何首乌悬浮细胞系的建立和稳定同位素示踪研究二苯乙烯苷合成路径
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摘要
二苯乙烯苷（2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside, THSG)是何首乌（Polygonum multiflorum Thunb.）的主要有效成分，具有抗炎、抗氧化、调节血脂、抗肿瘤、安神、预防和治疗阿尔茨海默症作用。目前二苯乙烯苷研究集中在提取和药理方面，对二苯乙烯苷的生物合成路径未见报道，因此二苯乙烯苷的合成路经值得研究。首先获得何首乌愈伤组织，然后建立何首乌悬浮细胞系。利用普通前体饲喂和稳定同位素前体示踪何首乌悬浮细胞，通过HPLC-MS/MS进行检测，根据检测结果推测二苯乙烯苷生物合成路径。本文主要研究结果如下：
（1）通过正交实验获得何首乌愈伤组织的诱导培养基：含有1mg·L~(-1)2,4-D和0.4mg·L~(-1)NAA的MS培养基。在此培养基中，15天就能诱导出愈伤组织，愈伤组织的诱导率为96.7%。检测了何首乌根、茎、叶的愈伤组织诱导效果和二苯乙烯苷的含量，发现何首乌根、茎和叶都能诱导出愈伤组织，其中根诱导出的愈伤组织中二苯乙烯苷含量最高，为1.5mg·g~(-1)，因此选择二苯乙烯苷含量高的根愈伤组织进行培养。何首乌愈伤组织比较致密，不能进行悬浮细胞培养。通过把何首乌愈伤组织接入液体MS培养基中培养4天，然后转接到含有不同植物生长激素的固体MS培养基中进行培养，获得了疏松易碎的愈伤组织，通过实验获得适合何首乌疏松愈伤组织生长的植物生长激素配比：0.2mg·L~(-1)6-BA和0.5mg·L~(-1)NAA。
（2）比较了何首乌在MS、B5和N6培养基生长的效果，发现MS培养基是何首乌液体最佳生长培养基，在此培养基中生长的细胞干重和二苯乙烯苷含量分别为6.35g·L~(-1)和42.23mg·L~(-1)，因此选择MS培养基作为何首乌悬浮培养基。
（3）通过把悬浮细胞铺在平板上，培养30天后，挑选生长快的小细胞团转接到新的平板继续培养，然后每隔15天转接一次，共转接6次，检测不同细胞团的二苯乙烯苷含量，最终获得高含量二苯乙烯苷的细胞系，此高含量何首乌悬浮细胞的干重和二苯乙烯苷的含量分别达到7.46g·L~(-1)DW和56.23mg·L~(-1)，而原细胞系悬浮细胞的干重和二苯乙烯苷含量分别6.55g·L~(-1)DW和43.39mg·L~(-1)，此高含量细胞系悬浮培养干重比原细胞系提高了13.89%，二苯乙烯苷含量比原细胞系提高了29.59%。通过发酵条件优化，获得何首乌悬浮细胞系最佳的培养条件为100rpm、26℃暗培养16天。
（4）为了筛选二苯乙烯苷合成路径的前体和饲喂研究，在何首乌悬浮细胞培养的第10天，在何首乌悬浮细胞MS培养基中分别加入不同浓度的苯丙氨酸，发现添加60mg·L~(-1)的苯丙氨酸时何首乌悬浮细胞中二苯乙烯苷含量最高，达到105.15mg·L~(-1)，比没有加苯丙氨酸的对照组（55.23mg·L~(-1)）增加了90.38%，这说明苯丙氨酸能增加二苯乙烯苷含量，可能是二苯乙烯苷的前体。在何首乌悬浮细胞培养基中分别加入不同浓度的肉桂酸，发现添加40mg·L~(-1)的肉桂酸时何首乌悬浮细胞达到最大二苯乙烯苷含量：123.03mg·L~(-1)，比没有加肉桂酸的对照组（55.23mg·L~(-1)）增加了122.76%，这说明肉桂酸能增加二苯乙烯苷含量，可能是二苯乙烯苷的前体。在何首乌悬浮细胞培养基中分别加入不同浓度的乙酸钠，发现添加20mg·L~(-1)的乙酸钠，何首乌悬浮细胞能达到最大二苯乙烯苷含量：89.08mg·L~(-1)，比没有加乙酸钠的对照组（55.23mg·L~(-1)）增加了61.29%，这说明乙酸钠能增加二苯乙烯苷含量，可能是二苯乙烯苷的前体。在液体MS培养基中分别加入不同浓度苯丙氨酸、肉桂酸和乙酸钠的混合前体，发现添加40mg·L~(-1)的肉桂酸和20mg·L~(-1)乙酸钠，何首乌悬浮细胞二苯乙烯苷含量最大：162.65mg·L~(-1)，比对照组（55.23mg·L~(-1)）增加了194.50%，说明混合前体效果最好。（5）在何首乌液体MS培养基中加入U~(-1)3C9苯丙氨酸示踪，通过HPLC-MS/MS检测，~(13)C标记的苯丙氨酸能结合进入二苯乙烯苷，这确证了苯丙氨酸是二苯乙烯苷的前体。在何首乌液体MS培养基中加入U~(-1)3C9肉桂酸示踪，通过HPLC-MS/MS检测，~(13)C标记的肉桂酸能结合进入二苯乙烯苷，这确证了肉桂酸也是二苯乙烯苷的前体，并且示踪实验证明了我们假定的二苯乙烯苷合成路径。
根据以上结论，我们证明了何首乌二苯乙烯苷的生物合成路径：苯丙氨酸作为前体，在苯丙氨酸解氨作用下合成肉桂酸，再经过几步反应合成二苯乙烯苷。
