Origin of the 6/5/6/5 Tetracyclic Cyclopiazonic Acids

• Published in: Marine drugs Vol. 22; no. 2; p. 74
• Main Authors: Zhang, Wenyuan, Jiang, Xuejian, Wang, Minjun, Zhang, Zhizhen, Wang, Nan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.01.2024
• Subjects: Acids; Adenosine triphosphatase; Analysis; Biosynthesis; Ca2+-transporting ATPase; Calcium ions; Cleavage; Cyclopiazonic acid; Enzymes; Evaluation; Fungi; Genes; Genetic engineering; Genetically modified organisms; Homologous recombination; Hypotheses; indole alkaloids; Marine invertebrates; Natural products; Neurotoxins; Oxidation; Properties; Recombination; sponge-associated fungus; Tetracycline; Tetracyclines; tetramic acid; Toxins; Tryptophan; China; Japan; indole alkaloids; cyclopiazonic acid; sponge-associated fungus; biosynthesis; tetramic acid
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md22020074

The natural product α-cyclopiazonic acid (α-CPA) is a very potent Ca -ATPase inhibitor. The CPA family of compounds comprise over 80 chemical entities with at least five distinct skeletons. While α-CPA features a canonical 6/5/6/5/5 skeleton, the 6/5/6/5 skeleton is the most prevalent among the CPA family. However, the origin of the unique tetracyclic skeleton remains unknown. The 6/5/6/5-type CPAs may derive from a precursor of acetoacetyl-l-tryptophan (AATrp) generated from a hypothetic thioesterase-like pathway. Alternatively, cleavage of the tetramic acid ring would also result in the formation of the 6/5/6/5 scaffold. HMP-F28 is a marine sponge-associated filamentous fungus known to produce CPAs that act as primary neurotoxins. To elucidate the origin of this subfamily of CPAs, we performed homologous recombination and genetic engineering experiments on strain HMP-F28. Our results are supportive of the ring cleavage pathway through which the tetracyclic 6/5/6/5-type CPAs are generated from 6/5/6/5/5-type pentacyclic CPAs.