Structure and functional differences of cysteine and 3-mercaptopropionate dioxygenases. A computational study

Thiol dioxygenases are important enzymes for human
health involved in the detoxification and catabolism of toxic thiolcontaining
natural products such as cysteine, which has relevance to
the development of Alzheimer’s and Parkinson’s diseases in the brain.
Recent crystal structure coordinates of cysteine and 3-
mercaptopropionate dioxygenase (CDO and MDO) showed major
differences in the second-coordination spheres of the two enzymes.
To understand the difference in activity between these two analogous
enzymes, we created large active site cluster models. We show that
CDO and MDO have different iron(III)-superoxo bound structures due
to differences in ligand coordination. Furthermore, our studies show
that the differences in the second-coordination sphere and particularly
the position of a positively charged Arg residue results in changes of
substrate positioning, mobility and enzymatic turnover. Furthermore,
the substrate scope of MDO is explored with cysteinate and 2-
mercaptosuccinic acid and their reactivity is predicted.