结构,功能和抑制由Mycobacterium结核病引起的腺酸酶 (ADSL)
Vigyasa Singh1, Devi Jaganathan1, Jamie Corro2
1Department of Pharmacology and Toxicology, R Ken Coit College of Pharmacy, 1703 E Mabel Street, Tucson, Arizona 85721-0207, United States.
ACS infectious diseases
|December 8, 2025
概括
来自Mycobacterium tuberculosis的腺酸酶 (ADSL) 是一种药物标. 比西醇和泰特拉克抑制了Mtb ADSL,显示出抗菌活性和新的结核病治疗的潜力.
科学领域:
- 生物化学 生化学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 腺酸酶 (ADSL) 对于Mycobacterium tuberculosis (Mtb) 中的纯素生物合成至关重要.
- 在开发抗结核新型抗微生物药物方面,ADSL是一个有前途的目标.
研究的目的:
- 为了表达,净化和描述Mtb ADSL.
- 选 Mtb ADSL 抑制剂,并分析它们的结合和活性.
- 为了确定Mtb ADSL的晶体结构,用于结构导向药物设计.
主要方法:
- 为Mtb ADSL活动开发了一种生物发光试验.
- 进行高通量查 (HTS) 和直角测定 (FP,AMP-Glo) 来识别抑制剂.
- 确定了Mtb ADSL的晶体结构,并进行了分子建模.
- 在M.结核病中评估了抗菌活性,细胞毒性和目标接触.
主要成果:
- 确定了比西醇和四甲基乙酸 (Tetrac) 作为选择性的Mtb ADSL抑制剂.
- 证实了比西和泰特拉克对M.结核病的直接结合和抗菌活性.
- 证明了目标抑制和细胞内疗效,具有较低的人类细胞毒性.
- 确定了Mtb ADSL的高分辨率晶体结构,与人类ADSL相比,显示了不同的活动站点特征.
结论:
- 比西醇和泰特拉克是开发针对Mtb ADSL的新型抗结核剂的有希望的化合物.
- 对Mtb ADSL的结构洞察力为选择性抑制剂的结构导向优化提供了基础.
- 选择性抑制Mtb ADSL提供了一个潜在的治疗策略来对抗结核病.
相关概念视频
Allosteric Proteins-ATCase
6.4K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
6.4K
ATP Synthase: Mechanism
16.6K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
16.6K
The Electron Transport Chain
19.5K
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
19.5K
ATP Synthase: Structure
15.0K
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
15.0K
Enzyme Inhibition
91.3K
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
91.3K
Sulfur Assimilation
301
Sulfur is an essential element in biological systems, contributing to synthesizing key biomolecules, including amino acids such as cysteine and methionine, and cofactors such as coenzyme A and biotin. Microorganisms primarily assimilate sulfur as sulfate (SO₄²⁻) from the environment, which must undergo a series of biochemical transformations before it can be incorporated into cellular components. As sulfate is highly oxidized, it must undergo assimilatory sulfate reduction to...
301


