综合利用木质纤维素生物转化合成有机酸

doi:10.12211/2096-8280.2024-011

合成生物学

• 特约评述 •

综合利用木质纤维素生物转化合成有机酸

柴猛¹^,², 王风清¹^,²^,³, 魏东芝¹^,²^,³

^1.华东理工大学生物反应器工程国家重点实验室，上海，200237
^2.鲁华生物技术研究所，上海 200237
^3.中国轻工业生物催化与智能制造重点实验室，上海 200237

收稿日期:2024-01-23 修回日期:2024-04-24 出版日期:2024-04-28
通讯作者: 王风清,魏东芝
作者简介:柴猛（1998—），男，博士研究生。研究方向为合成生物学与代谢工程。 E-mail：chaimeng980909@163.com
王风清（1977—），男，教授，博士生导师。研究方向为利用代谢工程和合成生物学的原理和方法，致力于微生物细胞工厂的研究和开发等。 E-mail：fqwang@ecust.edu.cn
魏东芝（1963—），男，教授，博士生导师。研究方向为生物元器件的发现、改造与应用研究，致力于发现和改进具有工业应用价值的微生物和生物催化剂，开拓生物转化新反应等。 E-mail：dzhwei@ecust.edu.cn
基金资助:
国家重点研发计划(2021YFC2100300);2023年“双一流”建设-一流学科重点项目或基础学科建设项目-“智能生物制造”

Synthesis of organic acids from lignocellulose by biotransformation

Meng Chai¹^,², Feng-Qing Wang¹^,²^,³, Dong-Zhi Wei¹^,²^,³

^1.State Key Laboratory of Bioreactor Engineering，East China University of Science and Technology，Shanghai 200237，China
^2.Luhua Institute of Biotechnology，Shanghai 200237，China
^3.Key Laboratory of Biocatalysis and Intelligent Manufacturing of China Light Industry，Shanghai 200237，China

Received:2024-01-23 Revised:2024-04-24 Online:2024-04-28
Contact: Feng-Qing Wang, Dong-Zhi Wei

摘要/Abstract

摘要：

开发环境友好型的生物可降解材料，被公认为是解决“白色污染”的重要途径。作为制备生物可降解材料的主要原料之一，有机酸的绿色高效制造备受关注。木质纤维素是储量庞大且可再生的自然资源，以木质纤维素为原料，通过生物转化的方式生产有机酸，是发展绿色可降解生物基材料的理想途径，具有过程绿色低碳的优势，符合建设绿色可持续发展经济和社会的需求。近年来，人们针对木质纤维素的生物炼制开展了大量研究，并在生物转化合成有机酸等领域取得了重要进展，特别是在高产有机酸微生物细胞工厂的设计开发上不断取得突破，使得生物基有机酸的生产水平屡创新高，丁二酸等品种的产量甚至突破了150 g/L，积极推动了生物基可降解材料产业的形成和发展。本文介绍了木质纤维素的组分并总结了木质纤维素的物理预处理法、化学预处理法、生物预处理法、物理-化学共处理法和化学-生物共处理法等多种预处理技术，以及抑制物的脱毒技术、还原催化分馏工艺、催化剂的回收以及偶联木质纤维素水解和发酵的制造工艺。其次，以木质纤维素为原料合成的高价值有机酸（丁二酸、3-羟基丙酸、粘康酸、2， 5-呋喃二甲酸和2-吡喃酮-4， 6-二羧酸）为例，从这些有机酸的生物合成途径，合成生物学改造策略和发酵条件优化等角度探讨了这些有机酸的研究现状。最后，对当前生物可降解材料产业链的发展趋势进行了总结和展望，讨论了开发新型预处理技术和优化联合生物处理工艺等策略对木质纤维素组分解离和利用的重要意义，并从提高微生物细胞工厂的鲁棒性以及设计木质纤维素的综合转化途径等方面进行系统分析，以期能为有机酸的工业化生产提供参考。

关键词: 木质纤维素, 有机酸, 生物基材料, 绿色生物制造

Abstract:

