CN104561221B - 一种利用两种或者两种以上的微生物菌种生产发酵产品的方法 - Google Patents
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Abstract
本发明涉及一种利用多种微生物共培养或者耦联发酵的方法。与维生素C发酵的大菌主要辅助小菌用来生长和产酸的关系不同，本发明的方法主要是利用多种微生物共培养或者耦联发酵的方法来克服代谢调控障碍来生产发酵产品。所述共培养是指将两种或者两种以上的微生物菌种从开始就混合培养，或者先培养一种菌种，等到培养到合适的时候再加入其他菌种进行培养。
Description
技术领域
本文介绍一种利用两种或者两种以上的微生物菌种共培养或者耦联培养，从而克服代谢网络调控障碍来生产发酵产品的方法。
背景技术
两种或多种微生物菌种共处这一现象，在自然界微生物群体中普遍存在。如污水处理中的多菌群系统、人和动物的肠道菌群等，他们一般是共生、互惠的关系。
在发酵产品中，用两种微生物菌种共培养来生产发酵产品的例子也有，如维生素C发酵就是利用混合菌将山梨糖转化成2-酮基-L-古龙酸。普通古龙酸菌(Ketogulonigeniumvulgare，俗称小菌)负责将山梨糖生物氧化；另一种微生物，如巨大芽孢杆菌(Bacillusmegaterium俗称大菌)，作为伴生菌起到辅助小菌生长和产酸的作用。从以下图片可以看到，随着发酵的进行，处于生长优势的大菌逐渐被小菌取代。
氨基酸发酵一般是纯种发酵。由于氨基酸属于初级代谢产物，根据细胞经济学原则，一般微生物菌种，它既不会累积过量代谢产物，也不会过多摄取自然界的营养，微生物的代谢物受微生物复杂、精巧、严格的调控机制来运作。而用纯种微生物来生产氨基酸都要克服这些代谢调控障碍。
二元胺，尤其是1，5-戊二胺的生物制备已经从上世纪50年代开始，人们就对此进行了研究，主要的制备方法有两种。一种是把纯化的赖氨酸盐用赖氨酸脱羧酶进行脱羧生成1，5-戊二胺，如专利JP2002-223770A；另一种方法是利用纯种微生物把糖代谢成1，5-戊二胺，如专利WO2008/092720A1。第一种方法由于要将赖氨酸盐进行纯化，使得步骤复杂，生产成本高；第二种方法由于利用纯种微生物来代谢生产1，5-戊二胺，代谢步骤长，并且需要克服代谢调控障碍，转化率低。虽然现在这个项目已经研究50多年了，但是仍然没有将生物法1，5-戊二胺产业化成功的案例。
发明内容
本专利主要介绍一种利用多种微生物共培养或者耦联发酵的方法。与维生素C发酵的大菌主要辅助小菌用来生长和产酸的关系不同，本文介绍的方法主要是利用多种微生物共培养或者耦联发酵的方法来克服代谢调控障碍来生产发酵产品，这种方法在二元胺和氨基酸生产过程中目前没有见到报道。
图3所示的是采用纯种微生物利用葡萄糖代谢生产1，5-戊二胺，lysC和dapA受到赖氨酸的反馈抑制和阻遏。图4为采用共培养的形式。一种微生物菌种利用葡萄糖生成Meso-diaminopimelate，而lysC和dapA不受Meso-diaminopimelate的反馈抑制和阻遏，从而解决了纯菌发酵生产1，5-戊二胺的代谢障碍。图5到图8主要描述采用共培养的方式解决了苏氨酸、色氨酸对相关基因的反馈阻遏和抑制。
附图说明
图1维生素C发酵初期镜照
图2维生素C发酵后期镜照
图3赖氨酸累积对lysC和dapA基因有反馈抑制示意图
图4Meso-diaminopimelate对lysC和dapA没有反馈抑制示意图
图5苏氨酸累积对lysC和dapA基因有反馈抑制示意图
图6homoserine对lysC和dapA没有反馈抑制示意图
图7tyrosine对tyrA有反馈抑制示意图
图8 4-hydroxyphenylpyruvate对tyrA没有反馈抑制示意图
具体实施方式
以下结合具体实施例，对本发明做进一步详细说明。应理解，以下实施例仅用于说明本发明而非用于限定本发明的范围。
实施例1
将保藏号为CCTCC M2013100的大肠杆菌菌株进行摇瓶培养，选用摇瓶500mi，装液量30ml，摇床转速180rpm，发酵温度35℃，发酵培养基配方如下。发酵起始pH7.0，接种后，培养50h，接入凯赛公司能够产赖氨酸脱羧酶的菌株蜂房哈夫尼菌，在30℃下继续培养30h。
| 组份 | g/L |
| Glucose | 30 |
| KH2PO4 | 1.2 |
| MgSO4 | 2 |
| (NH4)2SO4 | 8 |
| FeSO4 | 0.032 |
| MnSO4 | 0.032 |
| CSL | 15 |
| KCl | 0.5 |
| L-Methionine | 0.006 |
| L-threonine | 0.25 |
| L-D | 2.2 |
| 毛发水解液 | 10 |
| CuSO4 | 0.007 |
| ZnSO4 | 0.008 |
发酵结束后，测定发酵液中1，5-戊二胺含量5.3g/L。
实施例2
将凯赛生物公司购买的大肠杆菌MG1655 K12通过基因改造，减弱diaminopimelate decarboxylase酶活性，然后将其进行摇瓶培养，选用摇瓶500ml，装液量30m1，摇床转速180rpm，发酵温度35℃，发酵培养基配方如下。接种后，培养50h，接入凯赛公司能够产赖氨酸脱羧酶的菌株蜂房哈夫尼菌，在30℃下继续培养30h。
| 组份 | g/L |
| Glucose | 30 |
| KH2PO4 | 1.2 |
| MgSO4 | 2 |
| (NH4)2S04 | 8 |
| FeSO4 | 0.032 |
| MnSO4 | 0.032 |
| CSL | 15 |
| KCl | 0.5 |
| L-Methionine | 0.006 |
| L-threonine | 0.25 |
| L-D | 2.2 |
| 毛发水解液 | 10 |
| CuSO4 | 0.007 |
| ZnSO4 | 0.008 |
发酵结束后，测定发酵液中1，5一戊二胺含量9.5g/L。
Claims (2)
1.一种利用两种或者两种以上的微生物菌种共培养或者耦联培养，从而克服代谢调控障碍来生产发酵产品的方法，所述共培养是指将两种或者两种以上的微生物菌种从开始就混合培养，或者先培养一种菌种，等到培养到合适的时候再加入其他菌种进行培养，其特征在于：
所述的发酵产品为1，5‐戊二胺；
所述两种微生物菌种是大肠杆菌和能够产赖氨酸脱羧酶的蜂房哈夫尼菌，所述大肠杆菌是保藏号为CCTCC M2013100的大肠杆菌。
2.如权利要求1所述的方法，其特征在于：培养到一定阶段后，加入另外的菌种进行混合培养时加入另外的培养基。
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