An Alkaloid Biosynthetic Gene Bundle in Animals.

Area of Science:

• Natural Product Chemistry
• Marine Biology
• Bioinformatics
• Genomics

Background:

• Alkaloids are crucial in medicine, but animal-derived alkaloids remain underexplored compared to plant sources.
• Discovering novel alkaloid biosynthetic pathways in animals is challenging due to unknown enzymes and gene organization.
• Oroidin and related pyrrole-imidazole alkaloids are significant marine natural products with potential applications.

Purpose of the Study:

• To develop a computational method for agnostic discovery of animal alkaloid biosynthetic gene clusters (BGCs).
• To identify novel BGCs in marine sponges producing oroidin and related compounds.
• To understand the organization and origin of these unique gene clusters.

Main Methods:

• Developed a computational approach to identify genes clustered in specific chromosomal regions.
• Applied the method to genomic data from marine sponges known to produce oroidin.
• Utilized biochemical assays to validate the function of identified proteins within the 'oro' cluster.

Main Results:

• Discovered 36 novel BGCs in oroidin-producing sponges, challenging existing BGC paradigms.
• Identified a conserved 'oro' BGC present in all studied oroidin-producing species.
• Validated five 'oro' proteins, demonstrating their role in alkaloid biosynthesis.
• Showcased that 'bundles' of common animal genes can be repurposed for specialized natural product synthesis.

Conclusions:

• The developed computational method enables agnostic discovery of noncanonical BGCs, termed 'bundles'.
• The 'oro' BGC in marine sponges exemplifies the repurposing of primary metabolic genes for alkaloid production.
• This work provides a framework for accelerating the discovery and development of diverse animal-derived natural products.