Structure and Functional Differences of Cysteine and 3‐Mercaptopropionate Dioxygenases: A Computational Study

다국어 초록 (Multilingual Abstract)

Thiol dioxygenases are important enzymes for human health; they are involved in the detoxification and catabolism of toxic thiol‐containing natural products such as cysteine. As such, these enzymes have 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 in 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.
Spheres of influence: Although cysteine and 3‐mercaptopropionate dioxygenase bind and react similar substrates, there are key differences in the first‐ and second‐coordination spheres that affect their catalytic reaction mechanism and reactivity, as highlighted by density functional theory studies on large enzyme clusters.