The development of environmentally benign, biodegradable materials is considered an important way to address "white pollution". Importantly, organic acid is one of the crucial monomers for preparing biodegradable materials. In recent years, the synthesis of organic acids through green and efficient methods has attracted much attention. As the most promising carbon source recognized for renewability and affordability, lignocellulose is considered a promising carbon source for the biochemical industry. Converting lignocellulose into organic acid is critical to preparing biodegradable materials and achieving carbon neutrality, which meets the requirements of the green and sustainable development strategy. Hence, researchers are focusing their investigations on the lignocellulose biorefinery. To date, innovations in synthetic biology have significantly advanced organic acid manufacturing. For example, the yield of succinic acid has exceeded 150 g/L, which facilitates the formation and development of the bio-based biodegradable materials industry. In this paper, various lignocellulose pretreatment technologies were reviewed, including physical pretreatment, chemical pretreatment, biological pretreatment, physicochemical pretreatment, and other emerging pretreatment methods. To realize the goal of efficient utilization of lignocellulose, the refining processes of lignocellulose were also reviewed, including detoxification of inhibitors, reductive catalytic fractionation, consolidated bioprocessing, and other methods. After the pretreatment and refining process, lignocellulose is transformed to sugars and aromatic compounds, which can be utilized for producing various organic acid compounds, such as succinic acid, 3-hydroxypropionic acid, cis, cis-muconic acid, 2,5-furandicarboxylic acid, 2-pyrone-4, 6-dicarboxylic acid. Next, using the optimization of production of these organic acid compounds as examples, several synthetic biology strategies were summarized, including constructing biosynthetic pathways, optimizing regulatory elements, enlarging the substrates spectrum, and other strategies for improving cell production capacity. Finally, the development trends of the biodegradable materials industry are summarized and prospected. The development of emerging pretreatment and consolidated bioprocessing to facilitate the efficiency of lignocellulose utilization were discussed. Improving the robustness of microbial cell factories and designing the systematic lignocellulose conversion pathways could further optimize the performances of organic acid synthesis. The insights given in this review could facilitate further development on the industrial production of biodegradable materials, towards addressing the global energy crisis and "white pollution".

Key words: Lignocellulose, Organic acids, Bio-based materials, Green biomanufacturing

中图分类号:

Q819

柴猛, 王风清, 魏东芝. 综合利用木质纤维素生物转化合成有机酸[J]. 合成生物学, DOI: 10.12211/2096-8280.2024-011.

Meng Chai, Feng-Qing Wang, Dong-Zhi Wei. Synthesis of organic acids from lignocellulose by biotransformation[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2024-011.

图/表 10

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预处理类型	预处理技术	优点	缺点	参考文献
物理法	机械预处理	没有抑制物的产生且操作简单	设备昂贵且耗能高	[20]
	超声波预处理	处理效率高且无抑制剂产生	能耗较高且选择性较低	[22-23]
	微波预处理	反应迅速且选择性较高	设备昂贵且运行成本较高	[24-25]
	射线预处理	工艺方便、环保且经济	需要结合额外的物理或化学法预处理	[26-27]
	脉冲电场预处理	反应快速且节能，需要简单的非热设备	需要多个脉冲发生器，且可能产生有毒化学物质	[28-29]
	超临界CO₂爆破	所需处理温度较低且廉价的CO₂	需要较高的CO₂压力，设备成本较高	[30]
	等离子体预处理	过程中不产生有毒或污染化学物	能耗较高	[31]
化学法	酸处理	对糖的转化率较高，反应时间短	强酸毒性较大、腐蚀性强且处理过程会产生抑制物	[32]
	碱处理	工艺简单且条件温和，抑制物产生相对较少	下游回收过程复杂	[33-34]
	氧化剂预处理	选择性高	容易导致抑制物的产生	[35-36]
	离子溶液预处理	可回收重复使用，且热稳定性较好	成本较高且再生条件较高	[18,37]
	有机溶剂预处理	反应时间短	部分有机溶剂的腐蚀性和毒性较大，且具有易燃性和挥发性	[38]
	深共晶溶剂预处理	成本和毒性较高	粘稠度较高	[39-40]
生物法	真菌预处理	反应温和且能耗低	反应周期较长，回收率需要进一步提高	[41]
	细菌预处理	反应温和且能耗低	反应周期较长	[42]
	白蚁预处理	反应温和且能耗低	反应周期较长	[43]
物理-化学共处理	蒸气爆破处理	处理方式环保	能耗较高，对软木的处理效果较差	[44]
	热碱处理	处理成本低	需要较高的温度和压力	[45]
	氨纤维爆破预处理	条件温和且无抑制产生	反应能耗较高，且污染环境	[46]
化学-生物共处理	铜绿假单胞菌与稀酸共处理	处理效率提高	需要进一步优化细菌的处理条件	[47]
	鞘氨醇杆菌与NaOH共处理	提高了纤维素水解物的得率	需要进一步优化条件	[48]

