{"id":24106,"date":"2023-07-12T11:22:30","date_gmt":"2023-07-12T05:37:30","guid":{"rendered":"https:\/\/www.revoscience.com\/en\/?p=24106"},"modified":"2023-07-12T11:22:32","modified_gmt":"2023-07-12T05:37:32","slug":"drug-precursor-biosynthesis-hinges-on-carrier-mediated-ring-formation","status":"publish","type":"post","link":"https:\/\/www.revoscience.com\/en\/drug-precursor-biosynthesis-hinges-on-carrier-mediated-ring-formation\/","title":{"rendered":"Drug precursor biosynthesis hinges on carrier-mediated ring formation"},"content":{"rendered":"\n

Nitrogen\u2013nitrogen 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. <\/p>\n\n\n\n

The biosynthesis of some of these compounds hinges on the formation of nitrogen\u2013nitrogen (N\u2013N) single bonds between amino acids. However, the mechanisms by which a diversity of compounds is possible are poorly understood.<\/p>\n\n\n\n

\"\"
Microbial cultures were used in the study to investigate the biosynthesis of actinopyradizone (Photo: Kenichi Matsuda).a<\/em><\/figcaption><\/figure>\n\n\n\n

Dr. Kenichi Matsuda and Professor Toshiyuki Wakimoto at Hokkaido University led a team to elucidate the biosynthetic pathway of actinopyridazinone, an N\u2013N bond-containing cyclic compound that is an important scaffold for synthetic drugs. Their findings were published in the journal Angewandte Chemie International Edition.<\/p>\n\n\n\n

\u201cActinopyridazinone is produced by Streptomyces, a genus of bacteria that is the source of the majority of antibiotics of natural origin,\u201d Wakimoto explains. \u201cIt is the first natural compound known to possess a dihydropyridazinone ring. This ring is also known as a \u2018wonder nucleus,\u2019 as it has been extensively studied as a precursor for a wide range of drugs.\u201d<\/p>\n\n\n\n

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\u2013N 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.<\/p>\n\n\n\n

The gene cluster\u00a0apy\u00a0is the biosynthetic gene cluster associated with actinopyradizone synthesis. It contains 17 potential genes; knockout studies indicated that ten of these\u2014apy1,\u00a0apy2,\u00a0apy3,\u00a0apy4,\u00a0apy6,\u00a0apy8,\u00a0apy9, apy10, apy11\u00a0and\u00a0apy13\u2014were necessary for actinopyradizone synthesis. <\/p>\n\n\n\n

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.<\/p>\n\n\n\n

\u201cApy6 functions as a carrier molecule; and Apy3 loads the intermediate compound onto Apy6,\u201d Matsuda elaborates. \u201cApy4 then catalyses the removal of an acetyl group (\u2013COCH3); 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.\u201d<\/p>\n\n\n\n

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\u2013N 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\u2013N bond-containing cyclic compounds are very diverse.<\/p>\n","protected":false},"excerpt":{"rendered":"

Nitrogen\u2013nitrogen 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. <\/p>\n","protected":false},"author":2,"featured_media":24107,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[17],"tags":[],"class_list":["post-24106","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-research"],"featured_image_urls":{"full":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures.png",713,629,false],"thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-200x200.png",200,200,true],"medium":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-453x400.png",453,400,true],"medium_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures.png",713,629,false],"large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-675x595.png",675,595,true],"1536x1536":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures.png",713,629,false],"2048x2048":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures.png",713,629,false],"ultp_layout_landscape_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures.png",713,629,false],"ultp_layout_landscape":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-713x570.png",713,570,true],"ultp_layout_portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-600x629.png",600,629,true],"ultp_layout_square":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-600x600.png",600,600,true],"newspaper-x-single-post":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-713x490.png",713,490,true],"newspaper-x-recent-post-big":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-550x360.png",550,360,true],"newspaper-x-recent-post-list-image":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures-95x65.png",95,65,true],"web-stories-poster-portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures.png",640,565,false],"web-stories-publisher-logo":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures.png",96,85,false],"web-stories-thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2023\/07\/Microbial-cultures.png",150,132,false]},"author_info":{"info":["RevoScience"]},"category_info":"Research<\/a>","tag_info":"Research","comment_count":"0","_links":{"self":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/24106","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/comments?post=24106"}],"version-history":[{"count":0,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/24106\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media\/24107"}],"wp:attachment":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media?parent=24106"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/categories?post=24106"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/tags?post=24106"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}