬製鹽2%)中以28℃及120rpm的轉速培養2天。然後,當死亡率為99%時適當稀釋懸浮的菌體,並在GYEP平板培養基(葡萄糖2%、蛋白腖1%、酵母萃取物0.5%及曬製鹽2%、瓊脂2%、pH 7.0)中繼代培養兩次。
首先,選擇其顏色變為白色的菌落,以選擇預測除了含多元不飽和脂肪酸的油之外還產生具有減少硫酸化色素體的菌株。將藉由上述方法而得的突變菌株命名為破囊壼菌屬CJM01菌株,並於2018年5月30日寄存於Korean Collection for Type Cultures(KCTC)(即,一所布達佩斯條約下的國際存管機構),並獲得國內寄存號BCRC930212。
實施例2-2:新分離的微藻與突變菌株之能力的分析以產生含多元不飽和脂肪酸的油。
選自實施例2-1的CJM01及KC01菌株係如下培養,以比較CJM01菌株產生含多元不飽和脂肪酸的油的能力與KC01菌株產生多元不飽和脂肪酸的油的能力。
具體而言,為了培養依據本揭露之破囊壼菌屬微藻的CJM01及KC01菌株,係將該CJM01及KC01菌株培養在28℃、300rpm、1vvm及pH7.5的鹼性培養基條件下,於MJW01培養基(葡萄糖30g/L、MgSO4‧7H2O 3.0g/L、Na2SO4 10g/L、NaCl 1.0g/L、酵母萃取物9.0g/L、MSG‧1 H2O 1.0g/L、NaNO3 1.0g/L、KH2PO4 0.1g/L、K2HPO4 0.5g/L、CaCl2 0.5g/L及混合維生素溶液10ml/L)中培養4天。藉由離心回收真菌體,使用PBS緩衝液洗滌三次,然後在55℃乾燥12小時以測量菌體的重量。
利用乾燥真菌體之含二十二碳六烯酸的油的含量係如下測量。具體而言,將8.3M鹽酸溶液施加到2g乾燥真菌體上,以在80℃水解微藻菌體的細胞壁,向該乾燥菌體中加入30mL乙醚及20mL石油醚,攪拌30秒,然後將混合物離心分離3。重複該過程三次或更多次。然後,回收分離的溶劑層,放入預先測量過重量的圓形燒瓶中,用氮氣沖洗以除去溶劑,然後將所得產物放入已除去水分的容器中並乾燥。測量乾燥油的重量以計算總油含量。在用0.5N甲醇NaOH與14%三氟硼烷甲醇(BF3)預處理油之後,藉由層析術測量油中DHA的含量。
將藉由上述方法培養的破囊壼菌屬KC01菌株的培養性能,及選自由伽瑪射線照射的CJM01突變菌株的培養性能表示於表2及3中。從表2及表3中發現,生產了具有高功能性ω-3油的DHA。
表2及3中的“生物量”係意指培養液中菌體的濃度,且可與乾細
胞重量(DCW)組合使用。DHA的含量表示為其相對於生物量或總脂肪酸(TFA)的含量。
如以下結果所示,與親代菌株(破囊壼菌屬KC01菌株)相比,發現由CJM01突變菌株產生的DHA有所改善(參見表2及3)。具體而言,與KC01菌株相比,CJM01突變菌株產生的DHA增加約1.3倍。再者,發現CJM01突變菌株的DHA生產率比KC01菌株提高了約1.7倍,這是因為培養時間顯著縮短而獲得的真菌體卻沒有減少。
依據上述結果發現,與作為親代菌株的KC01菌株相比,作為突變菌株的CJM01菌株具有增加的DHA含量及改善的DHA傳導性。
為了評價CJM01菌株的培養特性,測定上述培養液中胺基酸的總含量。
具體而言,從上述各培養液中收集10mL樣本,用蒸餾水稀釋20倍並過濾,然後使用液相層析術分析胺基酸的總含量。分析胺基酸總濃度的結果,在KC01親代菌株的培養液中分別檢測到含量為10mg/L之天冬胺酸、絲胺酸、麩胺酸、甘胺酸、丙胺酸、纈胺酸、甲硫胺酸、異白胺酸、白胺酸、酪胺酸、苯丙胺酸、離胺酸及精胺酸,而在具有改善的DHA含量的CJM01菌株的培養液中則未檢測到大多數的胺基酸。
具體而言,係發現在CJM01突變菌株的情況下,與KC01親代菌
株相比,作為DHA以外副產物的胺基酸總濃度降低了約99%或更多(參見表4)。
因此,發現在CJM01突變菌株的情況下,與KC01親代菌株相比,真菌體的生長處於相同水平,且與真菌體的含量相比,脂質的總含量沒有甚大地降低,故與KC01親代菌株相比,CJM01突變菌株更有效地使用所提供的碳源用於DHA生物合成機制。
為了使用具有降低的胺基酸含量及改善的DHA含量的CJM01菌
株進一步改善DHA的含量及生產率,係從實施例2中選擇菌株,並最佳化培養基條件。