THSG (2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside) is the main active ingredient ofPolygonum multiflorum Thunb., which posses anti-inflammatory, antioxidant, regulating lipid,anti-tumor, calming the nerves, prevention and treatment of Alzheimer's disease. At presentthe study focus on the extraction and pharmacological effect of THSG, yet THSGbiosynthetic pathway has not been reported. We are committed to the biosynthesis pathway ofTHSG. First, calli were induced, then suspension cell line was established. Normal precursorswere added and stable isotope precursor was used to tracer cells of Polygonum multiflorumThunb. THSG was speculated by HPLC-MS/MS, on the basis of results THSG biosyntheticpathway was deducted. The main results of this article are as follows:
(1) Induction medium of Polygonum multiflorum Thunb. was obtained by orthogonalexperiments which contained1mg·L~(-1)2,4-D and0.4mg·L~(-1)NAA in MS medium. In thismedium, calli can be induced in15days, and induction rate of calli was96.7%. The inductioneffect of root, stems and leaves of Polygonum multiflorum Thunb. was evaluated and THSGcontent was examined, and found that root, stems and leaves of Polygonum multiflorumThunb. can be induced. The highest content of THSG in root calli was1.5mg·g~(-1), so rootcalli were used to transfer and culture. Calli were fine and close which can’t be suspended.Calli were transferred in liquid MS medium for4days, then transferred to solid MS mediumcontaining different plant growth hormone, at last loose and friable calli were acquired, andthe growth hormone were0.2mg·L~(-1)6-BAand0.5mg·L~(-1)NAA.
(2) The growth effect was compared in MS, B5and N6medium, and MS medium is the bestmedium. The cell DW (dry weight) and THSG content in this medium was respectively6.35g·L~(-1)and42.23mg·L~(-1), so MS medium was selected as suspension medium.
(3) Suspension cells were spread on the plate, and cultured for30days. Fast-growing smallcell clusters were selected and transferred on the plate, and then transferred once every15days for six times. THSG content of different small cell cluster was examined and ultimatelya high content cell line of THSG was acquired, and DW and THSG content of this high yieldcell line of Polygonum multiflorum Thunb. was7.46g·L~(-1)and56.23mg·L~(-1)respectively, yetDW and THSG content of the original cell line was respectively6.55g·L~(-1)and43.39mg·L~(-1). DW and THSG content of this high content cell line of Polygonum multiflorum Thunb.respectively increased by13.89%and29.59%than the original cell line. By optimization offermentation conditions, the best culture conditions were100rpm,26℃and dark culture for16days.
