Synthesis and inhibitory activity of mechanism-based 4-coumaroyl-CoA ligase inhibitors
| Autor: | Shinri Horoiwa, Takao Koeduka, Yoshiyuki Naito, Yoshiaki Nakagawa, Jun Hiratake, Yoshinori Takeuchi, Masaharu Mizutani, Tomoki Asai, Bunta Watanabe, Hideya Tokuoka, Bun-ichi Shimizu, Hiroaki Kirikae |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0106 biological sciences
0301 basic medicine Adenosine Coenzyme A Clinical Biochemistry Arabidopsis Pharmaceutical Science Thioester 01 natural sciences Biochemistry Substrate Specificity Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Biosynthesis Coenzyme A Ligases Drug Discovery Arabidopsis thaliana Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Sulfonamides DNA ligase Molecular Structure Phenylpropanoid biology Arabidopsis Proteins Organic Chemistry food and beverages biology.organism_classification Petunia Populus 030104 developmental biology Enzyme chemistry Glycine Molecular Medicine Soybeans 010606 plant biology & botany |
| Zdroj: | Bioorganic & Medicinal Chemistry. 26:2466-2474 |
| ISSN: | 0968-0896 |
| Popis: | 4-Coumaroyl-CoA ligase (4CL) is ubiquitous in the plant kingdom, and plays a central role in the biosynthesis of phenylpropanoids such as lignins, flavonoids, and coumarins. 4CL catalyzes the formation of the coenzyme A thioester of cinnamates such as 4-coumaric, caffeic, and ferulic acids, and the regulatory position of 4CL in the phenylpropanoid pathway renders the enzyme an attractive target that controls the composition of phenylpropanoids in plants. In this study, we designed and synthesized mechanism-based inhibitors for 4CL in order to develop useful tools for the investigation of physiological functions of 4CL and chemical agents that modulate plant growth with the ultimate goal to produce plant biomass that exhibits features that are beneficial to humans. The acylsulfamide backbone of the inhibitors in this study was adopted as a mimic of the acyladenylate intermediates in the catalytic reaction of 4CL. These acylsulfamide inhibitors and the important synthetic intermediates were fully characterized using two-dimensional NMR spectroscopy. Five 4CL proteins with distinct substrate specificity from four plant species, i.e., Arabidopsis thaliana, Glycine max (soybean), Populus trichocarpa (poplar), and Petunia hybrida (petunia), were used to evaluate the inhibitory activity, and the half-maximum inhibitory concentration (IC50) of each acylsulfamide in the presence of 4-coumaric acid (100 µM) was determined as an index of inhibitory activity. The synthetic acylsulfamides used in this study inhibited the 4CLs with IC50 values ranging from 0.10 to 722 µM, and the IC50 values of the most potent inhibitors for each 4CL were 0.10–2.4 µM. The structure–activity relationship observed in this study revealed that both the presence and the structure of the acyl group of the synthetic inhibitors strongly affect the inhibitory activity, and indicates that 4CL recognizes the acylsulfamide inhibitors as acyladenylate mimics. |
| Databáze: | OpenAIRE |
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