基于系统—合成生物学的天然产物异源生物合成研究
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摘要
天然产物是生物体内产生的具有重要生理功能或生物活性的有机小分子化合物,是许多临床药物的直接或间接来源,在工农业生产中也有广泛应用。天然产物的异源生物合成是具有光明前景的一种生产方式,该领域近年来发展迅速,许多不同类型、不同来源、不同功能的复杂小分子化合物或其中间体已成功在大肠杆菌、酿酒酵母等异源宿主中进行了生物合成。
天然产物的异源生物合成是合成生物学的重要研究内容,而合成生物学研究又与系统生物学密不可分。合成生物学和系统生物学都是新兴的前沿学科,系统生物学中的许多模型和方法同样适用于合成生物学研究。本文采用基于两者相结合(系统-合成生物学)的策略来初步构建天然产物异源生物合成的in silico研究平台。分别选取红霉素生物合成的关键中间体6-脱氧红霉内酯B (6-deoxyerythronolide B, 6dEB)和紫杉醇生物合成的关键中间体紫杉二烯(taxadiene)等为研究对象,作为聚酮和萜类化合物的代表进行in silico研究平台的初步构建,主要取得了以下成果:
(1)针对6dEB异源合成产率低的问题(也是目前异源合成普遍存在的问题),采用系统生物学方法分析了6dEB在异源宿主中的最大理论产率,以及为提高产率而可能需要改造的潜在基因位点。理论产率分析结果表明,大肠杆菌是更高效的6dEB异源合成宿主,而葡萄糖是更理想的底物。以大肠杆菌作宿主,葡萄糖为底物,设计了两套算法(FDCA、LMOMA-Based)并用于预测一些可能提高6dEB产率的关键基因改造位点。进一步的计算分析发现,比生长速率、非生长维持能量消耗、比氧吸收速率和比碳源吸收速率是影响6dEB理论产率的关键因素。调节这些因素可使6dEB的产率得到提高。
(2)前体途径的选择和前体供应的改善是萜类等天然产物异源生物合成的关键问题。本文用in silico的方式回答了萜类异源合成中前体供应途径的选择问题。通过包括理论产率分析和途径热力学分析在内的in silico分析比较,发现1-脱氧木酮糖-5-磷酸(1-deoxylulose 5-phosphate, DXP)途径比甲羟戊酸(mevalonate, MVA)途径在前体供应中更有优势,在萜类异源合成中更具潜力,而大肠杆菌也是更高效的萜类异源合成宿主(与酿酒酵母、枯草芽孢杆菌相比)。通过采用FDCA和LMOMA-Based算法预测了改善萜类前体供应水平的潜在基因改造位点,为构建高效的萜类异源合成宿主提供了理性指导。
(3)基于上述研究成果,选择大肠杆菌为宿主、DXP途径为前体供应途径,对紫杉醇生物合成途径的关键中间体紫杉二烯进行了异源合成研究。经过上游DXP途径和下游紫杉二烯合成途径的途径工程强化改造,最终在大肠杆菌中得到了目前异源合成紫杉二烯的最高水平,其在生物反应器上的产量达到876±60 mg L-1。该结果表明DXP途径确实具有强大的萜类前体供应潜力,经过途径改造后完全能胜任萜类异源合成的需求。
(4)由细胞色素P450酶所催化的反应广泛存在于天然产物生物合成途径中。这些酶在异源宿主尤其是大肠杆菌等原核宿主中难以实现高效功能表达,已成为制约紫杉醇等天然产物异源合成的关键瓶颈之一。本文选取了紫杉醇生物合成途径中的首个P450酶(CYP725A4,负责催化紫杉二烯在5α位的羟基化反应)为代表,利用生物信息学方法对其序列进行疏水性和跨膜区分析,构建了其分子进化树,在此基础上用同源建模方法构建了其天然态以及切除N端跨膜区后的三级结构,并对CYP725A4实现功能表达所必需的辅助还原酶也进行了天然态和切除N端跨膜区后的三级结构建模。这些工作为后续的分子工程和功能表达奠定了基础。
由于所选取的目标化合物具有良好的代表性,所采用的研究方法也具有通用性,因此本文所构建的天然产物合成生物学研究平台也普遍适用于其他天然产物类别的研究,具有良好的普适性。随着系统生物学与合成生物学的发展,该平台也将得到逐步完善并趋于成熟。
Natural products are a large group of bioactive compounds produced by living organisms. Many of them have pharmacological use in drug discovery and development, and even industrial or agricultural use. Biosynthesis of natural products in heterologous hosts has become increasingly attractive due to new culture techniques that allow for large scale production. Various natural products or their key intermediates have been successfully obtained in heterologous hosts such as E. coli and S. cerevisiae.
