仿突变生物合成调控对土曲霉C23-3次生代谢产物的影响

doi:10.13560/j.cnki.biotech.bull.1985.2024-0110

生物技术通报 ›› 2024, Vol. 40 ›› Issue (8): 275-287.doi: 10.13560/j.cnki.biotech.bull.1985.2024-0110

仿突变生物合成调控对土曲霉C23-3次生代谢产物的影响

马小翔¹(), 马泽源¹, 刘亚月¹^,²^,³, 周龙建¹^,²^,³, 和羿帆⁴, 张翼¹^,²^,³()

1.广东海洋大学食品科技学院广东省水产品加工与安全重点实验室广东省海洋生物制品工程实验室广东海洋大学深圳研究院湛江市脑健康相关海洋药物与营养品重点实验室，湛江 524088
2.南方海洋科学与工程广东省实验室（湛江），湛江 524006
3.海洋食品精深加工关键技术省部共建协同创新中心大连工业大学，大连 116034
4.加州大学圣地亚哥分校斯克里普斯海洋研究所海洋生物技术与生物医药中心，拉霍亚，美国 92093

收稿日期:2024-01-31 出版日期:2024-08-26 发布日期:2024-07-02
通讯作者: 张翼，男，博士，教授，研究方向：海洋天然产物；E-mail: hubeizhangyi@163.com
作者简介:马小翔，女，硕士研究生，研究方向：海洋天然产物；E-mail: ma.xiao.xiang@163.com
第一联系人：马泽源为本文共同第一作者
基金资助:
广东省基础与应用基础研究基金自然科学基金（面上项目）(2022A1515010783);广东省普通高校重点领域专项（生物医药与健康）(2021ZDZX2064);深圳市科创委基础研究面上项目(JCYJ20220530162014032);湛江市海洋青年人才创新项目(2022E05010)

Effects of Simulated Mutational Biosynthetic Regulation on the Secondary Metabolites of Aspergillus terreus C23-3

MA Xiao-xiang¹(), MA Ze-yuan¹, LIU Ya-yue¹^,²^,³, ZHOU Long-jian¹^,²^,³, HE Yi-fan⁴, ZHANG Yi¹^,²^,³()

1. College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Zhanjiang 524088
2. Southern Marine Science and Engineering Guangdong Laboratory（Zhanjiang）, Zhanjiang 524006
3. Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034
4. Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California（San Diego）, La Jolla 92093, USA

Received:2024-01-31 Published:2024-08-26 Online:2024-07-02

摘要/Abstract

摘要：

【目的】丁内酯I是土曲霉（Aspergillus terreus）产生的一种具有多样生物活性的小分子天然产物，对其结构多样性拓展的探索具有重要意义。以一株高产丁内酯I的海洋来源土曲霉C23-3作为基础菌株，研究丁内酯前体小分子类似物和前体合成酶抑制剂对其次生代谢的影响。【方法】以海水马铃薯液体培养基为基础培养基，以3种前体小分子类似物和3种对羟基苯丙酮酸的合成酶抑制剂作为化学诱导剂，在静置发酵条件下进行菌株的化学调控培养。采用高效液相色谱、高效液相色谱-离子阱质谱联用及基于质谱的分子网络和数据库挖掘分析次生代谢产物的产量和多样性。【结果】多数前体小分子类似物和合成酶抑制剂对丁内酯I产量均有不同程度抑制，而高浓度的前体小分子类似物3,4-二羟基苯丙酮酸、两种合成酶抑制剂联用及这三者的联用表现出了较强的抑制效果；并且在丁内酯I的合成受到强烈抑制条件下，丁内酯类、土震素类、洛伐他汀类等多类次生代谢产物的合成也下降，但一种环肽类化合物产量超过10倍的大幅提升，可能是菌体对作为群体感应信号及全局性转录因子lae A诱导子的丁内酯I合成受到压制胁迫的一种应激反应，具体机制有待深入研究。【结论】丁内酯I的前体确为对羟基苯丙酮酸，3,4-二羟基苯丙酮酸及对羟基苯丙酮酸合成酶抑制剂可用作抑制丁内酯I合成的小分子工具，以用于仿突变生物合成的进一步探索以获得多样化丁内酯衍生物，也可诱导产生环肽类化合物。

关键词: 海洋真菌, 化学调控, 仿突变生物合成, 丁内酯, 前体类似物, 合成酶抑制剂, LC-MS/MS, 分子网络

Abstract:

