Biosynthetic origin of hygromycin A
El-Sayed E Habib1, J Neel Scarsdale, Kevin A Reynolds
1Departments of Medicinal Chemistry,Virginia Commonwealth University, Richmond, Virginia 23219, USA.
Antimicrobial Agents and Chemotherapy
|June 25, 2003
Summary
This study reveals the biosynthetic pathway of hygromycin A, an antibiotic targeting bacterial ribosomes. Understanding this pathway aids in developing new antibiotics against drug-resistant pathogens.
Area of Science:
- Microbiology
- Biochemistry
- Synthetic Biology
Background:
- Hygromycin A is a bacterial ribosomal peptidyl transferase inhibitor.
- It has a unique binding site, offering potential for new antibiotic development against multidrug-resistant pathogens.
Purpose of the Study:
- To elucidate the biosynthetic origins of hygromycin A's three structural moieties.
- To establish the convergent biosynthetic pathway for hygromycin A.
Main Methods:
- Stable-isotope incorporation studies using labeled precursors like mannose, glucose, propionate, and 4-hydroxybenzoic acid.
- Analysis of labeling patterns to determine the origin of each structural component.
- Investigating the role of chorismic acid in 4-hydroxybenzoic acid biosynthesis.
Main Results:
- The 6-deoxy-5-keto-D-arabino-hexofuranose moiety originates from mannose via an L-fucose intermediate.
- The aminocyclitol moiety is derived from myo-inositol through an unprecedented oxidation and transamination.
- The 3,4-dihydroxy-alpha-methylcinnamic acid moiety is formed via a polyketide synthase-like pathway from propionate and 4-hydroxybenzoic acid.
- 4-hydroxybenzoic acid is derived from chorismic acid, not tyrosine, phenylalanine, or benzoic acid.
Conclusions:
- The established convergent biosynthetic pathway for hygromycin A provides a versatile platform for combinatorial and directed biosynthesis.
- This pathway can be exploited to generate novel antibiotics targeting ribosomal peptidyl transferase activity.
- Understanding hygromycin A biosynthesis is crucial for developing next-generation antibiotics against resistant bacteria.
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