Biosynthetic studies on taxol

نویسنده

  • P. E. Fleming
چکیده

The biosynthesis of the plant antitumor agent, taxol, was studied by feeding radioactive or stable isotope-labeled precursors to cut stems or to inner bark tissue of Taxus brevifolia. The labeled taxol was purified to radiochemical purity and subjected to chemical degradation or was analyzed by electrospray tandem mass spectrometry. It was demonstrated that in the plant taxol is synthesized from baccatin-111, containing the fully functionalized diterpene moiety, and a precursor of the phenylpropanoid side chain. The latter arises from phenylalanine not via cinnamic acid, but via B-phenylalanine and phenylisoserine. Benzoylation of the side chain occurs only after its attachment to the diterpene moiety. The benzoate moiety is also formed from phenylalanine via B-phenylalanine and phenylisoserine, not via cinnamic acid. Due to its unique mode of action and promising early clinical results, taxol(1) commands considerable interest as a new plant anticancer agent (2). The complexity of its structure presents a considerable challenge to synthetic organic chemistry and raises the question how the plant assembles this formidable molecule (3-5). We have studied this latter issue by feeding experiments with potential precursors labeled strategically with radioactive or stable isotopes (6). Our studies focused initially on the origin of the phenylpropanoid side chain and its mode of attachment to the diterpene moiety. Feeding experiments with radiolabeled precursors were carried out with cut twigs of Taxus brevifolia to which the radioactive material was administered through the cut stem in a small volume of water. Extensive purification of the resulting taxol, first by repeated HPLC and then by co-crystallization with non-labeled carrier material was found necessary to achieve constant specific radioactivity or, in other cases, to remove traces of radioactive impurities. Under these conditions incorporation of [7-14C]benzoic acid, as its N-acetylcysteamine thioester (0.09%), and [ 13-3Hlbaccatin-III (0.12%) was obtained. Degradation of the radioactive taxol from the benzoate feeding experiment showed that 88% of the radioactivity was recovered in the side chain fragment and only 1 1 % in the baccatin-111, suggesting that under the conditions of the experiment relatively little of the diterpene moiety was synthesized de novo. Upon degradation of the taxol from the baccatin-I11 feeding experiments, all the radioactivity was recovered in the baccatin-111 moiety, none in the side chain fragment.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Hazel (Corylus avellana L.) as a New Source of Taxol and Taxanes

Taxol is used to treatment of variety cancers including ovarian, breast, lung, head and neck carcinomas and the AIDS-related Karposi’s carcinoma, and was originally obtained from bark of taxus brevifolia. However the amount of extracted taxol from taxus is extremely low and cannot be considered as a suitable commercial source and it has led to studies for finding new sources of Taxol. In 1998, ...

متن کامل

The Effect of Temperature, pH, and Different Solubilizing Agents on Stability of Taxol

       Inabilities to attain adequate aqueous solubility and stability have made the preparation of a clinically suitable formulation of taxol difficult. Addition of nicotinamide (ND), 2-hydroxypropyl- b-cyclodextrin (HPßCD), polyethylene glycol, (PEG), bile salts (BS, 50:50 sodium cholate: deoxycholate...

متن کامل

A Review on Taxol Production through Biotechnological Approaches

Taxol is a very important anticancer drug which was first isolated from Yew plant (Taxus spp.). However, Taxol supply by extraction from natural sources, has several limitations, and cannot meet current market's demands. Therefore, it seems necessary to use alternative production methods. Producing Taxol through biotechnological approaches is among the main options which have some advantages su...

متن کامل

Systematic Analysis of the Anticancer Agent Taxol-Producing Capacity in Colletotrichum Species and Use of the Species for Taxol Production

Paclitaxel (taxol) has long been used as a potent anticancer agent for the treatment of many cancers. Ever since the fungal species Taxomyces andreanae was first shown to produce taxol in 1993, many endophytic fungal species have been recognized as taxol accumulators. In this study, we analyzed the taxol-producing capacity of different Colletotrichum spp. to determine the distribution of a taxo...

متن کامل

Influence of taxol and CNTs on the stability analysis of protein microtubules

Microtubules are used as targets for anticancer drugs due to their crucial role in the process of mitosis. Recent studies show that carbon nanotubes (CNTs) can be classified as microtubule-stabilizing agents as they interact with protein microtubules (MTs), leading to interference in the mitosis process. CNTs hold a substantial promising application in cancer therapy in conjunction with other c...

متن کامل

Darkness: A Crucial Factor in Fungal Taxol Production

Fungal Taxol acquired lots of attention in the last few decades mainly because of the hope that fungi could be manipulated more easily than yew trees to scale up the production level of this valuable anticancer drug. Several researchers have studied diverse factors to enhance fungal Taxol production. However, up to date fungal Taxol production has never been enhanced to the commercial level. We...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره   شماره 

صفحات  -

تاریخ انتشار 2004