【Objective】Butyrolactone I is a small molecular natural product of Aspergillus terreus with versatile bioactivities, thus the exploration of its structural diversity extension is significant. A marine-derived A. terreus strain C23-3 featuring producing butyrolactone I was used as the base strain to study the effects of butyrolactone I precursor analogs and precursor synthase inhibitors on its secondary metabolism.【Method】The strain was statically fermented under chemically regulative conditions established by seawater potato liquid medium supplied with three precursor small molecules and three 4-hydroxyphenylpyruvate synthase inhibitors. The high-performance liquid chromatography（HPLC）, HPLC -ion trap mass spectrometry（MS）, and MS based molecular networking together with database mining were used to further analyze the yields and diversity of secondary metabolites.【Result】The most of the precursor analogs and synthase inhibitors suppressed the synthesis of butyrolactone I to different extents. Moreover, the precursor analog 3,4-dihydroxyphenylpyruvate at a high dose, the combination of the two 4-hydroxyphenylpyruvate synthase inhibitors and the combination of these three demonstrated remarkable inhibitory effects. In addition, the global synthesis for sorts of secondary metabolites including butenoids, territrems, lovastatins, etc., was downregulated when butyrolactone I was inhibited for production. However, the yield of a cyclopeptide was upregulated by more than ten folds under this situation, which was supposed to be a stress response to the synthetic suppression of butyrolactone I as a quorum sensing molecule and inducer of global transcriptive factor lae A. The detailed mechanism deserves further investigation.【Conclusion】The present study manifests that 4-hydroxyphenylpyruvate is the precursor of butyrolactone I and reveals that 3,4-dihydroxyphenylpyruvate and 4-hydroxyphenylpyruvate synthase inhibitors can be used as small molecule tools to suppress the production of butyrolactone I, which may be applied in further study on simulated mutational biosynthesis to generate diverse butyrolactone derivatives and induce the production of cyclopeptide.

Key words: marine fungus, chemical regulation, simulated mutational biosynthesis, butyrolactone, precursor analog, synthase inhibitor, LC-MS/MS, molecular network

马小翔, 马泽源, 刘亚月, 周龙建, 和羿帆, 张翼. 仿突变生物合成调控对土曲霉C23-3次生代谢产物的影响[J]. 生物技术通报, 2024, 40(8): 275-287.

MA Xiao-xiang, MA Ze-yuan, LIU Ya-yue, ZHOU Long-jian, HE Yi-fan, ZHANG Yi. Effects of Simulated Mutational Biosynthetic Regulation on the Secondary Metabolites of Aspergillus terreus C23-3[J]. Biotechnology Bulletin, 2024, 40(8): 275-287.

图/表 8

图1 本文所用前体小分子诱导剂和酶抑制剂的结构

Fig. 1 Structures of the precursor-like small molecular inducers and enzyme inhibitors used in this study

图2 不同培养时间菌株 C23-3 的胞内、胞外及总丁内酯I含量 A：用于计算提取物中丁内酯I含量的标准曲线；B-D：分别为胞内、胞外和总的丁内酯I含量，培养时间从接种后开始计算。*, **, ***, ****指的是其他天数与第1天对比的差异性，分别是P值<0.05、0.01、0.001和0.000 1。组间差异分析用的是Ordinary one-way ANOVA multiple comparisons

Fig. 2 Extracellular, intracellular, and total contents of butyrolactone I of strain C23-3 at different culture time A: Standard curve used to calculate the content of butyrolactone I in the extracts. B-D: Extracellular, intracellular, and total contents of butyrolactone I, the incubation time is calculated from the time after inoculation. *, **, ***, **** refers to the difference between the other days and the first day, which are P values < 0.05, 0.01, 0.001, and 0.000 1, respectively. Ordinary one-way ANOVA multiple comparisons were used for difference analysis between groups

图3 不同酶抑制剂或诱导剂作用下菌株C23-3的丁内酯I总产量（A）与总提取物量（B） ADA：酶抑制剂1,3-金刚烷二乙酸；NTSP：酶抑制剂N-（对甲苯磺酰）-L-苯丙氨酸；PS：酶抑制剂苯乙肼硫酸盐；HT：诱导剂3-羟基-L-酪氨酸；DHPPA：诱导剂3,4-二羟基对苯丙酮酸；Far：诱导剂金合欢醇；DMSO：溶剂DMSO对照组；blank：空白组。缩写后的数字表示浓度，单位为mmol/L。*, **, ***指的是其他组与blank对比的差异性，分别是P值<0.05、0.01和0.001。组间差异分析用的是Ordinary one-way ANOVA multiple comparisons