Heterologous biosynthesis of natural products becomes a key component of synthetic biology. The research of synthetic biology, however, is highly related to systems biology. Both disciplines are newly developed; the models and methods developed for systems biology are also suitable for the research of synthetic biology. Strategies based on their integration (termed systems-synthetic biology) were performed to construct the in silico platform for natural products heterologous biosynthesis research. The key intermediate in erythromycin and other polyketides biosynthesis, 6-deoxyerythronolide B (6dEB), and the key intermediate in taxol biosynthesis, taxadiene, were selected as the representative compounds for study. The main results were achieved and shown as follows:
(1) To solve the problem of low yield of 6dEB (as well as other natural products), systems biology methods were used to analyze the theoretical 6dEB yields in heterologous hosts, and in silico efforts were invested onpredicting some potential key gene targets for improving 6dEB biosynthesis. The theoretical capability of different hosts on producing 6dEB was first evaluated by analyzing the maximum theoretical molar yield of 6dEB (MTMY of 6dEB or MTMY6dEB) under the three feasible carbon sources, glucose, propionate, and glycerol. Results support that glucose is the best substrate for 6dEB production from an economic and long-term standpoint, although presently propionate is more favorable in experiment. By comparing with S. cerevisiae and B. subtilis, E. coliis found to be the most efficient heterologous host for 6dEB biosynthesis due to the highest MTMY values under the same conditions. Besides, two strategies including the flux distribution comparison analysis (FDCA) method and the linear minimization of metabolic adjustment-based (LMOMA-Based) method were developed and specifically employed for in silico strain improvement for 6dEB production, and finally we obtained some potential gene targets for future experimental improvement. Further analysis also indicated that the specific growth rate (SGR), the non-growth associated maintenance (NGAM), the specific oxygen uptake rate (SOUR), and the specific carbon source uptake rate (SCUR) are the key factors directly affecting the MTMY of 6dEB production. For instance, increasing the SGR or NGAM decrease the MTMY, while increasing the SOUR or SCUR increase the MTMY. These findings may guide for further experimental improvement of 6dEB yields in practice.
(2) The selection of precursor provision pathways and the improvement of precursor provision in heterologous hosts are key problems in the research of natural products heterologous biosynthesis. Here, we tried to solve these problems from an in silico standpoint of view. The central precursor of terpenoids, isopentenyl diphosphate (IPP), proceeds via two separate pathways, the 1-deoxylulose 5-phosphate (DXP) pathway and the mevalonate (MVA) pathway, in different organisms. Previous works far support the utilization of the MVA pathway for IPP over the DXP pathway for terpenoid biosynthesis. In this study, however, the MTMY of IPP (MTMYIPP) and the thermodynamic properties of these two pathways were analyzed and compared in silico, and results indicated that DXP is superior to MVA for IPP provision. Despite the organisms, for either glucose or glycerol as sole carbon source, the MTMYIPP produced by DXP pathway is obviously higher than MVA pathway. If both pathways were adopted, the MTMYIPP would be a bit higher than DXP pathway alone, but not better enough to support introducing a foreign pathway into the host due to a higher metabolic burden. Besides, the MTMYIPP values in either S. cerevisiae or B. subtilis are inferior to E. coli’s, regardless of the kinds of carbon sources. Furthermore, FDCA and LMOMA-Based methods were also applied to predict the key gene targets for improving IPP provision in E. coli, which may play a key role in constructing a high-performance heterologous host for terpenoids biosynthesis.
