摘要：

甾體化合物（簡稱甾體）分布廣泛、功能卓越，在機(jī)體生長、物種繁育以及代謝調(diào)控等方面，發(fā)揮著難以取代的生理功能。因此，天然甾體及其衍生物被廣泛用于生殖健康、內(nèi)分泌調(diào)控等領(lǐng)域，是器官移植、重癥感染等許多危重疾病的“剛需藥”和“救命藥”。甾體結(jié)構(gòu)復(fù)雜、構(gòu)型精巧，很難通過化學(xué)全合成來生產(chǎn)，當(dāng)前主要以天然甾體皂素或甾醇為原料，通過化學(xué)與生物轉(zhuǎn)化相結(jié)合的半合成法獲得。然而，甾體藥物的生產(chǎn)路線長、工藝復(fù)雜、收率低，涉及大量有毒有害試劑和重金屬催化劑的使用，污水廢渣排放量大、處理難度高，總體成本居高不下。為改變此局面，推動(dòng)產(chǎn)業(yè)的轉(zhuǎn)型升級(jí)，大力開發(fā)綠色生物制造技術(shù)是行業(yè)健康發(fā)展的大勢所趨。當(dāng)前，甾體制藥工業(yè)正處于以生物催化轉(zhuǎn)化取代化學(xué)合成的產(chǎn)業(yè)升級(jí)階段，隨著高效酶和細(xì)胞轉(zhuǎn)化的成功應(yīng)用，傳統(tǒng)的甾體生產(chǎn)模式正發(fā)生著深刻變化。在此基礎(chǔ)上，若能進(jìn)一步利用合成生物學(xué)技術(shù)，創(chuàng)建可高效從頭合成甾體的微生物細(xì)胞工廠，則將徹底改變甾體制藥的工業(yè)模式，切實(shí)實(shí)現(xiàn)甾體藥物的綠色制造。近年來，已有利用微生物從頭合成部分甾體化合物的報(bào)道，然而由于甾體的天然合成機(jī)制異常復(fù)雜，如何實(shí)現(xiàn)細(xì)胞工廠的高效生產(chǎn)，仍是目前面臨的主要挑戰(zhàn)。本文從甾體藥物生產(chǎn)方式的演變出發(fā)，系統(tǒng)綜述了甾體生物催化轉(zhuǎn)化和從頭合成的最新進(jìn)展，重點(diǎn)闡述了甾體生物催化轉(zhuǎn)化酶的挖掘及改造、微生物代謝轉(zhuǎn)化甾醇機(jī)制的解析及轉(zhuǎn)化細(xì)胞工廠的開發(fā)、微生物從頭合成甾體人工路線的創(chuàng)建三部分內(nèi)容，以期對(duì)甾體藥物綠色生物制造的現(xiàn)狀和趨勢做出合理的總結(jié)與展望。

關(guān)鍵詞: 甾體化合物, 綠色生物制造, 生物催化轉(zhuǎn)化, 從頭生物合成, 微生物細(xì)胞工廠

Abstract:

Steroids are widely distributed in natural organisms and play essential roles in growth, breeding, metabolic regulation, and endocrine homeostasis. To date, diverse steroids have been proved to have numerous therapeutic effects on reproductive health, endocrine regulation, inflammation, etc. and can be used as life-saving drugs for some serious diseases, such as cancer, organ transplantation, and serious infection. Therefore, the industrial synthesis of steroid drugs has developed rapidly and steroid drugs have become the second largest drug category just ranked after antibiotics. Due to the complex structure and delicate configuration, steroids are difficult to be produced at an industrial scale by chemical total synthesis. At present, steroids are mainly produced by semi-synthesis ways with natural steroidal sapogenins or sterols as raw materials via the combination of chemical and biological transformations. However, the above routes are long and complex resulting in the low yield and the overuse of toxic reagents and heavy metal catalysts, thus resulting in a large quantity of wastewater and residue as well as high production costs. Therefore, it is necessary to develop green biomanufacturing technologies, such as biocatalysis, biotransformation, and biosynthesis, for the industrial production of steroids. Currently, the production mode of steroids has been profoundly changed due to the successful application of enzyme-catalyzed reactions and microbial transformations in the industrial production of steroids. It is expected that the production of steroids will be changed into a biomanufacturing mode if the robust microbial cell factories for the de novo biosynthesis of steroids can be developed via the biosynthetic way. The de novo synthesis of steroids by microorganisms has been materialized. However, due to the extraordinarily complex metabolic mechanism of steroids in the nature, the efficient production of steroids in engineered hosts still remains a challenge. Here, starting from the evolution of steroidal pharmaceutical industry, we systematically review recent advances in biomanufacturing technologies of steroids, including the identification and application of steroidal biocatalysis and biotransformation, the characterization and modification of the metabolic mechanisms of steroids in certain microorganisms, and the development of de novo biosynthesis pathways of steroids in engineered cell factories. From the above three aspects, this review provides a reasonable summary and prospect for the current status and future development trend of green bio-manufacturing technologies in the steroidal pharmaceutical industry.

Key words: steroids, green biomanufacturing, biocatalysis and biotransformation, de novo biosynthesis, microbial cell factories

中圖分類號(hào): 

Q819

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