Recent advances in chemoenzymatic synthesis of important steroids

ZHENG Mengmeng; LIU Benben; LIN Zhi; QU Xudong

doi:10.12211/2096-8280.2024-002

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Recent advances in chemoenzymatic synthesis of important steroids

Invited Review | 更新时间：2025-03-19

- Recent advances in chemoenzymatic synthesis of important steroids
- Synthetic Biology Journal Vol. 5, Issue 5, Pages: 941-959(2024)
- 作者机构：
  
  1.上海交通大学生命科学技术学院，微生物代谢国家重点实验室，上海 200240
  2.上海交通大学张江高等研究院，上海 201203
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2024-002
  CLC： Q816
- Received：02 January 2024，
  
  Revised：2024-03-20，
  
  Published：31 October 2024
- 稿件说明：
移动端阅览
郑梦梦，刘犇犇，林芝，瞿旭东. 重要甾体化合物的化学酶法合成研究进展［J］. 合成生物学， 2024， 5（5）： 941-959

ZHENG Mengmeng， LIU Benben， LIN Zhi， QU Xudong. Recent advances in chemoenzymatic synthesis of important steroids［J］. Synthetic Biology Journal， 2024， 5（5）： 941-959
郑梦梦，刘犇犇，林芝，瞿旭东. 重要甾体化合物的化学酶法合成研究进展［J］. 合成生物学， 2024， 5（5）： 941-959 DOI： 10.12211/2096-8280.2024-002.

ZHENG Mengmeng， LIU Benben， LIN Zhi， QU Xudong. Recent advances in chemoenzymatic synthesis of important steroids［J］. Synthetic Biology Journal， 2024， 5（5）： 941-959 DOI： 10.12211/2096-8280.2024-002.

摘要

甾体化合物因其多功能生物活性和理化特性备受生物医药行业的高度重视，被誉为自然界的“生命之钥”。随着植物甾醇代谢途径的不断解析，国内逐渐形成了“植物甾醇原料-甾体药物中间体-甾体药物”的工业合成路线。日益发展的甾药行业需要不断开发新的合成技术推进甾体药物自上而下高效合成。基于生物信息学、合成生物学、代谢工程以及酶工程的快速发展，甾体化合物的合成技术也取得了重大突破。本文对重要甾体化合物的最新合成进展，包括甾体药物中间体的多样化合成、复杂甾体的化学酶法合成和酵母从头合成植物甾醇原料等方面进行了综述，特别强调了近年来P450羟化酶、3-甾酮-Δ

-脱氢酶、还原酶以及酶级联参与的化学酶法在高效简易合成复杂甾体药物中的代表性工作；在此基础上，也从新一代甾药中间体的开发、新型甾体生物催化剂的挖掘、以分枝杆菌为底盘的甾体合成途径的构建等方面对甾体化合物未来的研究机会和挑战进行了展望。

Abstract

Steroids exhibit a range of biological activities and are commonly described as the ‘key to life’ in nature. Steroidal-based medications have emerged as the second largest pharmaceutical category following antibiotics

owing to their remarkable bioactivities such as anti-infective

anti-inflammatory

anti-allergic

and antitumor properties. This category encompasses more than 400 drug compounds

representing approximately 17% of FDA-approved medications. The synthesis of steroidal products continues to attract significant attention due to their diverse bioactivities and physicochemical characteristics in pharmaceutical applications. With the increasing demand for steroidal drugs and the fluctuating availability of sapogenin resources

the use of

Mycobacteria

to convert inexpensive phytosterols to produce key intermediates for steroid drugs has been established as the most mature and sustainable industrial route. However

the complex structure of ste

roids

particularly their highly oxygenated skeleton

poses challenges for the well-established semi-synthesis route of complex steroid medications. Recent strides in bioinformatics and genetics have significantly advanced the studies on synthesis of steroidal compounds. This review highlights recent advancements in the synthesis of high-value steroids

including the diverse steroid drug intermediate production

via

external steroidal modifying enzymes expression in engineered

Mycobacteria

chemo-enzymatic synthesis of complex steroids

and yeast-based de novo synthesis. It specifically highlights the significant achievements in the chemo-enzymatic synthesis

which combines the precise site- and stereoselectivity of enzymatic transformations with the efficiency of chemosynthesis

enabling the concise synthesis of complex steroidal products. Recent advancements in chemoenzymatic strategies

especially those involving P450 hydroxylase

3-sterone-Δ

-dehydrogenase

reductase

and enzyme cascades

have significantly contributed to the efficient and straightforward synthesis of complex steroid medications. On this basis

the future research opportunities and challenges are also discussed

aiming to provide a reference for the efficient development of more value-added steroid compounds

including the development of new generation steroid intermediates

the discovery of novel steroid biocatalysts

and the establishment of steroid synthesis pathways in mycobacteria.

关键词

Keywords

references

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