(3) Based on above results, E. coli was selected as the host, and DXP pathway was determined to be the IPP provision pathway for biosynthesis of taxadiene– the key intermediate during taxol biosynthesis. The pathway engineering strategy was performed to improve taxadiene production in E. coli. Firstly, dxs, idi, and certain isp genes involved in DXP pathway were over-expressed with T7 promoter to generate more IPP; secondly, pathway engineering methods including promoter replacement and codon usage optimization were also performed on downstream taxadiene synthesis pathway (TXDP) for improving taxadiene biosynthesis. Finally, a high specific taxadiene production strain was successfully obtained, and 876±60 mg L-1 taxadiene was achieved in bioreactor. It confirms that the endogenic DXP pathway in E. coli has powerful potential in supplying IPP and thus an excellent choice for taxol as well as other terpenoids heterologous biosynthesis.
(4) P450 enzymes widely exist in natural products biosynthetic pathways. Difficulties in functional expression of these enzymes in prokaryotic hosts such as E. coli are the bottleneck of research on taxol or other natural products biosynthesis. In this paper, bioinformatic strategies were employed to analyze the hydrophobic profile and the transmembrane helices of CYP725A4 sequence, and a molecular phylogenetic tree of CYP725A4 was constructed. Then, based on the results, the tertiary structures of native and N-terminal truncated CYP725A4 were reconstructed via the homology modeling, and similar operations were performed for native and truncated versions of cytochrome P450 reductase used for the functional expression of CYP725A4. Besides, some strategies for improving the functional expression in heterologous hosts were also outlined. These results may give guidances for ulterior works on molecular engineering and effective functional expression of CYP725A4 or other P450s in heterologous hosts.
Because of the well representative research targets and the versatility of the research methods, the platform constructed by this work are also suitable for other kinds of natural products biosynthesis research. In future, the platform will get well developed step-by-step with the development of systems biology and synthetic biology.
天然产物的异源生物合成是合成生物学的重要研究内容,而合成生物学研究又与系统生物学密不可分。合成生物学和系统生物学都是新兴的前沿学科,系统生物学中的许多模型和方法同样适用于合成生物学研究。本文采用基于两者相结合(系统-合成生物学)的策略来初步构建天然产物异源生物合成的in silico研究平台。分别选取红霉素生物合成的关键中间体6-脱氧红霉内酯B (6-deoxyerythronolide B, 6dEB)和紫杉醇生物合成的关键中间体紫杉二烯(taxadiene)等为研究对象,作为聚酮和萜类化合物的代表进行in silico研究平台的初步构建,主要取得了以下成果:
(1)针对6dEB异源合成产率低的问题(也是目前异源合成普遍存在的问题),采用系统生物学方法分析了6dEB在异源宿主中的最大理论产率,以及为提高产率而可能需要改造的潜在基因位点。理论产率分析结果表明,大肠杆菌是更高效的6dEB异源合成宿主,而葡萄糖是更理想的底物。以大肠杆菌作宿主,葡萄糖为底物,设计了两套算法(FDCA、LMOMA-Based)并用于预测一些可能提高6dEB产率的关键基因改造位点。进一步的计算分析发现,比生长速率、非生长维持能量消耗、比氧吸收速率和比碳源吸收速率是影响6dEB理论产率的关键因素。调节这些因素可使6dEB的产率得到提高。
(2)前体途径的选择和前体供应的改善是萜类等天然产物异源生物合成的关键问题。本文用in silico的方式回答了萜类异源合成中前体供应途径的选择问题。通过包括理论产率分析和途径热力学分析在内的in silico分析比较,发现1-脱氧木酮糖-5-磷酸(1-deoxylulose 5-phosphate, DXP)途径比甲羟戊酸(mevalonate, MVA)途径在前体供应中更有优势,在萜类异源合成中更具潜力,而大肠杆菌也是更高效的萜类异源合成宿主(与酿酒酵母、枯草芽孢杆菌相比)。通过采用FDCA和LMOMA-Based算法预测了改善萜类前体供应水平的潜在基因改造位点,为构建高效的萜类异源合成宿主提供了理性指导。
(3)基于上述研究成果,选择大肠杆菌为宿主、DXP途径为前体供应途径,对紫杉醇生物合成途径的关键中间体紫杉二烯进行了异源合成研究。经过上游DXP途径和下游紫杉二烯合成途径的途径工程强化改造,最终在大肠杆菌中得到了目前异源合成紫杉二烯的最高水平,其在生物反应器上的产量达到876±60 mg L-1。该结果表明DXP途径确实具有强大的萜类前体供应潜力,经过途径改造后完全能胜任萜类异源合成的需求。
