Mammalian Cysteine Dioxygenase

Cysteine dioxygenase (CDO) is a mononuclear nonheme Fe(II) enzyme that catalyzes the oxidation of l-cysteine to l-cysteinesulfinic acid (CSA) by addition of both atoms of molecular oxygen to the cysteine sulfur. Mammalian CDO is highly expressed in the liver, the pancreas, the adipose tissue, the kidney and the lungs, and the CSA produced is further converted to either taurine or sulfate plus pyruvate. To maintain cysteine levels within the narrow range required for health, mammalian CDO is regulated by the modulation of enzyme turnover and through formation of a Cys93-Tyr157 crosslink that increases its activity over 10-fold. Imbalances in cysteine metabolism have been observed in several neurological disorders, and CDO has been identified as a tumor suppressor. Bacterial CDOs also exist, as do a variety of related thiol dioxygenases that have been less well studied. High-resolution crystal structures of CDO reveal iron coordination by three histidines. Cysteine coordinates the iron by its amino and thiolate groups, leaving a sixth coordination site open for dioxygen. A cysteine persulfenate has been trapped in the active site, but despite substantial spectroscopic studies and theoretical calculations, the details of the mechanism are still a matter of debate and it is uncertain if this is an intermediate. 3D Structure Structure of rat CDO with cysteine persulfenate (or cysteine persulfenic acid) bound based on PDB code 4ieu1. The cupin fold of CDO is shown with the secondary structures labeled; the iron at the center of the β-barrel is shown as a black sphere. The Cys–Tyr crosslink is shown, along with the active site Arg, the iron coordinating His residues and the bound cysteine persulfenate. Figure generated using the PyMOL Molecular Graphics System, Version 1.5.0.4 Schrodinger, LLC.2 Keywords: thiol oxidation; sulfur metabolism; nonheme iron; cysteine; dioxygenase; cysteinesulfinic acid; taurine; sulfate