KR20000037547A - Method for manufacturing taxol using metal ion - Google Patents
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- KR20000037547A KR20000037547A KR1019980052163A KR19980052163A KR20000037547A KR 20000037547 A KR20000037547 A KR 20000037547A KR 1019980052163 A KR1019980052163 A KR 1019980052163A KR 19980052163 A KR19980052163 A KR 19980052163A KR 20000037547 A KR20000037547 A KR 20000037547A
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Abstract
Description
본 발명은 금속이온을 이용한 택솔의 제조방법에 관한 것으로서, 더욱 상세하게는 택솔을 생산하는 진균, 특히 페스탈로티아 헤테로코니스(Pestalotia heterocornis) KCTC 0340BP를 철, 망간 및 마그네슘 이온을 과량 함유한 배지에서 배양함으로써 배양액 중에 택솔을 고수율로 축적시킬 수 있는 택솔의 제조방법에 관한 것이다.The present invention relates to a method for preparing taxol using metal ions, and more particularly, to a fungus producing taxol, in particular, Pestalotia heterocornis KCTC 0340BP in a medium containing excess iron, manganese and magnesium ions. The present invention relates to a method for producing taxol, which can accumulate taxol in a high yield by culturing.
택솔은 주목과 주목속에 속하는 주목(Taxus cuspidata), 태평양주목(Taxus brevifolia) 등의 잎, 줄기, 뿌리 등에 존재하는 물질로 1971년 바니 등(M.C, Wani, H.L. Taylor, M.E. Wall, P. Coggon, and A.t. McPhail, J. Am. Chem. Soc., 93, 2325, 1971)에 의해 그 화학적 구조가 처음으로 밝혀졌으며, 그 구조는 다음 화학식 1로 표시되는 바와 같다.Taxol is a substance found in the leaves, stems, and roots of Taxus cuspidata and Taxus brevifolia, which belongs to the attention and the genus, and in 1971 (MC, Wani, HL Taylor, ME Wall, P. Coggon, and At McPhail, J. Am. Chem. Soc., 93, 2325, 1971), the chemical structure was first identified, and the structure is represented by the following formula (1).
택솔은 여러 가지 암세포주에 대하여 뛰어난 항암활성을 나타내어 의약품으로 개발되고 있으며, 특히 자궁암에 대해서는 임상실험 페이즈 I단계를 거쳐 페이즈 II 단게에 있다. 이 물질은 주목의 줄기껍질 부분에 약 0.041∼0.02% 정도로 가장 많이 함유되어 있는 것으로 밝혀져 있다.Taxol is being developed as a drug because it shows excellent anticancer activity against various cancer cell lines. Especially, uterine cancer is in Phase II stage after phase I clinical trial. This substance is found to contain the most at about 0.041 to 0.02% in the stem bark of yeast.
그러나, 주목은 정원수로 일부 재배되는 외에는 성장속도가 매우 느려 지금까지 목재 등의 용도로는 환영받지 못한 식물로, 그 수가 매우 적다. 더구나, 주목으로부터 추출되는 택솔의 양이 너무 적고(1g의 택솔을 얻기 위해 10,000g의 주목 껍질이 필요하다), 추출 방법이 까다로우며 생산량도 적다.However, attention is a plant that has not been welcomed for the purpose of timber and the like so far, except for being partially grown as garden water, and the number thereof is very small. Moreover, the amount of taxol extracted from the yew is too small (10,000 g of yeast hulls are needed to obtain 1 g of taxol), the extraction method is difficult and the yield is low.
따라서, 미합중국 특허 제4,924,011호에서는 탁솔을 제조하기 위한 화학적 방법에 대하여 개시하고 있으나, 이 방법은 복잡한 과정을 요구하므로 경제성이 떨어지는 문제점이 있다.Therefore, although US Pat. No. 4,924,011 discloses a chemical method for preparing taxol, this method requires a complicated process and thus has a problem of low economic efficiency.