(4) In order to screen precursors of THSG biosynthetic pathway and feeding studies,Different concentration of phenylalanine was added in suspension medium of Polygonummultiflorum Thunb. in the10thday,105.15mg·L~(-1)of THSG was acquired which increased by90.38%in60mg·L~(-1)phenylalanine than the control group (55.23mg·L~(-1)). Differentconcentrations of cinnamic acid were added in suspension cell medium. THSG can can reachthe maximum content in40mg·L~(-1)cinnamic acid:123.03mg·L~(-1)which increased by122.76%than the control group (55.23mg·L~(-1)). Different concentration of sodium acetatewas added in suspension medium.20mg·L~(-1)sodium acetate was added in suspensionmedium. The maximum production of THSG can be reached:89.08mg·L~(-1)than the controlgroup (55.23mg·L~(-1)) which increased by61.29%. Mixed precursors of differentconcentration of phenylalanine, cinnamic acid and sodium acetate were added in liquid MSmedium, and the maximum content of THSG acquired in40mg·L~(-1)cinnamic acid and20mg·L~(-1)sodium acetate was162.65mg·L~(-1)than the control group (55.23mg·L~(-1)) whichincreased by194.50%, so mixed precursor had best effect.
(5) U~(-1)3C9phenylalanine was added in liquid MS medium of Polygonum multiflorum Thunb.Then THSG was detected by HPLC-MS/MS,~(13)C phenylalanine can be combined into THSG,which confirmed phenylalanine was precursor of THSG. U~(-1)3C9cinnamic acid was added inliquid MS medium. Then THSG was detected by HPLC-MS/MS,~(13)C cinnamic acid can becombined into THSG, which confirmed that cinnamic acid was a precursor of THSG, and thetracer experiment proved hypothetical THSG biosynthetic pathway.
Based on the above findings, we proved THSG biosynthetic pathway: phenylalanine asprecursor under phenylalanine ammonia lyase, then synthesize cinnamic acid, after a fewsteps biosynthetic reaction further synthesize THSG.
（1）通过正交实验获得何首乌愈伤组织的诱导培养基：含有1mg·L~(-1)2,4-D和0.4mg·L~(-1)NAA的MS培养基。在此培养基中，15天就能诱导出愈伤组织，愈伤组织的诱导率为96.7%。检测了何首乌根、茎、叶的愈伤组织诱导效果和二苯乙烯苷的含量，发现何首乌根、茎和叶都能诱导出愈伤组织，其中根诱导出的愈伤组织中二苯乙烯苷含量最高，为1.5mg·g~(-1)，因此选择二苯乙烯苷含量高的根愈伤组织进行培养。何首乌愈伤组织比较致密，不能进行悬浮细胞培养。通过把何首乌愈伤组织接入液体MS培养基中培养4天，然后转接到含有不同植物生长激素的固体MS培养基中进行培养，获得了疏松易碎的愈伤组织，通过实验获得适合何首乌疏松愈伤组织生长的植物生长激素配比：0.2mg·L~(-1)6-BA和0.5mg·L~(-1)NAA。
（2）比较了何首乌在MS、B5和N6培养基生长的效果，发现MS培养基是何首乌液体最佳生长培养基，在此培养基中生长的细胞干重和二苯乙烯苷含量分别为6.35g·L~(-1)和42.23mg·L~(-1)，因此选择MS培养基作为何首乌悬浮培养基。
（3）通过把悬浮细胞铺在平板上，培养30天后，挑选生长快的小细胞团转接到新的平板继续培养，然后每隔15天转接一次，共转接6次，检测不同细胞团的二苯乙烯苷含量，最终获得高含量二苯乙烯苷的细胞系，此高含量何首乌悬浮细胞的干重和二苯乙烯苷的含量分别达到7.46g·L~(-1)DW和56.23mg·L~(-1)，而原细胞系悬浮细胞的干重和二苯乙烯苷含量分别6.55g·L~(-1)DW和43.39mg·L~(-1)，此高含量细胞系悬浮培养干重比原细胞系提高了13.89%，二苯乙烯苷含量比原细胞系提高了29.59%。通过发酵条件优化，获得何首乌悬浮细胞系最佳的培养条件为100rpm、26℃暗培养16天。
