Chemistry & Biology
Volume 20, Issue 8, 22 August 2013, Pages 991-1001
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Article
Peroxiredoxin-1 from the Human Hookworm Ancylostoma ceylanicum Forms a Stable Oxidized Decamer and Is Covalently Inhibited by Conoidin A

https://doi.org/10.1016/j.chembiol.2013.06.011Get rights and content
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Highlights

  • Hookworms rely on peroxiredoxins as antioxidants and for intracellular signaling

  • Peroxiredoxin-1 expressed in adult hookworms is covalently inactivated by conoidin A

  • Hookworm Prx-1 is a decamer and has a structure similar to human peroxiredoxin IV

  • Conoidin A may be useful to validate peroxiredoxins as anthelminthic drug targets

Summary

Hookworms are parasitic nematodes that have a devastating impact on global health, particularly in developing countries. We report a biochemical and structural analysis of a peroxiredoxin from the hookworm Ancylostoma ceylanicum, AcePrx-1. Peroxiredoxins provide antioxidant protection and act as signaling molecules and chaperones. AcePrx-1 is expressed in adult hookworms and can be inactivated by 2,3-bis(bromomethyl)quinoxaline-1,4-dioxide (conoidin A). Conoidin A inactivates AcePrx-1 by alkylating or crosslinking the catalytic cysteines, while maintaining the enzyme in the “locally unfolded” conformation. Irreversible oxidation of the resolving cysteine may contribute additional inhibitory activity. A crystal structure of oxidized AcePrx-1 reveals a disulfide-linked decamer. A helix macrodipole near the active site increases the reactivity of the catalytic cysteines to conoidin A. This work demonstrates the promise of conoidin compounds as probes to evaluate peroxiredoxins as drug targets in human parasites.

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