Abstract
Cysteine dioxygenase is a mononuclear iron-dependent enzyme responsible for the oxidation of cysteine with molecular oxygen to form cysteine sulfinate. This reaction commits cysteine to either catabolism to sulfate and pyruvate or the taurine biosynthetic pathway. Cysteine dioxygenase is a member of the cupin superfamily of proteins. The crystal structure of recombinant rat cysteine dioxygenase has been determined to 1.5-A resolution, and these results confirm the canonical cupin beta-sandwich fold and the rare cysteinyltyrosine intramolecular cross-link (between Cys(93) and Tyr(157)) seen in the recently reported murine cysteine dioxygenase structure. In contrast to the catalytically inactive mononuclear Ni(II) metallocenter present in the murine structure, crystallization of a catalytically competent preparation of rat cysteine dioxygenase revealed a novel tetrahedrally coordinated mononuclear iron center involving three histidines (His(86), His(88), and His(140)) and a water molecule. Attempts to acquire a structure with bound ligand using either cocrystallization or soaking crystals with cysteine revealed the formation of a mixed disulfide involving Cys(164) near the active site, which may explain previously observed substrate inhibition. This work provides a framework for understanding the molecular mechanisms involved in thiol dioxygenation and sets the stage for exploration of the chemistry of both the novel mononuclear iron center and the catalytic role of the cysteinyl-tyrosine linkage.
Highlights
The cytosolic enzyme cysteine dioxygenase (CDO)3 (EC 1.13.11.20) catalyzes the irreversible oxidation of cysteine to cysteine sulfinate (Reaction 1)
Clinical evidence indicates that a block in cysteine catabolism, thought to be at CDO, leads to an altered cysteine to sulfate ratio that is associated with sulfate depletion and other adverse effects [1]
The overall structure of CDO consists of a small ␣-helical domain containing three ␣-helices near the N terminus followed by 13 -strands subdivided into a main -sandwich domain and two -hairpins at the C terminus (Fig. 2)
Summary
Cysteine dioxygenase is a mononuclear iron-dependent enzyme responsible for the oxidation of cysteine with molecular oxygen to form cysteine sulfinate. This reaction commits cysteine to either catabolism to sulfate and pyruvate or the taurine biosynthetic pathway. The active site geometry reported here provides a framework for understanding the molecular mechanisms involved in thiol dioxygenation and sets the stage for exploring the chemistry of this new type of mononuclear iron center
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