（4）为了筛选二苯乙烯苷合成路径的前体和饲喂研究，在何首乌悬浮细胞培养的第10天，在何首乌悬浮细胞MS培养基中分别加入不同浓度的苯丙氨酸，发现添加60mg·L~(-1)的苯丙氨酸时何首乌悬浮细胞中二苯乙烯苷含量最高，达到105.15mg·L~(-1)，比没有加苯丙氨酸的对照组（55.23mg·L~(-1)）增加了90.38%，这说明苯丙氨酸能增加二苯乙烯苷含量，可能是二苯乙烯苷的前体。在何首乌悬浮细胞培养基中分别加入不同浓度的肉桂酸，发现添加40mg·L~(-1)的肉桂酸时何首乌悬浮细胞达到最大二苯乙烯苷含量：123.03mg·L~(-1)，比没有加肉桂酸的对照组（55.23mg·L~(-1)）增加了122.76%，这说明肉桂酸能增加二苯乙烯苷含量，可能是二苯乙烯苷的前体。在何首乌悬浮细胞培养基中分别加入不同浓度的乙酸钠，发现添加20mg·L~(-1)的乙酸钠，何首乌悬浮细胞能达到最大二苯乙烯苷含量：89.08mg·L~(-1)，比没有加乙酸钠的对照组（55.23mg·L~(-1)）增加了61.29%，这说明乙酸钠能增加二苯乙烯苷含量，可能是二苯乙烯苷的前体。在液体MS培养基中分别加入不同浓度苯丙氨酸、肉桂酸和乙酸钠的混合前体，发现添加40mg·L~(-1)的肉桂酸和20mg·L~(-1)乙酸钠，何首乌悬浮细胞二苯乙烯苷含量最大：162.65mg·L~(-1)，比对照组（55.23mg·L~(-1)）增加了194.50%，说明混合前体效果最好。（5）在何首乌液体MS培养基中加入U~(-1)3C9苯丙氨酸示踪，通过HPLC-MS/MS检测，~(13)C标记的苯丙氨酸能结合进入二苯乙烯苷，这确证了苯丙氨酸是二苯乙烯苷的前体。在何首乌液体MS培养基中加入U~(-1)3C9肉桂酸示踪，通过HPLC-MS/MS检测，~(13)C标记的肉桂酸能结合进入二苯乙烯苷，这确证了肉桂酸也是二苯乙烯苷的前体，并且示踪实验证明了我们假定的二苯乙烯苷合成路径。
根据以上结论，我们证明了何首乌二苯乙烯苷的生物合成路径：苯丙氨酸作为前体，在苯丙氨酸解氨作用下合成肉桂酸，再经过几步反应合成二苯乙烯苷。
THSG (2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside) is the main active ingredient ofPolygonum multiflorum Thunb., which posses anti-inflammatory, antioxidant, regulating lipid,anti-tumor, calming the nerves, prevention and treatment of Alzheimer's disease. At presentthe study focus on the extraction and pharmacological effect of THSG, yet THSGbiosynthetic pathway has not been reported. We are committed to the biosynthesis pathway ofTHSG. First, calli were induced, then suspension cell line was established. Normal precursorswere added and stable isotope precursor was used to tracer cells of Polygonum multiflorumThunb. THSG was speculated by HPLC-MS/MS, on the basis of results THSG biosyntheticpathway was deducted. The main results of this article are as follows:
(1) Induction medium of Polygonum multiflorum Thunb. was obtained by orthogonalexperiments which contained1mg·L~(-1)2,4-D and0.4mg·L~(-1)NAA in MS medium. In thismedium, calli can be induced in15days, and induction rate of calli was96.7%. The inductioneffect of root, stems and leaves of Polygonum multiflorum Thunb. was evaluated and THSGcontent was examined, and found that root, stems and leaves of Polygonum multiflorumThunb. can be induced. The highest content of THSG in root calli was1.5mg·g~(-1), so rootcalli were used to transfer and culture. Calli were fine and close which can’t be suspended.Calli were transferred in liquid MS medium for4days, then transferred to solid MS mediumcontaining different plant growth hormone, at last loose and friable calli were acquired, andthe growth hormone were0.2mg·L~(-1)6-BAand0.5mg·L~(-1)NAA.