Fig. 3 Butyrolactone I contents（A）and total extract mass（B）of strain C23-3 under the effect of different enzyme inhibitors or inducers ADA: Enzyme inhibitor 1,3-adamantane diacetic acid; NTSP: enzyme inhibitor N-（p-toluenesulfonyl）-L-phenylalanine; PS: enzyme inhibitor phenelzine sulfate; HT: inducer 3-hydroxy-L-tyrosine; DHPPA: inducer 3,4-dihydroxy-p-phenylpyruvate; Far: inducer farnesol; DMSO: the DMSO control group; blank: the blank group. The number after the abbreviations indicate the concentrations, and the unit is mmol/L. *, **, *** refer to the differences between the other groups and blank, which were P values < 0.05, 0.01, and 0.001, respectively. Ordinary one-way ANOVA multiple comparisons were used for difference analysis between groups

图4 不同培养条件下菌株Aspergillus terreus C23-3提取物LC-MS/MS-PDA色谱图 A：BPC色谱图；B：PDA色谱图；C：各化合物UV色谱图

Fig. 4 LC-MS/MS-PDA chromatogram of Aspergillus terreus C23-3 extracts under different cultural conditions A: BPC chromatogram; B: PDA chromatogram; C: UV chromatogram of each compound

图5 菌株C23-3不同培养条件下代谢产物基于二级质谱联系的分子网络图及局部放大图 A-C：分别是化合物丁内酯I、土震素B、洛伐他汀同系物的代谢物簇放大图。Compounds 1、3、6、7：分别是丁内酯I、土震素B、洛伐他汀、洛伐他汀羟酸；Compounds 2、4、5、8、9：已知化合物的可能衍生物，分别是[M（丁内酯I-H2O）+H]+、[M（土震素B-O）+H]+、[M（土震素B-CH2）+H]+、[M（洛伐他汀-H2O）+Na]+、[M（洛伐他汀-O）+Na]+。分子网络图中的节点包含7种颜色，分别表示化合物的7个样品来源：依次是空白组、溶剂DMSO对照组、添加3,4-二羟基苯丙酮酸（0.05 mmol/L、10 mmol/L）、添加N-（对甲苯磺酰）-L-苯丙氨酸（2.1 mmol/L）和苯乙肼硫酸盐（0.15 mmol/L）、添加3,4-二羟基苯丙酮酸（0.05 mmol/L）和N-（对甲苯磺酰）-L-苯丙氨酸（2.1 mmol/L）和苯乙肼硫酸盐（0.15 mmol/L）、添加3,4-二羟基苯丙酮酸（10 mmol/L）和N-（对甲苯磺酰）-L-苯丙氨酸（2.1 mmol/L）和苯乙肼硫酸盐（0.15 mmol/L）实验组

Fig. 5 Molecular network and its partial enlarged diagram of the metabolites of strain C23-3 under different cultural conditions based on MS2 relationships A-C：Enlarged images of metabolites clusters of butyrolactone I, territrem B and lovastatin congeners. Compounds 1, 3, 6, 7: Butyrolactone I，territrem B，lovastatin，and lovastatin hydroxy acid. Compounds 2, 4, 5, 8, 9：Possible derivatives of known compounds，i.e.,[M（butyrolactone I isomer）+ H]+,[M（butyrolactone I-2H）+ H]+,[M（butyrolactone I isomer + O）+ H]+,[M（butyrolactone I - H2O）+ H]+,[M（territrem B-O）+ H]+,[M（territrem B - CH2）+ H]+,[M（lovastatin - H2O）+ H]+,[M（lovastatin - O）+ H]+，and[M（lovastatin + 2H）+ H]+，respectively. The nodes in the molecular network are marked in 7 colors, , sequentially representing the 7 sample sources of compounds: blank group, control group with solvent DMSO; groups with the addition of 3,4-dihydroxyphenylpyruvate（0.05, 10 mmol/L）, N-（p-toluenesulfonyl）-L-phenylalanine（2.1 mmol/L）+ phenelzine sulfate（0.15 mmol/L）, 3,4-dihydroxyphenylpyruvate（0.05 mmol/L）+ N-（p-toluenesulfonyl）-L-phenylalanine（2.1 mmol/L）+ phenelzine sulfate（0.15 mmol/L）, 3,4-dihydroxyphenylpyruvate（10 mmol/L）+N-（p-toluenesulfonyl）-L-phenylalanine（2.1 mmol/L）+ phenelzine sulfate（0.15 mmol/L）respectively