한편, 국내에 자생하고 있는 주목 나무 종자의 씨눈에는 지금까지 보고된 바 있는 주목나무 수피 내 택솔을 함유량의 최대치보다 200배 이상 많은 양의 택솔이 함유되어 있다고 보고된 바 있다.On the other hand, the seed of the seedling tree growing in Korea has been reported to contain taxol in the amount of taxol in the bark of yew tree, which has been reported up to 200 times more than the maximum content.
그리고, PCT/US 93/03416에서 미국 몬타나 대학 식물 병리학자인 안드레아 스티얼(Anderea stierle) 등은 주목 나무의 내수피(inner bark)로부터 택솔을 생산하는 곰팡이인 탁소마이세스 안드레아나(Taxomyces andreanae)를 분리하는 방법에 대해 개시하고 있다. 그러나, 이같은 곰팡이에서 생산되는 택솔의 양은 1ℓ 당 1∼2㎍의 미량에 불과하다는 문제점이 있다.And in PCT / US 93/03416, Andrea Stearle, a plant pathologist at the University of Montana in the United States, described Taxaxiesces andreanae, a fungus that produces taxols from the inner bark of yew trees. A method of separating is disclosed. However, there is a problem that the amount of taxol produced in such a fungus is only a trace amount of 1 to 2 μg per 1 liter.
이같은 문제점을 해결하기 위하여 본 출원인은 택솔 및 택산을 생산하는 신균주를 발견학, 이를 동정·확인한 결과 페스탈로티아 헤테로코니스(Pestalotia heterocornis)로 명명하고, 이를 1997년 6월 30일자로 한국유전자 은행기탁하고 수탁번호를 부여받았으며(수탁번호 KCTC 0340BP), 이에 대하여 1997년 7월 11일자로 특허출원한 바 있다(대한민국 특허출원 제97-32358호).In order to solve this problem, the applicant has identified, as a result of the heuristics, identification and identification of new strains producing taxols and taxanes, and named them as Pestalotia heterocornis. It was deposited and was given accession number (accession number KCTC 0340BP) and filed a patent application on July 11, 1997 (Korean Patent Application No. 97-32358).
여기서는 탁수스 속 나무가 자생하고 있는 토양의 일부를 취하고, 이 토양을 50∼95% 알콜에 침적시키고 그 침적물을 여과하여 잔사를 얻고, 상기 잔사에 멸균 식염수를 가하여 진탕하여 진탕액을 만들고, 상기 진탕액의 상등액 일부를 진균이 증식할 때까지 아가(agar) 배지 상에서 2∼5일간 증식시키고, 상기 증식균사를 진균 실험용 증식 배지로 옮겨 진균 배양물을 증식시키고, 상기 진균 배양물을 함유하는 배지의 적어도 일부를 분리하고 균사를 완전히 분쇄하여 얻은 혼합물에 액체 크로마토그래피 용매를 첨가하고, 상기 용매 중에 함유되어 있는 진균 배양물의 크로마토그래프를 얻고, 상기 배양물의 일부를 취하여 탁산, 택솔 및 바카틴(baccatin)을 각각 정량하고, 크로마토그래프를 택솔, 바카틴 및 세팔로만닌(cephalomannine)으로 이루어진 그룹으로부터 선택되는 1 이상의 탁산 표준물과 비교하는 단계를 거쳐 페스탈로티아 헤테로코니스(Pastalotia Heterocornis) KCTC 0340BP를 분리하였다.Here, a part of the soil in which the tree of Taxus is grown is taken up, and this soil is immersed in 50-95% alcohol and the deposit is filtered to obtain a residue, and the residue is shaken with sterile saline to make a shake solution. A portion of the supernatant of the shake solution is grown on agar medium for 2 to 5 days until the fungus grows, and the proliferating mycelia are transferred to the fungal experimental growth medium to grow the fungal culture, and the medium containing the fungal culture. A liquid chromatography solvent is added to the mixture obtained by isolating at least a portion of the mixture and grinding the hyphae completely, to obtain a chromatograph of the fungal culture contained in the solvent, and taking a portion of the culture to obtain taxane, taxol and baccatin (baccatin). ) And the chromatographs are divided into groups consisting of Taxol, Bacatin and Cephalomannine. Selected at least one taxane through the step of comparing and standards were isolated Fes phthaloyl thiazol hetero cornice (Pastalotia Heterocornis) KCTC 0340BP.
