Self-Resistance during Muraymycin Biosynthesis: a Complementary Nucleotidyltransferase and Phosphotransferase with...

Area of Science:

• Microbiology
• Biochemistry
• Natural Products Chemistry

Background:

• Muraymycins are antibacterial natural products produced by *Streptomyces* species.
• They function by inhibiting translocase I (MraY), a key enzyme in bacterial cell wall biosynthesis.
• The core structure of muraymycins involves a disaccharide composed of 5'-*C*-glycyluridine (GlyU) and 5″-amino-5″-deoxyribose (ADR).

Purpose of the Study:

• To functionally characterize two enzymes, Mur29 and Mur28, involved in muraymycin biosynthesis.
• To elucidate the biochemical mechanisms by which these enzymes modify muraymycins.
• To investigate the role of these enzymatic modifications in bacterial self-resistance to muraymycins.

Main Methods:

• In vitro biochemical assays were employed to determine the enzymatic activities of Mur29 and Mur28.
• Kinetic analyses were performed using synthetic substrates and muraymycin derivatives.
• Antibacterial and enzyme inhibitory activities of modified muraymycins were assessed.

Main Results:

• Mur29 was identified as a Mg·ATP-dependent nucleotidyltransferase that adenylates muraymycins.
• Mur28 was identified as a Mg·ATP-dependent phosphotransferase that phosphorylates muraymycins.
• Both adenylated and phosphorylated muraymycins exhibited significantly reduced MraY inhibitory and antibacterial activities.

Conclusions:

• Mur29 and Mur28 catalyze complementary self-resistance mechanisms in *Streptomyces* during muraymycin biosynthesis.
• Enzymatic modification by Mur29 (adenylation) and Mur28 (phosphorylation) temporally protects the producing organism from its own antibiotic.
• These findings provide insights into the intricate regulation of natural product biosynthesis and resistance.