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Drug precursor biosynthesis hinges on carrier-mediated ring formation

Date:
July 11, 2023
Source:
Hokkaido University
Summary:
The entire biosynthetic pathway of actinopyridazone has been unveiled, revealing that an unprecedented carrier protein-mediated ring-forming step is key to its synthesis.
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The entire biosynthetic pathway of actinopyridazone has been unveiled, revealing that an unprecedented carrier protein-mediated ring-forming step is key to its synthesis.

Nitrogen-nitrogen bond-containing cyclic compounds such as pyrazole, triazole, pyridazine and many others are critical building blocks for a variety of medicinal compounds, both natural and synthetic. The biosynthesis of some of these compounds hinges on the formation of nitrogen-nitrogen (N-N) single bonds between amino acids. However, the mechanisms by which a diversity of compounds is possible is poorly understood.

Dr. Kenichi Matsuda and Professor Toshiyuki Wakimoto at Hokkaido University led a team to elucidate the biosynthetic pathway of actinopyridazinone, an N-N bond-containing cyclic compound that is an important scaffold for synthetic drugs. Their findings were published in the journal Angewandte Chemie International Edition.

"Actinopyridazinone is produced by Streptomyces, a genus of bacteria that is the source of the majority of antibiotics of natural origin," Wakimoto explains. "It is the first natural compound known to possess a dihydropyridazinone ring. This ring is also known as a 'wonder nucleus,' as it has been extensively studied as a precursor for a wide range of drugs."

In previous work, the team used bioinformatics to identify a group of gene sequences that are potentially involved in the biosynthesis of natural products that contain N-N bonds, and from these genome sequences, they discovered the novel class of compounds called actinopyradizones. With a series of genetic and biochemical experiments, they were also able to unveil the first steps in the pathway; in this study, they focused on understanding how the dihydropyridazone ring is formed.

The gene cluster apy is the biosynthetic gene cluster associated with actinopyradizone synthesis. It contains 17 potential genes; knockout studies indicated that ten of these -- apy1, apy2, apy3, apy4, apy6, apy8, apy9, apy10, apy11 and apy13 -- were necessary for actinopyradizone synthesis. Biochemical analyses of the knockouts allowed the team to deduce that Apy3, an AMP-dependent synthetase/ligase, Apy4, a serine hydrolase, and Apy6, a carrier protein-rhodanese fusion, were the key proteins responsible for the formation of the dihydropyridazone ring.

"Apy6 functions as a carrier molecule; and Apy3 loads the intermediate compound onto Apy6," Matsuda elaborates. "Apy4 then catalyses the removal of an acetyl group (-COCH3); the resulting molecule is unstable and spontaneously reacts to form a dihydropyridazone ring. The most notable feature of actinopyridazone biosynthesis is the unprecedented carrier protein-mediated machinery for dihydropyridazinone formation."

Matsuda said that this study is the first description of the biosynthetic pathway for actinopyradizone, and is only the second study to report the enzyme-dependent biosynthesis of a N-N bond-containing ring structure. The first such compound is piperazic acid, whose biosynthetic pathways are completely unrelated; hence, this study has also highlighted that the biosynthetic pathways of N-N bond-containing cyclic compounds are very diverse.


Story Source:

Materials provided by Hokkaido University. Note: Content may be edited for style and length.


Journal Reference:

  1. Kuga Arima, Satoko Akiyama, Kazuo Shin‐ya, Kenichi Matsuda, Toshiyuki Wakimoto. Carrier Protein Mediated Formation of the Dihydropyridazinone Ring in Actinopyridazinone Biosynthesis. Angewandte Chemie International Edition, 2023; 62 (29) DOI: 10.1002/anie.202305155

Cite This Page:

Hokkaido University. "Drug precursor biosynthesis hinges on carrier-mediated ring formation." ScienceDaily. ScienceDaily, 11 July 2023. <www.sciencedaily.com/releases/2023/07/230711133238.htm>.
Hokkaido University. (2023, July 11). Drug precursor biosynthesis hinges on carrier-mediated ring formation. ScienceDaily. Retrieved June 19, 2024 from www.sciencedaily.com/releases/2023/07/230711133238.htm
Hokkaido University. "Drug precursor biosynthesis hinges on carrier-mediated ring formation." ScienceDaily. www.sciencedaily.com/releases/2023/07/230711133238.htm (accessed June 19, 2024).

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