그리고, 페스탈로티아 헤테로코니스(Pestalotia Heterocornis) KCTC 0340BP를 진균의 증식이 일어나게 할 수 있는 영양 배지에 노출시키고, 상기 진균이 증식 및 복제할 수 있는 조건을 포함한 진균을 함유하는 배지를 위한 배양 조건을 제공하고, 상기 배양 배지 또는 진균으로부터 목적으로 하는 탁산을 분리하거나 농축하는 과정을 거쳐 탁산을 제조하였다. 이때, 영양 배지는 벤조산, 벤조산 대사 물질 전구체 및 소디움 벤조에이트로 이루어지는 군으로부터 선택된 화합물로 이루어진다.Then, Pestolopia Heterocornis KCTC 0340BP is exposed to a nutrient medium capable of causing the growth of fungi, and culture conditions for the medium containing fungi including conditions under which the fungi can proliferate and replicate. Taxane was prepared by a process of separating or concentrating the desired taxane from the culture medium or fungi. At this time, the nutrient medium is composed of a compound selected from the group consisting of benzoic acid, benzoic acid metabolite precursor and sodium benzoate.
그러나, 이와같은 방법으로 택솔을 생산하는 경우 택솔의 양이 1ℓ당 30㎍이어서 이를 산업화하는 데는 아직까지 만족스럽지 못한 문제점이 있다.However, in the case of producing taxol in this manner, the amount of the taxol is 30 µg per liter, so there is a problem that is not satisfactory yet for industrialization.
본 발명의 목적은 택솔을 생산하는 진균, 특히 페스탈로티아 헤테로코니스(Pestalotia Heterocornis)를 주목나무나 주목나무 추출물을 함유한 배지원에서 배양함으로써 고수율로 택솔을 제조하는 방법을 제공하는 데 있다.It is an object of the present invention to provide a method for producing taxol in high yield by culturing fungi producing Taxol, in particular, Pestolotia Heterocornis, in a culture medium containing yew or yeast extract.
도 1 은 철, 망간, 마그네슘, 코발트, 나트륨, 구리, 아연 이온이 페스탈로티아 헤테로코니스(Pestalotia heterocornis) KCTC 0340BP의 성장에 미치는 영향을 확인한 그래프이고,1 is a graph confirming the effect of iron, manganese, magnesium, cobalt, sodium, copper, zinc ions on the growth of Pestolotia heterocornis KCTC 0340BP,
도 2 는 철, 망간, 마그네슘 이온이 택솔 생산에 미치는 영향을 확인한 그래프이다.Figure 2 is a graph confirming the effect of iron, manganese, magnesium ions on taxol production.
이와같은 목적을 달성하기 위한 본 발명의 택솔의 제조방법은 택솔을 생산하는 진균을 금속이온이 함유된 배양액에서 배양하는 데 그 특징이 있다.The method for preparing taxol of the present invention for achieving the above object is characterized by culturing fungi producing taxol in a culture solution containing metal ions.
이와같은 본 발명을 더욱 상세하게 설명하면 다음과 같다.The present invention will be described in more detail as follows.
본 발명에서는 택솔을 생산하는 진균, 특히 페스탈로티아 헤테로코니스(Pestalotia heterocornis) KCTC 0340BP로부터 고수율로 택솔을 제조하기 위해 배양배지 내에 금속이온을 첨가한다.In the present invention, metal ions are added into the culture medium to prepare taxol in high yield from the fungi producing taxol, in particular, Pestolotia heterocornis KCTC 0340BP.
이때, 사용할 수 있는 금속이온은 철, 망간, 마그네슘 이온 중에서 선택된 1종 이상의 것이다.In this case, the metal ion that can be used is one or more selected from iron, manganese and magnesium ions.
