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Study on improving drug for hyperchoresterolemia directed by sterol biosynthesis in Morus alba cell cultures

桑树细胞培养中甾醇生物合成导向的高胆固醇血症改善药物的研究

基本信息

批准号：
09672168
负责人：
NOMURA Taro
金额：
$ 1.92万
依托单位：
Toho University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672168/
关键词：
Morus alba Morus bombycis Callus cultures Isoprenylated phenol Isoprene biosynthesis Fatty acid β-oxidation Tricarboxylic acid cycle Inhibitor to biosynthesis β-酸化組織培養インプレン生合成インプレニルフェノールクワカルスイソプレノイド生合成 HMG CoA還元酵素コンパク

项目摘要

Morus alba cells and suspension cultures produce sterols and isoprenylated phenols in high yield. In the experiment with[2-ィイD113ィエD1C]acetate, comparison of incorporation of C-13 into polyketide moieties of isoprenylated phenols, kuwanons J, Q, R, and V, revealed that increasing of oxidation degrees decreased in corporation of C-13. This fact indicated that foremost biosynthesis of lesser hydroxylated compound, kuwanon V, followed by successive hydroxylation reactions to form kuwanon R and then kuwanon J. It was also suggested that chalco-moracin was biosynthesized from mulberrofuran E in the same way. There are two independent isoprene biosyntheses in M.alba cell cultures, one is sensitive to compactin (ML-236B), an inhibitor of HMG-CoA reductase, and the other is non-sensitive. In one of the two isoprene biosyntheses, non-sensitive to compactin, incorporated acetate was not intact acetate administered, but reconstructed acetate through tricarboxylic acid cycle (TCA cycle). To examine the participation of TCA cycle in the isoprene biosynthesis, fatty acid fraction was investigated. Palmitate was isolated from the callus cultures administered [2-ィイD113ィエD1C]acetate. The ィイD113ィエD1C-NMR spectrum of the palmitate demonstrated that the specified positions corresponding to the methyl group of the acetate were labeled with C-13. This fact suggested that the acetate from fatty acid through β-oxidation was incorporated into the isoprene unit via TCA cycle. This is the first example of contribution of fatty acid to the isoprene biosynthesis. It was thus indicated that fatty acid biosynthesis was also important factor in the development of improving drug for hyperchoresterolemia.

桑树细胞和悬浮培养物高产量地产生甾醇和异戊二烯基酚。在与[2-ィイD113ィエD1C]乙酸酯的实验中，将C-13与异戊二烯基酚、库旺酮J、Q、R和V的聚酮基段进行了比较，发现C-13的加入降低了氧化度的增加。这一事实表明，次羟基化合物kuwanon V的生物合成首先是kuwanon V，然后是kuwanon R，然后是kuwanon J。此外，还提出了由桑黄隆E生物合成查尔可莫拉星的方法。白曲霉细胞中存在两种独立的异戊二烯生物合成，一种对HMG-CoA还原酶抑制剂致密蛋白(ML-236B)敏感，另一种不敏感。在两种对紧缩素不敏感的异戊二烯生物合成中，掺入的醋酸盐不是完整的醋酸盐，而是通过三羧酸循环(TCA循环)重建的醋酸酯。为了研究TCA循环在异戊二烯生物合成中的作用，对脂肪酸组成进行了研究。从用[2-ィイD113ィエD1C]乙酸酯处理的愈伤组织培养物中分离到棕榈酸酯。棕榈酸酯的ィイD113核磁共振D1C-ィエ谱表明，与乙酸酯的甲基对应的特定位置用C-13标记。这一事实表明，脂肪酸通过β氧化生成的乙酸酯通过三氯乙酸循环进入异戊二烯单元。这是第一个脂肪酸对异戊二烯生物合成的贡献的例子。由此可见，脂肪酸的生物合成也是开发治疗高胆固醇血症药物的重要因素。