具體而言,基於實施例2-2中使用的MJW01培養基,為了增加培養基中氮源的含量並降低生產成本,係降低作為有機氮源之酵母萃取物的濃度,加入作為無機氮源的(NH4)2SO4,並增加NaNO3的濃度以使MJW01培養基轉化為MJW02培養基(葡萄糖30g/L、MgSO4‧7H2O 5.0g/L、Na2SO4 3g/L、NaCl 0.5g/L、酵母萃取物1.0g/L、MSG‧1H2O 1.0g/L、NaNO3 8.0g/L、(NH4)2SO4 3.0g/L、KH2PO4 0.1g/L、K2HPO4 0.5g/L、CaCl2 0.1g/L及混合維生素溶液10ml/L)。
為了比較MJW01培養基的條件及MJW02培養基的條件,係分別在上述培養基中培養CJM01菌株。結果,如下表5所示,菌體的含量隨著酵母萃取物濃度之降低而減少,但培養時間則隨著無機氮源之增加而顯著地縮短。因此,發現MJW02培養基中DHA的含量等於或大於MJW01培養基中DHA的含量,且相對於DHA在MJW01培養基中的生產率,MJW02培養基中DHA的生產率增加了1.13倍。
如上所述,發明所屬技術領域中具有通常知識者將能理解,在不改變技術精神或其必要特徵的情況下,本揭露可以其他詳細形式容易地執行。因此,應當理解的係前述具體實施例在所有態樣中皆為說明性而非限制性者。本揭露的範疇係由下述之申請專利範圍所表示者,而非發明說明書,且應當理解,申請專利範圍的含義與範圍,以及從其等同物衍生的所有變化或修改之形式皆落入本揭露的範疇內。
<110> 南韓商CJ第一製糖股份有限公司
<120> 新穎的破囊壼菌屬微藻菌株及使用該微藻菌株製造多元不飽和脂肪酸的方法
<130> OPA19013
<150> KR 10-2018-0075945
<151> 2018-06-29
<160> 3
<170> KoPatentIn 3.0
<210> 1
<211> 1792
<212> DNA
<213> 未知
<220>
<223> 破囊壼菌屬
<400> 1
<210> 2
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 18s-001F
<400> 2
<210> 3
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 18s-013R
<400> 3
為照片或實驗數據。
Claims (9)
- 一種破囊壼菌屬CJM01微藻(國內寄存號:BCRC930212),與野生微藻相比,藉由該破囊壼菌屬CJM01微藻產生的二十二碳六烯酸(DHA)的生產量增加且胺基酸的生產量減少。
- 如申請專利範圍第1項所述之破囊壼菌屬CJM01微藻,其中,該破囊壼菌屬CJM01微藻包括基於脂肪酸的總重量,為40重量%至60重量%的二十二碳六烯酸。
- 如申請專利範圍第1項所述之破囊壼菌屬CJM01微藻,其中,該破囊壼菌屬CJM0I微藻具有0.5至0.7g/l/小時之二十二碳六烯酸的生產率。
- 一種製造生物量之方法,包括:培養如申請專利範圍第1項所述之破囊壼菌屬CJM01微藻;及從該破囊壼菌屬CJM01微藻、其培養產物、其乾燥產物、或其粉狀產物中回收含二十二碳六烯酸之生物量。
- 如申請專利範圍第4項所述之方法,其中,該培養係在異營條件下進行。
- 如申請專利範圍第4項所述之方法,其中,該培養係使用包含碳源及氮源之培養基。
- 如申請專利範圍第6項所述之方法,其中,該碳源係選自由葡萄糖、果糖、麥芽糖、半乳糖、甘露糖、蔗糖、阿拉伯糖、本糖及甘油所組成之群組的至少一種。
- 如申請專利範圍第6項所述之方法,其中,該氮源係i)選自由酵母萃取物、牛肉卒取物、蛋白腖及胰化蛋白所組成之群組的有機氮源,或ii)選 自由醋酸銨、硝酸銨、氯化銨、硫酸銨、硝酸鈉、尿素及麩胺酸單鈉(MSG)所組成之群組的無機氮源。
- 一種製造生物油之方法,包括:培養如申請專利範圍第1項所述之破囊壼菌屬CJM01微藻;及從該破囊壼菌屬CJM01微藻、其培養產物、其乾燥產物、或其粉狀產物中回收含二十二碳六烯酸(DHA)的脂質。
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