Paclitaxel(Taxol)is a natural broad-spectrum anticancer drug,which is well-known for its potent anticancer activity.Its production mainly relies on the extraction and purification from the rare Taxus plant,followed by chemical semi-synthesis.The limited natural resource for paclitaxel imposes a significant constraint on its production capacity.In recent years,with the complete decoding of the Taxus genome and the rapid development of synthetic biology,constructing recombinant cells through synthetic biology techniques has emerged as an effective method to address this challenge.Since paclitaxel biosynthesis involves more than 20 steps of complicated enzymatic reactions and about half of them are P450 enzyme-mediated hydroxylation reactions,the complete elucidation of its biosynthetic pathway remains elusive.Meanwhile,the production of paclitaxel by engineered microbes is still at the initial stage,and there are numerous by-products,which seriously compromise the efficient synthesis of paclitaxel.Therefore,this article reviews research progress related to paclitaxel synthesis pathways,Taxus omics analyses,construction of chassis cells,synthesis of key precursors,modifications of crucial enzymes,and catalytic mechanisms underlying paclitaxel biosynthesis.Special attention is given to the recent breakthrough in elucidating the formation of oxetane ring and the discovery of Taxane 1-β-and 9-α-hydroxylases.Recent advances in the study of the catalytic mechanism of Taxadiene-5-α-hydroxylase and significant progress in engineering tobacco and yeast chassis will also be commented.Furthermore,challenges and future prospects involved in the paclitaxel synthetic biology research are discussed,such as the issues of low enzyme catalytic efficiency,significant product promiscuity,unknown specific reaction sequences,and the biosynthesis of critical paclitaxel intermediates,aiming to enhance the understandings of paclitaxel biosynthetic pathways and catalytic mechanisms for greener and more efficient production of paclitaxel.
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