A novel TetR-type repressor directly modulates precursor supply and utilization for erythromycin biosynthesis

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Actinomycetes produce antibiotics, with TetR family regulators (TFRs) modulating biosynthesis.
• SACE_1906, a TFR in *Saccharopolyspora erythraea*, was previously identified as a factor that reduces erythromycin yield.

Purpose of the Study:

• To elucidate the precise mechanism by which SACE_1906 regulates erythromycin biosynthesis.
• To identify the binding sites and effector molecules of SACE_1906.

Main Methods:

• Analysis of gene transcription inhibition by SACE_1906.
• Identification of SACE_1906 DNA binding sites using conserved sequences.
• Measurement of intracellular precursor levels (propionyl-CoA and methylmalonyl-CoA) upon SACE_1906 deletion.
• Investigation of acetaldehyde's effect on SACE_1906 binding affinity.

Main Results:

• SACE_1906 directly represses transcription of its own gene, *SACE_1905*, and the entire erythromycin biosynthetic gene cluster.
• SACE_1906 binds to conserved sites in the *SACE_1905-1906-int* region.
• SACE_1906 deletion alters propionyl-CoA and methylmalonyl-CoA levels by repressing propionyl-CoA carboxylase genes.
• Acetaldehyde acts as an effector, reducing SACE_1906 binding to its target DNA.

Conclusions:

• SACE_1906 negatively regulates erythromycin biosynthesis by controlling precursor supply and gene cluster transcription.
• Acetaldehyde modulates SACE_1906 activity, providing a novel small-molecule-mediated regulatory pathway for antibiotic production in actinomycetes.