图6 化合物20的一级和二级质谱图

Fig. 6 MS1 and MS2 spectra of compound 20

图7 菌株C23-3丁内酯I总产量随酶抑制剂和诱导剂添加的变化 Blank：空白组；DMSO：溶剂DMSO对照组；NTSP：N-（对甲苯磺酰）-L-苯丙氨酸；PS：苯乙肼硫酸盐。#P<0.05，DMSO对照组比空白组；*P<0.05，实验组比DMSO对照组；**P<0.01，样品组比对照组，***P<0.001，样品组比对照组

Fig. 7 Butyrolactone I content variation of strain C23-3 with the addition of enzyme inhibitors and inducers Blank: Blank group; DMSO: the solvent DMSO control group; NTSP: N-（p-toluenesulfonyl）-L-phenylalanine, PS: phenelzine sulfate. # P<0.05, DMSO control group vs blank group; * P<0.05, experimental group vs DMSO Control group; ** P<0.01, the sample group vs the control group, *** P<0.001, the sample group vs the control group

表1 化合物1-20在不同培养条件下的含量（峰面积积分）相对于空白对照的变化

Table 1 Variation of compounds 1-20's contents（integrated peak areas）under different cultural conditions compared to CK

化合物序号Compound No.	化合物注释 Compound note	不同培养条件下的产物产量变化幅度 Changes in product yield under different cultivation conditions/%
化合物序号Compound No.	化合物注释 Compound note	DMSO group	0.05 mmol/L 3,4-DHPPA group	10 mmol/L 3,4-DHPPA group	2.1 mmol/L NTSP + 0.15 mmol/L PS group	2.1 mmol/L NTSP + 0.15 mM PS + 0.05 mmol/L 3,4-DHPPA group	2.1 mmol/L NTSP + 0.15 mM PS + 10 mmol/L 3,4-DHPPA group
1	丁内酯I Butyrolactone I	↓62.50	↓32.71	↓90.06	↓74.04	↓68.76	↓92.19
2	丁内酯I脱水产物 Butyrolactone I dehydrated product	↓71.53	↓34.28	↓78.36	↓100.00	↓67.42	↓100.00
3	土震素B Territrem B	↑4.40	↓26.45	↑9.58	↓73.15	↓78.94	↓57.47
4	土震素B脱氧产物 Territrem B deoxylation products	↑65.52	↓100.00	↑38.07	↓80.67	↓84.58	↓100.00
5	土震素B降碳产物 Territrem B carbon reduction products	↑50.57	↓56.52	↓33.36	↓100.00	↓100.00	↓86.79
土震素B类化合物总产量 Total production of territrem B compound		↑5.12	↓27.10	↑9.36	↓73.42	↓79.14	↓57.95
6	洛伐他汀Lovastatin	↑6.60	↓28.74	↓29.12	↑86.14	↑46.16	↓100.00
7	洛伐他汀羟酸 Lovastatin hydroxy acid	↓91.26	↓85.64	↓88.04	↓62.17	↓83.70	↓85.34
8	洛伐他汀脱水产物 Lovastatin dehydrated products	↓34.19	↑10.05	↓57.14	↑50.70	↑15.97	↓98.61
9	洛伐他脱氧产物 Lovastatin deoxygenation products	↓64.96	↓100.00	↓100.00	↑95.58	↑12.68	↓100.00
洛伐他汀类化合物总产量 Total production of lovastatin compounds		↓43.48	↓48.02	↓60.20	↑16.07	↓15.59	↓93.41
10	N/A	↓25.36	↓12.73	↓16.03	↓6.82	↓17.87	↓34.47
11	Aspernolide C	↑30.46	↓20.96	↑24.90	↓79.36	↓80.96	↓55.49
12	Isochromophilone VI脱氢产物 Isochromophilone VI dehydrogenation product	↓1.59	↓29.31	↓6.46	↓71.79	↓75.73	↓58.11
13	Epi-aszonaleni A	↑11.30	↓24.58	↓9.34	↓66.76	↓70.52	↓40.02
14	N/A	↓28.33	↑0.59	↓54.44	↓24.12	↓53.74	↓90.22
15	Asterriquinone CT3	↓21.98	↓31.05	↑34.49	↓81.50	↓84.16	↓11.36
16	Perinadine A	↓43.49	↑38.06	↓66.44	↓15.69	↓46.11	↓88.34
17	12a-dehydroxyisoterreulactone A or Terreulactone C	↓67.24	↓26.58	↓85.57	↑6.36	↓22.89	↓100.00
18	Teraspiridole B	↑8.11	↑14.79	↑148.27	↓13.45	↓38.63	↑94.77
19	N/A	↓26.37	↑1.29	↑13.45	↑50.55	↓3.21	↑19.44
20	N/A	↑111.26	↓81.63	↑1208.42	↑570.07	↑181.73	↑1399.99