预处理类型	预处理技术	优点	缺点	参考文献
物理法	机械预处理	没有抑制物的产生且操作简单	设备昂贵且耗能高	[20]
	超声波预处理	处理效率高且无抑制剂产生	能耗较高且选择性较低	[22-23]
	微波预处理	反应迅速且选择性较高	设备昂贵且运行成本较高	[24-25]
	射线预处理	工艺方便、环保且经济	需要结合额外的物理或化学法预处理	[26-27]
	脉冲电场预处理	反应快速且节能，需要简单的非热设备	需要多个脉冲发生器，且可能产生有毒化学物质	[28-29]
	超临界CO₂爆破	所需处理温度较低且廉价的CO₂	需要较高的CO₂压力，设备成本较高	[30]
	等离子体预处理	过程中不产生有毒或污染化学物	能耗较高	[31]
化学法	酸处理	对糖的转化率较高，反应时间短	强酸毒性较大、腐蚀性强且处理过程会产生抑制物	[32]
	碱处理	工艺简单且条件温和，抑制物产生相对较少	下游回收过程复杂	[33-34]
	氧化剂预处理	选择性高	容易导致抑制物的产生	[35-36]
	离子溶液预处理	可回收重复使用，且热稳定性较好	成本较高且再生条件较高	[18,37]
	有机溶剂预处理	反应时间短	部分有机溶剂的腐蚀性和毒性较大，且具有易燃性和挥发性	[38]
	深共晶溶剂预处理	成本和毒性较高	粘稠度较高	[39-40]
生物法	真菌预处理	反应温和且能耗低	反应周期较长，回收率需要进一步提高	[41]
	细菌预处理	反应温和且能耗低	反应周期较长	[42]
	白蚁预处理	反应温和且能耗低	反应周期较长	[43]
物理-化学共处理	蒸气爆破处理	处理方式环保	能耗较高，对软木的处理效果较差	[44]
	热碱处理	处理成本低	需要较高的温度和压力	[45]
	氨纤维爆破预处理	条件温和且无抑制产生	反应能耗较高，且污染环境	[46]
化学-生物共处理	铜绿假单胞菌与稀酸共处理	处理效率提高	需要进一步优化细菌的处理条件	[47]
	鞘氨醇杆菌与NaOH共处理	提高了纤维素水解物的得率	需要进一步优化条件	[48]

脱毒分类	脱毒方法	适用范围	参考文献
物理脱毒	吸附剂脱毒	呋喃、脂肪酸和酚类物质	[50]
	膜脱毒法	酸法预处理抑制物	[51]
化学脱毒	碱法脱毒	酸类与呋喃类	[52]
	还原剂脱毒	呋喃类与酚类	[53]
	氨基酸脱毒	呋喃类与醛类	[54]
生物脱毒	酶法脱毒	酚类	[55]
	高耐受抑制物的菌株	糠醛类与呋喃类	[56]
复合脱毒方法	离子交换树脂与活性炭	酚类与呋喃类	[57]