(2) The growth effect was compared in MS, B5and N6medium, and MS medium is the bestmedium. The cell DW (dry weight) and THSG content in this medium was respectively6.35g·L~(-1)and42.23mg·L~(-1), so MS medium was selected as suspension medium.
(3) Suspension cells were spread on the plate, and cultured for30days. Fast-growing smallcell clusters were selected and transferred on the plate, and then transferred once every15days for six times. THSG content of different small cell cluster was examined and ultimatelya high content cell line of THSG was acquired, and DW and THSG content of this high yieldcell line of Polygonum multiflorum Thunb. was7.46g·L~(-1)and56.23mg·L~(-1)respectively, yetDW and THSG content of the original cell line was respectively6.55g·L~(-1)and43.39mg·L~(-1). DW and THSG content of this high content cell line of Polygonum multiflorum Thunb.respectively increased by13.89%and29.59%than the original cell line. By optimization offermentation conditions, the best culture conditions were100rpm,26℃and dark culture for16days.
(4) In order to screen precursors of THSG biosynthetic pathway and feeding studies,Different concentration of phenylalanine was added in suspension medium of Polygonummultiflorum Thunb. in the10thday,105.15mg·L~(-1)of THSG was acquired which increased by90.38%in60mg·L~(-1)phenylalanine than the control group (55.23mg·L~(-1)). Differentconcentrations of cinnamic acid were added in suspension cell medium. THSG can can reachthe maximum content in40mg·L~(-1)cinnamic acid:123.03mg·L~(-1)which increased by122.76%than the control group (55.23mg·L~(-1)). Different concentration of sodium acetatewas added in suspension medium.20mg·L~(-1)sodium acetate was added in suspensionmedium. The maximum production of THSG can be reached:89.08mg·L~(-1)than the controlgroup (55.23mg·L~(-1)) which increased by61.29%. Mixed precursors of differentconcentration of phenylalanine, cinnamic acid and sodium acetate were added in liquid MSmedium, and the maximum content of THSG acquired in40mg·L~(-1)cinnamic acid and20mg·L~(-1)sodium acetate was162.65mg·L~(-1)than the control group (55.23mg·L~(-1)) whichincreased by194.50%, so mixed precursor had best effect.
(5) U~(-1)3C9phenylalanine was added in liquid MS medium of Polygonum multiflorum Thunb.Then THSG was detected by HPLC-MS/MS,~(13)C phenylalanine can be combined into THSG,which confirmed phenylalanine was precursor of THSG. U~(-1)3C9cinnamic acid was added inliquid MS medium. Then THSG was detected by HPLC-MS/MS,~(13)C cinnamic acid can becombined into THSG, which confirmed that cinnamic acid was a precursor of THSG, and thetracer experiment proved hypothetical THSG biosynthetic pathway.
Based on the above findings, we proved THSG biosynthetic pathway: phenylalanine asprecursor under phenylalanine ammonia lyase, then synthesize cinnamic acid, after a fewsteps biosynthetic reaction further synthesize THSG.
引文
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