택솔을 고수율로 생성하기 위한 금속이온의 함량은 0.05∼50g으로서 통상의 배지에 소량으로 첨가되던 것과는 달리 과량인 것이 바람직하다.The content of metal ions for producing taxol in high yield is preferably 0.05 to 50 g, which is excessive in contrast to the small amount added to a conventional medium.
이하, 본 발명을 실시예에 의거 상세히 설명하면 다음과 같은 바, 본 발명이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the Examples.
실시예 1Example 1
페스탈로티아 헤테로코니스(Pestalotia heterocornis) KCTC 0340BP를 포테이토덱스트로스 아가 배지에서 6일간 배양하였다.Pestalotia heterocornis KCTC 0340BP was incubated for 6 days in potato dextrose agar medium.
금속이온이 상기한 진균의 성장에 미치는 영향을 관찰하기 위해 염화철(FeCl3), 염화망간(MnCl2·4H2O), 황산마그네슘(MgSO4·7H2O), 염화코발트(CoCl2·6H2O), 몰리브덴산나트륨(Na2MoO4·2H2O), 질산구리(Cu(NO3)2·3H2O), 황산아연(ZnSO4) 등과 같은 금속이온을 포함하는 화합물을 각각 10, 50, 100, 200, 400, 600, 800, 1000, 2000, 3000mg/ℓ로 첨가한 포테이토 덱스트로즈 아가(agar) 배지를 준비하였다.To observe the effect of metal ions on the growth of fungi, iron chloride (FeCl 3 ), manganese chloride (MnCl 2 · 4H 2 O), magnesium sulfate (MgSO 4 · 7H 2 O), and cobalt chloride (CoCl 2 · 6H 2 O), sodium molybdate (Na 2 MoO 4 · 2H 2 O), copper nitrate (Cu (NO 3 ) 2 · 3H 2 O), zinc sulfate (ZnSO 4 ), and a compound containing a metal ion each 10 Potato dextrose agar medium added at, 50, 100, 200, 400, 600, 800, 1000, 2000, 3000 mg / L was prepared.
준비된 각각의 배지 중심에서 상기와 같이 배양한 진균을 동일한 크기로 접종하고 6일간 배양하였다. 배양 6일 후 각각의 배지에서 진균의 균사체가 자란 지름을 측정하고 금속이온이 첨가되지 않은 포테이토 덱스트로스 아가 배지에서 형성된 균사체의 지름의 크기를 100으로 하여 상대적인 성장속도를 계산하였다.Fungi cultured as above in the center of each prepared medium were inoculated to the same size and incubated for 6 days. After 6 days of culture, the growth rate of the fungus mycelium was measured in each medium, and the relative growth rate was calculated using 100 as the diameter of the mycelium formed in the potato dextrose agar medium containing no metal ions.
그 결과, 염화철, 염화망간, 황산마그네슘 등의 금속이온이 포함된 성분을 과량 첨가하였을 때 첨가하기 전과 비교하여 진균의 성장속도가 10∼60% 가량 증가한 것을 확인하였다. 나머지 금속이온의 경우는 첨가하기 전과 비교하여 성장속도가 감소하거나 유사하다는 것을 확인하였다.As a result, it was confirmed that the growth rate of the fungus increased by about 10 to 60% compared to before adding when an excessive amount of a component containing metal ions such as iron chloride, manganese chloride, magnesium sulfate. In the case of the remaining metal ions, the growth rate was reduced or similar to that before the addition.
결과적으로, 철, 망간, 마그네슘 등의 금속이온은 페스탈로티아 헤테로코니스(Pestalotia heterocornis) KCTC 0340BP의 성장에 매우 중요한 요소인 것을 알 수 있다.As a result, it can be seen that metal ions such as iron, manganese and magnesium are very important factors for the growth of Pestalotia heterocornis KCTC 0340BP.
그 확인 결과는 도 1과 같다.The confirmation result is as shown in FIG.