(4)由细胞色素P450酶所催化的反应广泛存在于天然产物生物合成途径中。这些酶在异源宿主尤其是大肠杆菌等原核宿主中难以实现高效功能表达,已成为制约紫杉醇等天然产物异源合成的关键瓶颈之一。本文选取了紫杉醇生物合成途径中的首个P450酶(CYP725A4,负责催化紫杉二烯在5α位的羟基化反应)为代表,利用生物信息学方法对其序列进行疏水性和跨膜区分析,构建了其分子进化树,在此基础上用同源建模方法构建了其天然态以及切除N端跨膜区后的三级结构,并对CYP725A4实现功能表达所必需的辅助还原酶也进行了天然态和切除N端跨膜区后的三级结构建模。这些工作为后续的分子工程和功能表达奠定了基础。
由于所选取的目标化合物具有良好的代表性,所采用的研究方法也具有通用性,因此本文所构建的天然产物合成生物学研究平台也普遍适用于其他天然产物类别的研究,具有良好的普适性。随着系统生物学与合成生物学的发展,该平台也将得到逐步完善并趋于成熟。
Natural products are a large group of bioactive compounds produced by living organisms. Many of them have pharmacological use in drug discovery and development, and even industrial or agricultural use. Biosynthesis of natural products in heterologous hosts has become increasingly attractive due to new culture techniques that allow for large scale production. Various natural products or their key intermediates have been successfully obtained in heterologous hosts such as E. coli and S. cerevisiae.
Heterologous biosynthesis of natural products becomes a key component of synthetic biology. The research of synthetic biology, however, is highly related to systems biology. Both disciplines are newly developed; the models and methods developed for systems biology are also suitable for the research of synthetic biology. Strategies based on their integration (termed systems-synthetic biology) were performed to construct the in silico platform for natural products heterologous biosynthesis research. The key intermediate in erythromycin and other polyketides biosynthesis, 6-deoxyerythronolide B (6dEB), and the key intermediate in taxol biosynthesis, taxadiene, were selected as the representative compounds for study. The main results were achieved and shown as follows:
(1) To solve the problem of low yield of 6dEB (as well as other natural products), systems biology methods were used to analyze the theoretical 6dEB yields in heterologous hosts, and in silico efforts were invested onpredicting some potential key gene targets for improving 6dEB biosynthesis. The theoretical capability of different hosts on producing 6dEB was first evaluated by analyzing the maximum theoretical molar yield of 6dEB (MTMY of 6dEB or MTMY6dEB) under the three feasible carbon sources, glucose, propionate, and glycerol. Results support that glucose is the best substrate for 6dEB production from an economic and long-term standpoint, although presently propionate is more favorable in experiment. By comparing with S. cerevisiae and B. subtilis, E. coliis found to be the most efficient heterologous host for 6dEB biosynthesis due to the highest MTMY values under the same conditions. Besides, two strategies including the flux distribution comparison analysis (FDCA) method and the linear minimization of metabolic adjustment-based (LMOMA-Based) method were developed and specifically employed for in silico strain improvement for 6dEB production, and finally we obtained some potential gene targets for future experimental improvement. Further analysis also indicated that the specific growth rate (SGR), the non-growth associated maintenance (NGAM), the specific oxygen uptake rate (SOUR), and the specific carbon source uptake rate (SCUR) are the key factors directly affecting the MTMY of 6dEB production. For instance, increasing the SGR or NGAM decrease the MTMY, while increasing the SOUR or SCUR increase the MTMY. These findings may guide for further experimental improvement of 6dEB yields in practice.
