Griseocazines: Neuroprotective Multiprenylated Cyclodipeptides Identified through Targeted Genome Mining

Area of Science:

• Natural Product Discovery
• Medicinal Chemistry
• Synthetic Biology

Background:

• Prenylation enhances pharmacological properties of bioactive molecules.
• Cyclodipeptides are a class of natural products with diverse biological activities.
• Genome mining is a powerful tool for discovering novel biosynthetic gene clusters.

Purpose of the Study:

• To identify novel prenylated cyclodipeptides using genome mining.
• To characterize the biosynthetic pathway and enzymatic mechanisms of prenylation.
• To evaluate the pharmacological activity of the identified compounds.

Main Methods:

• Global genome mining of Streptomyces griseocarneus 132 for prenylated cyclodipeptide biosynthetic gene clusters (BGCs).
• Identification and characterization of the gczABC BGC, containing cyclodipeptide synthase and prenyltransferase genes.
• Heterologous expression of the BGC for compound isolation and structural elucidation.
• Biotransformation assays to determine the substrate specificity and stereoselectivity of prenyltransferases GczB and GczC.

Main Results:

• Discovery and isolation of griseocazines, novel prenylated cyclodipeptides.
• Griseocazines exhibited potent neuroprotective activity.
• Prenyltransferases GczB and GczC were shown to stereospecifically attach geranyl and farnesyl groups to a cyclodipeptide scaffold (cWW).

Conclusions:

• The gczABC BGC from Streptomyces griseocarneus encodes the biosynthesis of neuroprotective prenylated cyclodipeptides.
• Griseocazines represent a new class of pharmacologically relevant natural products.
• The identified prenyltransferases offer insights into the enzymatic mechanisms of cyclodipeptide prenylation.