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Substrate Trapping in the Siderophore Tailoring Enzyme PvdQ
Kenneth D Clevenger1, Romila Mascarenhas2, Daniel Catlin2
1Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.
Abstract:
Siderophore biosynthesis by Pseudomonas aeruginosa enhances virulence and represents an attractive drug target. PvdQ functions in the type-1 pyoverdine biosynthetic pathway by removing a myristoyl anchor from a pyoverdine precursor, allowing eventual release from the periplasm. A circularly permuted version of PvdQ bypasses the self-processing step of this Ntn-hydrolase and retains the activity, selectivity, and structure of wild-type PvdQ, as revealed by a 1.8 Å resolution X-ray crystal structure. A 2.55 Å resolution structure of the inactive S1A/N269D-cpPvdQ mutant in complex with the pyoverdine precursor PVDIq reveals a specific binding pocket for the d-Tyr of this modified peptide substrate. To our knowledge, this structure is the first of a pyoverdine precursor peptide bound to a biosynthetic enzyme. Details of the observed binding interactions have implications for control of pyoverdine biosynthesis and inform future drug design efforts.
Insights
Pseudomonas aeruginosa pyoverdine biosynthesis is key to its virulence. Researchers studied the PvdQ enzyme, finding its structure and interactions with a pyoverdine precursor, which could aid drug design.
Area of Science:
- Microbiology
- Structural Biology
- Biochemistry
Background:
- Pseudomonas aeruginosa utilizes siderophore biosynthesis, particularly pyoverdine, to enhance virulence.
- The enzyme PvdQ is crucial in the pyoverdine pathway, cleaving a myristoyl anchor from a precursor.
- Targeting siderophore biosynthesis presents a promising strategy for developing new antimicrobial therapies.
Purpose of the Study:
- To characterize the structure and function of PvdQ, an enzyme involved in pyoverdine biosynthesis.
- To investigate a circularly permuted variant of PvdQ (cpPvdQ) for potential therapeutic applications.
- To elucidate the binding interactions between PvdQ and its pyoverdine precursor.
Main Methods:
- X-ray crystallography was used to determine the high-resolution structures of wild-type PvdQ and a mutant form.
- Biochemical assays were employed to assess the activity and selectivity of PvdQ and its variants.
- Structural analysis of the PvdQ-precursor complex provided insights into substrate binding.
Main Results:
- A circularly permuted PvdQ (cpPvdQ) retained wild-type activity, selectivity, and structure, bypassing self-processing.
- The X-ray crystal structure of an inactive mutant complexed with the pyoverdine precursor PVDIq revealed a specific binding pocket.
- This is the first reported structure of a pyoverdine precursor bound to its biosynthetic enzyme.
Conclusions:
- The structural and functional characterization of PvdQ and its cpPvdQ variant offers insights into pyoverdine biosynthesis.
- Understanding the specific binding interactions can inform the design of novel inhibitors targeting PvdQ.
- These findings have significant implications for developing new drugs against Pseudomonas aeruginosa infections.
