First Ring-Expanded Maytansin Lactone Accessed by a New Mutasynthetic Variant

Area of Science:

• Microbiology
• Synthetic Biology
• Natural Product Chemistry

Background:

• Actinosynnema pretiosum produces ansamitocin, a toxic maytansinoid.
• Genetic engineering can create mutant strains for novel compound production.
• Mutasynthesis combines biological and chemical methods to access new molecules.

Purpose of the Study:

• To develop a mutasynthetic strategy for producing new proansamitocin derivatives.
• To broaden the scope of chemo-biosynthetic access to novel maytansinoids.
• To create previously inaccessible maytansinoid structures.

Main Methods:

• Construction of a multiblocked mutant strain of Actinosynnema pretiosum (ΔAHBA and Δasm12, asm21).
• Utilizing the mutant strain for mutasynthetic production of proansamitocin derivatives.
• Characterization of the newly produced maytansinoid compounds.

Main Results:

• Successful mutasynthetic production of new proansamitocin derivatives.
• Demonstration that blocking early biosynthesis and tailoring enzymes expands chemo-biosynthetic access.
• First-time creation of a ring-expanded macrolactone derived from ansamitocin.

Conclusions:

• The engineered mutant strain enables efficient mutasynthetic production of diverse maytansinoids.
• This strategy significantly broadens the chemical space accessible for maytansinoid discovery.
• The novel ring-expanded ansamitocin derivative represents a new structural class for potential applications.