脱毒分类	脱毒方法	适用范围	参考文献
物理脱毒	吸附剂脱毒	呋喃、脂肪酸和酚类物质	[50]
	膜脱毒法	酸法预处理抑制物	[51]
化学脱毒	碱法脱毒	酸类与呋喃类	[52]
	还原剂脱毒	呋喃类与酚类	[53]
	氨基酸脱毒	呋喃类与醛类	[54]
生物脱毒	酶法脱毒	酚类	[55]
	高耐受抑制物的菌株	糠醛类与呋喃类	[56]
复合脱毒方法	离子交换树脂与活性炭	酚类与呋喃类	[57]

生产菌株	底物	改造策略	发酵条件优化	生产方式	产量	产率	生产强度	参考文献
E. coli NZN111	木薯淀粉和生木薯	敲除pflB、ldhA	优化发酵温度以及底物添加量等条件	好氧-厌氧两阶段发酵	127.1 g/L	—	—	[71-72]
E. coli AFP111	葡萄糖	在ptsG突变的菌株中敲除pflB和ldhA	控制葡萄糖的补加量以及菌体生长速度	好氧-厌氧两阶段发酵	99.2 g/L	110% （摩尔转化率）	1.30 g/L/h	[73]
E. coli SD121	葡萄糖	过表达ppc，敲除pflB、ldhA和ptsG	控制溶氧以及生物量	好氧-厌氧两阶段发酵	116.2 g/L	1.73 mol/mol	1.55 g/L/h	[74]
E. col AFP111/pTrcC-cscA	蔗糖和糖蜜	在E. coli AFP111的基础上，融合表达CscA与OmpC的锚定基序	控制pH以及底物添加量	好氧-厌氧两阶段发酵	79.0 g/L	1.20 mol/mol	1.05 g/L/h	[75]
C. glutamicum S071/pGEX4-NCgl0275	葡萄糖	过表达Ncgl0275、pyc^P458S、pck、ppc、fdh和gapA	优化葡萄糖的补加量以及生物量	好氧-厌氧两阶段发酵	152.2 g/L	1.67 mol/mol	1.11 g/L/h	[76]
C. glutamicum ΔldhA-pCRA717	葡萄糖	过表达pyc，敲除ldhA	优化碳酸氢盐浓度，溶氧以及pH	好氧-厌氧两阶段发酵	146.0 g/L	1.40 mol/mol	3.2 g/L/h	[77]
S. cerevisiae PMCFfg	葡萄糖	敲除fum1、gpd1、pdc1、pdc5和pdc6，过表达pyc2、mdh3、fumC和frds1	控制尿素、碳酸钙和生物素的浓度	好氧发酵	12.9 g/L	0.21 mol/mol	—	[78]
Y. lipolytica Hi-SA2	葡萄糖	合理分配亚细胞区室还原性TCA循环的代谢流	控制葡萄糖添加量	好氧发酵	111.9 g/L	0.79 g/g	1.79 g/L/h	[79]
A. succinogenes 130Z-pMDH	葡萄糖和木糖	过表达mdh	优化温度以及pH	厌氧发酵	34.2 g/L	0.71 g/g	0.36 g/L/h	[80]
Y. lipolytica PGC01003	甘油	敲除Ylsdh5	优化pH、通气量以及底物添加量	好氧发酵	160.2 g/L	0.40 g/g	0.40 g/L/h	[81]
A. succinogenes CGMCC1593	玉米秸秆	—	优化稀碱预处理、底物浓度、酶负荷和发酵温度	同步糖化和发酵（SSF）	47.4 g/L	0.72 g/g	0.99 g/L/h	[82]
E. coli XW136	半纤维素水解液	以E.coli KJ122为出发菌株在木糖AM1培养基中连续传代，得到SA滴度提高5倍的突变体，敲除yqhD引入ackA::P _yadC fucO-ucpAadhE::fucO	优化半纤维素水解液的制备，以及发酵过程pH 的控制	分批发酵	32.0 g/L	0.90 g/g	—	[83]
T. thermosaccharolyticum M5和A. succinogenes 130Z	木聚糖	—	优化底物浓度、pH、MgCO₃浓度以及接种时间	联合生物处理（CBP）	32.5 g/L	0.39 g/g	—	[84]