表1 化合物1-20在不同培养条件下的含量（峰面积积分）相对于空白对照的变化

Table 1 Variation of compounds 1-20's contents（integrated peak areas）under different cultural conditions compared to CK

化合物序号Compound No.	化合物注释 Compound note	不同培养条件下的产物产量变化幅度 Changes in product yield under different cultivation conditions/%
化合物序号Compound No.	化合物注释 Compound note	DMSO group	0.05 mmol/L 3,4-DHPPA group	10 mmol/L 3,4-DHPPA group	2.1 mmol/L NTSP + 0.15 mmol/L PS group	2.1 mmol/L NTSP + 0.15 mM PS + 0.05 mmol/L 3,4-DHPPA group	2.1 mmol/L NTSP + 0.15 mM PS + 10 mmol/L 3,4-DHPPA group
1	丁内酯I Butyrolactone I	↓62.50	↓32.71	↓90.06	↓74.04	↓68.76	↓92.19
2	丁内酯I脱水产物 Butyrolactone I dehydrated product	↓71.53	↓34.28	↓78.36	↓100.00	↓67.42	↓100.00
3	土震素B Territrem B	↑4.40	↓26.45	↑9.58	↓73.15	↓78.94	↓57.47
4	土震素B脱氧产物 Territrem B deoxylation products	↑65.52	↓100.00	↑38.07	↓80.67	↓84.58	↓100.00
5	土震素B降碳产物 Territrem B carbon reduction products	↑50.57	↓56.52	↓33.36	↓100.00	↓100.00	↓86.79
土震素B类化合物总产量 Total production of territrem B compound		↑5.12	↓27.10	↑9.36	↓73.42	↓79.14	↓57.95
6	洛伐他汀Lovastatin	↑6.60	↓28.74	↓29.12	↑86.14	↑46.16	↓100.00
7	洛伐他汀羟酸 Lovastatin hydroxy acid	↓91.26	↓85.64	↓88.04	↓62.17	↓83.70	↓85.34
8	洛伐他汀脱水产物 Lovastatin dehydrated products	↓34.19	↑10.05	↓57.14	↑50.70	↑15.97	↓98.61
9	洛伐他脱氧产物 Lovastatin deoxygenation products	↓64.96	↓100.00	↓100.00	↑95.58	↑12.68	↓100.00
洛伐他汀类化合物总产量 Total production of lovastatin compounds		↓43.48	↓48.02	↓60.20	↑16.07	↓15.59	↓93.41
10	N/A	↓25.36	↓12.73	↓16.03	↓6.82	↓17.87	↓34.47
11	Aspernolide C	↑30.46	↓20.96	↑24.90	↓79.36	↓80.96	↓55.49
12	Isochromophilone VI脱氢产物 Isochromophilone VI dehydrogenation product	↓1.59	↓29.31	↓6.46	↓71.79	↓75.73	↓58.11
13	Epi-aszonaleni A	↑11.30	↓24.58	↓9.34	↓66.76	↓70.52	↓40.02
14	N/A	↓28.33	↑0.59	↓54.44	↓24.12	↓53.74	↓90.22
15	Asterriquinone CT3	↓21.98	↓31.05	↑34.49	↓81.50	↓84.16	↓11.36
16	Perinadine A	↓43.49	↑38.06	↓66.44	↓15.69	↓46.11	↓88.34
17	12a-dehydroxyisoterreulactone A or Terreulactone C	↓67.24	↓26.58	↓85.57	↑6.36	↓22.89	↓100.00
18	Teraspiridole B	↑8.11	↑14.79	↑148.27	↓13.45	↓38.63	↑94.77
19	N/A	↓26.37	↑1.29	↑13.45	↑50.55	↓3.21	↑19.44
20	N/A	↑111.26	↓81.63	↑1208.42	↑570.07	↑181.73	↑1399.99

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仿突变生物合成调控对土曲霉C23-3次生代谢产物的影响

Effects of Simulated Mutational Biosynthetic Regulation on the Secondary Metabolites of Aspergillus terreus C23-3

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