Enzymology of the nematode cuticle: A potential drug target?

• The nematode cuticle and its enzymology represent a novel target in nematode control.
• Cuticle collagens are the major structural components of this vital structure.
• Prolyl 4-hydroxylase, disulphide bonding and proline isomerisation are key modifications that occur within the endoplasmic reticulum (ER).
• Collagen N- and C-terminal processing and tyrosine cross-linking are critical and exploitable post-ER events.
• Moulting and collagenase enzymes are prime targets for inhibitor design in parasitic nematode control.

All nematodes possess an external structure known as the cuticle, which is crucial for their development and survival. This structure is composed primarily of collagen, which is secreted from the underlying hypodermal cells. Extensive studies using the free-living nematode Caenorhabditis elegans demonstrate that formation of the cuticle requires the activity of an extensive range of enzymes. Enzymes are required both pre-secretion, for synthesis of component proteins such as collagen, and post-secretion, for removal of the previous developmental stage cuticle, in a process known as moulting or exsheathment. The excretion/secretion products of numerous parasitic nematodes contain metallo-, serine and cysteine proteases, and these proteases are conserved across the nematode phylum and many are involved in the moulting/exsheathment process. This review highlights the enzymes required for cuticle formation, with a focus on the post-secretion moulting events. Where orthologues of the C. elegans enzymes have been identified in parasitic nematodes these may represent novel candidate targets for future drug/vaccine development.

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