综合利用木质纤维素生物转化合成有机酸

Synthesis of organic acids from lignocellulose by biotransformation

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生产菌株	底物	改造策略	发酵条件优化	生产方式	产量	得率	生产强度	参考文献
R. toruloides MCR-ALD6-g2945	葡萄糖和木糖	外源表达A. pseudoterreus来源的羧酸转运体	优化培养基的碳氮比	补料分批发酵	45.4 g/L	0.11 g/g	0.44 g/L/h	[89]
O. polymorpha XFML	葡萄糖和木糖	优化葡萄糖和木糖共利用系统以及重塑中枢代谢途径	控制补糖速度	补料分批发酵	79.6 g/L	0.35 g/g^a	0.41 g/L/h^a	[90]
A. niger An3HP9/pyc2/ald6a∆/3HP-6	玉米秸秆水解物	优化3-HP代谢途径关键基因的表达，提高前体供应水平以及强化外排转运蛋白	优化发酵温度以及培养基成份	分批发酵	36.0 g/L	0.48 g/g	0.21 g/L/h	[91]
C. glutamicum MH15	葡萄糖和木糖	构建甘油利用途径，并微室化定位甘油合成途径，弱化乳酸和乙酸等副产物合成以及构建糖转运转运利用系统	控制补糖速度和底物浓度	补料分批发酵	62.6 g/L	0.51 g/g	—	[92]

生产菌株	底物	改造策略	发酵条件优化	生产方式	产量	得率	生产强度	参考文献
E.coli GX2xMA	葡萄糖和木糖	引入木糖代谢途径并优化葡萄糖利用途径	优化底物浓度	分批发酵	4.09 g/L	0.31 g/g	—	[97]
P. putida LC224	葡萄糖和木糖	敲除hexR并优化木糖异构酶途径，结合代谢模型和适应性进化工程策略	控制补糖速度以及溶氧	补料分批发酵	33.7 g/L	46%（摩尔转化率）	0.18 g/L/h	[98]
S. cerevisiae TN22	葡萄糖和木糖	解除芳香氨基酸对莽草酸合成途径的反馈抑制，消除乙醇积累和优化辅因子供给	添加聚丙烯乙二醇4000提取MA	补料分批发酵	4.5 g/L	—	—	[95]
C. glutamicum MA-2	葡萄糖和儿茶酚	敲除MA环异构酶（CatB）并过表达儿茶酚1,2-二氧酶（CatA）	控制补料速度和溶氧	补料分批发酵	85.0 g/L	—	1.42 g/L/h^a	[99]
P. putida MA-1	葡萄糖和儿茶酚	敲除catBC	控制溶氧和pH，用氮气对儿茶酚进行脱气以防止其氧化	补料分批发酵	64.2 g/L	—	4.50 g/L/h	[100]

生产菌株	底物	改造策略	发酵条件优化	生产方式	产量	得率	生产强度	参考文献
E.coli GYT7	葡萄糖	过表达抗反馈抑制的3-脱氧-D-阿拉伯庚酮糖-7-磷酸合成酶，提高前体和优化辅因子的供应水平，并结合计算机模拟分析代谢流	偶联pH进行补料	补料分批发酵	16.7 g/L	0.20 g/g	0.17 g/L/h	[123]
E. coli WJ060、E. coli BL21(DE3)- pET30a-AbquiC和E. coli BL21(DE3)-pRSF-2ABC	葡萄糖	模块化工程，利用葡萄糖合成DHS，接着合成为PCA，最后被催化为PDC	优化全细胞催化的pH以及负载量等条件	补料分批发酵	49.2 g/L	27.2% （摩尔转化率）	—	[124]
P. putida KT- PDC2	对香豆酸	引入PDC合成途径，增强前体PCA的供应	控制溶氧	补料分批发酵	22.7 g/L	1.0 mol/mol	0.21 g/L/h	[125]
P. putida PpY1100-pDVZ21X	葡萄糖和香草酸	引入利用香草酸合成PDC的途径	优化培养基成份，控制pH	补料分批发酵	99.9 g/L	99% （摩尔转化率）	1.69 g/L/h	[126]

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