실시예 2Example 2
상기 실시에 1을 통해서 철, 망간, 마그네슘 이온이 페스탈로티아 헤테로코니스(Pestalotia heterocornis) KCTC 0340BP의 성장에 매우 중요한 요소인 것을 확인하고, 이를 이용하여 택솔의 생산시 상기의 금속이온의 첨가효과를 다음과 같은 방법으로 관찰하였다.Through Example 1, it was confirmed that iron, manganese and magnesium ions are very important factors for the growth of Pestalotia heterocornis KCTC 0340BP. Observation was carried out in the following manner.
상기 진균을 포테이토 덱스트로스 아가 배지에서 12시간 명암조건으로 배양하였다. 완전히 자란 균사체를 취하여 다음 표 1과 같은 조성을 갖는 배양액 50∼300㎖에 접종한 다음, 20∼30℃, 100∼400rpm 조건에서 성장기까지 배양하였다.The fungi were incubated in potato dextrose agar medium for 12 hours under dark and light conditions. Fully grown mycelia were inoculated into 50-300 ml of culture medium having the composition shown in Table 1 below, followed by incubation at 20-30 ° C. and 100-400 rpm.
이 배양액을 기본으로 하고, 염화철, 염화망간, 황산마그네슘의 양을 각각 배지 1ℓ당 5, 50, 100, 500mg, 1, 2, 3, 4, 5, 6, 8, 10g씩 다르게 첨가한 100㎖ 배양액에 접종하여 2주간 배양하였다. 최종 배양액을 취하여 10,000rpm, 15분 이상으로 원심분리하여 상등액을 취하였다. 상기 방법으로 얻어진 상등액을 하와이 바이오테크놀로지 그룹사로부터 구입한 TA 01, TA 02, TA 03 키트를 이용하여 택솔 및 그 유도체를 정량하였다.Based on this culture solution, 100 ml of iron chloride, manganese chloride, and magnesium sulfate were added in different amounts of 5, 50, 100, 500 mg, 1, 2, 3, 4, 5, 6, 8, and 10 g per 1 liter of medium, respectively. Inoculation was incubated for 2 weeks. The final culture solution was taken and centrifuged at 10,000 rpm for 15 minutes or longer to obtain the supernatant. Taxol and its derivatives were quantified using the TA 01, TA 02, and TA 03 kits purchased from Hawaii Biotechnology Group.
그 결과는 도 2에 나타낸 바와 같이 금속이온의 양을 종래의 배지와 유사한 양, 즉 배지 1ℓ당 5mg으로 첨가하면 배양액 1ℓ 당 30㎍의 택솔 생산량을 얻을 수 있었으나, 금속이온, 특히 염화철, 염화망간, 황산마그네슘 등을 단독 또는 혼합하여 배지 1ℓ당 50mg 내지 50g 첨가하면 배양액 1ℓ당 최고 100㎍의 택솔 생산량을 얻을 수 있음을 알 수 있다.As a result, as shown in FIG. 2, when the amount of metal ions was added in an amount similar to that of the conventional medium, that is, 5 mg per 1 L of media, 30 µg of Taxol production per 1 L of culture medium was obtained. When magnesium sulfate or the like is added alone or in a mixture, 50 mg to 50 g per 1 L of medium can be obtained up to 100 µg of Taxol production per 1 L of culture.
이상에서 상세히 설명한 바와 같이, 본 발명에 따라 페스탈로티아 헤테로코니스(Pestalotia heterocornis) KCTC 0340BP를 철, 망간 및 마그네슘 이온이 함유된 배양액에서 배양하여 택솔을 제조하는 경우 택솔의 생산량을 ℓ당 30㎍이던 것을 최고 100㎍까지 증대시킬 수 있어 산업적으로 이용하기에 유용하다.As described in detail above, in the case of preparing Taxol by culturing Pestolotia heterocornis KCTC 0340BP according to the present invention in a culture solution containing iron, manganese and magnesium ions, the production of Taxol was 30 µg / l. It can be increased up to 100µg, which is useful for industrial use.
Claims (4)
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| KR1019980052163A KR20000037547A (en) | 1998-12-01 | 1998-12-01 | Method for manufacturing taxol using metal ion |
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1998
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