在Mycobacterium fortuitum中通过基因调节将植物转化为C9非氧化衍生物
Xiangcen Liu1,2, Beiru He1,3, Jingxian Zhang1
1Lab of Biorefinery, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 99 Haike Road, Pudong, Shanghai, 201210, China.
Applied microbiology and biotechnology
|October 13, 2023
概括
科学家们确定了五种阻断类固醇C9氧化酶的酶,使得从植物中有效生产药物中间体androst-4-ene-3,17-dione (AD) 和4-HBC.
科学领域:
- 生物技术是生物技术.
- 微生物工程 微生物工程
- 类固醇的生物转化
背景情况:
- 安德罗斯特-4--3,17- (AD) 和22--23,24-双-4--3-one (4-HBC) 是从植物中衍生出来的关键药物中间体.
- 通过3 - 固醇9α-氧化酶 (KSH) 介导的类固醇C9氧化阻碍了AD和4-HBC的积累.
研究的目的:
- 在Mycobacterium fortuitum ATCC 35855.5中识别和描述负责C9氧化酶的酶.
- 通过操纵关键的代谢途径来改造M. fortuitum以提高AD和4-HBC的产生.
主要方法:
- 在M. fortuitum.中识别和删除5个KshA基因 (KSH的氧化成分).
- 通过淘汰Opccr和增强Hsd4A,或淘汰hsd4A和fadA5.5,对MFKDΔkshA菌株进行基因改造.
主要成果:
- 确定了五种活性KshAs,并表明它们共同控制C9基化.
- 删除所有五个KshAs阻断了C9化,产生5.37 g/LAD和0.55 g/L4-HBC.
- 代谢工程提高了AD产量至8.24g/L和4-HBC产量至5.36g/L.
结论:
- 这五种已识别的KshA对于限制AD和4-HBC生物合成至关重要.
- 工程菌株 (AD的MFKDΔkshAΔopccr_hsd4A,4-HBC的MFKDΔkshAΔhsd4AΔfadA5) 显示出显著改善的产量.
- 这项研究为M. fortuitum的先进代谢工程提供了基础,用于制造类固醇.
相关概念视频
Phase I Reactions: Oxidation of Aliphatic and Aromatic Carbon-Containing Systems
210
Phase I biotransformation reactions are integral to drug metabolism, predominantly involving oxidative, reductive, and hydrolytic transformations. Chief among these are oxidative reactions, which enhance the hydrophilicity of xenobiotics and introduce polar functional groups to facilitate their elimination from the body.
Oxidation reactions are fundamental in aromatic carbon-containing systems. An example is the hydroxylation of phenobarbital, a process that transforms it into...
Oxidation reactions are fundamental in aromatic carbon-containing systems. An example is the hydroxylation of phenobarbital, a process that transforms it into...
210
Biosynthesis of Lipids
16
Microbial membranes exhibit remarkable diversity in lipid composition, reflecting evolutionary adaptations to various environmental conditions. The three domains of life—Bacteria, Archaea, and Eukarya—synthesize membrane lipids through distinct biosynthetic pathways, leading to fundamental structural differences that impact membrane stability, function, and adaptability.Fatty Acid-Based Lipids in Bacteria and EukaryaBacteria and eukaryotes share a common fatty acid biosynthesis...
16
Lipid Catabolism
22
Triglycerides serve as crucial long-term energy storage molecules in microorganisms, providing a dense source of metabolic energy. Their breakdown is mediated by lipases, which hydrolyze triglycerides into glycerol and free fatty acids. Each of these components follows distinct metabolic pathways, ultimately contributing to ATP synthesis and cellular energy homeostasis.Glycerol MetabolismGlycerol, released from triglyceride hydrolysis, is phosphorylated by glycerol kinase to form...
22
Drug Biotransformation: Overview
2.4K
Pharmaceutical substances known as xenobiotics are predominantly lipophilic and nonionized. This enables them to permeate lipid bilayers, such as cell membranes, and interact with intracellular target receptors. Lipophilic drugs have an advantage in crossing biological barriers and reaching their intended sites of action. However, lipophilic drugs often have a restricted capacity for renal expulsion or elimination from the body. When these drugs enter the kidneys and undergo glomerular...
2.4K
Gene Regulation During Sporulation
20
Sporulation is a complex developmental process that allows certain Gram-positive bacteria, such as Bacillus subtilis and Clostridium species, to survive extreme environmental conditions. This process is tightly regulated by a series of signaling cascades and transcriptional controls, ensuring the formation of a highly resistant endospore.Sporulation is triggered by unfavorable conditions, such as nutrient depletion, and is governed by a phosphorelay system. One of the sensor kinases, such as...
20


