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Structure and Mechanism of the Formylglycine-generating Enzyme

  • Author(s): Appel, Mason
  • Advisor(s): Bertozzi, Carolyn R
  • Klinman, Judith P
  • et al.
No data is associated with this publication.
Abstract

The ability of enzymes to make rapid the conversion between chemical entities represents an enabling feature for life. The strategies by which enzymes achieve this feat are manifold in their details and physiological consequences. Though the central importance of biological catalysis has been known for well over a century, the true breadth of enzyme function is still beginning to be appreciated. A fundamental description of enzyme catalysis is essential to understanding biological processes, and is also necessary in order to realize the promise of engineered enzymes for transforming medicine and manufacturing.

The formylglycine-generating enzyme (FGE) is responsible for activating sulfatase enzymes in aerobic organisms by catalyzing the post-translational modification of a cysteine residue to formylglycine. Formylglycine permits sulfatase activity by acting as a covalent cofactor. Thus, the diverse roles of sulfatases in both animal and microbial biology underscore the importance of FGE. However, early investigations made clear that this enzyme operates by a novel mechanism with a unique protein fold. In turn, elucidation of the details of this biochemical transformation have remained enigmatic for almost two decades.

This dissertation describes the structural and biochemical interrogation of FGE in pursuit of understanding its catalytic mechanism. Chapter 1 places into context the physiological importance and biochemical curiosities of formylglycine and FGE. In Chapter 2, I present the first structural and spectroscopic characterization of copper-bound FGE, defining it as a novel enzyme with intriguing features related to function. Finally, Chapter 3 reveals detailed structural and kinetic proof for several critical steps of catalysis by FGE, allowing the formulation of a mechanistic framework for further investigation.

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This item is under embargo until March 9, 2022.