(2) The selection of precursor provision pathways and the improvement of precursor provision in heterologous hosts are key problems in the research of natural products heterologous biosynthesis. Here, we tried to solve these problems from an in silico standpoint of view. The central precursor of terpenoids, isopentenyl diphosphate (IPP), proceeds via two separate pathways, the 1-deoxylulose 5-phosphate (DXP) pathway and the mevalonate (MVA) pathway, in different organisms. Previous works far support the utilization of the MVA pathway for IPP over the DXP pathway for terpenoid biosynthesis. In this study, however, the MTMY of IPP (MTMYIPP) and the thermodynamic properties of these two pathways were analyzed and compared in silico, and results indicated that DXP is superior to MVA for IPP provision. Despite the organisms, for either glucose or glycerol as sole carbon source, the MTMYIPP produced by DXP pathway is obviously higher than MVA pathway. If both pathways were adopted, the MTMYIPP would be a bit higher than DXP pathway alone, but not better enough to support introducing a foreign pathway into the host due to a higher metabolic burden. Besides, the MTMYIPP values in either S. cerevisiae or B. subtilis are inferior to E. coli’s, regardless of the kinds of carbon sources. Furthermore, FDCA and LMOMA-Based methods were also applied to predict the key gene targets for improving IPP provision in E. coli, which may play a key role in constructing a high-performance heterologous host for terpenoids biosynthesis.
(3) Based on above results, E. coli was selected as the host, and DXP pathway was determined to be the IPP provision pathway for biosynthesis of taxadiene– the key intermediate during taxol biosynthesis. The pathway engineering strategy was performed to improve taxadiene production in E. coli. Firstly, dxs, idi, and certain isp genes involved in DXP pathway were over-expressed with T7 promoter to generate more IPP; secondly, pathway engineering methods including promoter replacement and codon usage optimization were also performed on downstream taxadiene synthesis pathway (TXDP) for improving taxadiene biosynthesis. Finally, a high specific taxadiene production strain was successfully obtained, and 876±60 mg L-1 taxadiene was achieved in bioreactor. It confirms that the endogenic DXP pathway in E. coli has powerful potential in supplying IPP and thus an excellent choice for taxol as well as other terpenoids heterologous biosynthesis.
(4) P450 enzymes widely exist in natural products biosynthetic pathways. Difficulties in functional expression of these enzymes in prokaryotic hosts such as E. coli are the bottleneck of research on taxol or other natural products biosynthesis. In this paper, bioinformatic strategies were employed to analyze the hydrophobic profile and the transmembrane helices of CYP725A4 sequence, and a molecular phylogenetic tree of CYP725A4 was constructed. Then, based on the results, the tertiary structures of native and N-terminal truncated CYP725A4 were reconstructed via the homology modeling, and similar operations were performed for native and truncated versions of cytochrome P450 reductase used for the functional expression of CYP725A4. Besides, some strategies for improving the functional expression in heterologous hosts were also outlined. These results may give guidances for ulterior works on molecular engineering and effective functional expression of CYP725A4 or other P450s in heterologous hosts.
Because of the well representative research targets and the versatility of the research methods, the platform constructed by this work are also suitable for other kinds of natural products biosynthesis research. In future, the platform will get well developed step-by-step with the development of systems biology and synthetic biology.
引文
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