Structural aspects of therapeutic enzymes to treat metabolic disorders.

Protein therapeutics represents a niche subset of pharmacological agents that is rapidly gaining importance in medicine. In addition to the exceptional specificity that is characteristic of protein therapeutics, several classes of proteins have also been effectively utilized for treatment of conditions that would otherwise lack effective pharmacotherapeutic options. A particularly striking class of protein therapeutics is exogenous enzymes administered for replacement therapy in patients afflicted with metabolic disorders. To date, at least 11 enzymes have either been approved for use, or are in clinical trials for the treatment of selected inherited metabolic disorders. With the recent advancement in structural biology, a significantly larger amount of structural information for several of these enzymes is now available. This article is an overview of the correlation between structural perturbations of these enzymes with the clinical presentation of the respective metabolic conditions, as well as a discussion of the relevant structural modification strategies engaged in improving these enzymes for replacement therapies.