Flavin-Mediated Reductive Deiodination: Conformational Events and Reactivity Pattern in the Active Site of Human Iodotyrosine Deiodinase

Human iodotyrosine deiodinase (hIYD) catalyzes the reductive
deiodination
of iodotyrosine using a flavin mononucleotide cofactor to maintain
the iodine concentration in the body. Mutations in the hIYD gene are
linked to human hypothyroidism, emphasizing its role in thyroid function
regulation. The present work employs microsecond-scale molecular dynamics
simulations and quantum chemical calculations to elucidate the conformational
dynamics and reactivity in the active site at various stages of hIYD
enzymatic
cycle. The flavin is found to employ a unique butterfly motion of
its isoalloxazine ring accompanied by a novel active-and-resting state
of its ribose 2′-OH group at different stages of the enzymatic
cycle. The flavin dynamics are found to control substrate binding
affinity, the active site lid closure, and NADPH recognition. The
predicted hIYD model shows enhanced stabilization of NADPH due to
additional interactions with the N-terminal and intermediate domains.
The enzyme uses a group of basic residues (R100, R101, R104, K182,
and R279) to stabilize flavin in different stages of catalysis, suggesting
potential mutations to control enzyme activity. The reactivity descriptors
and stereoelectronic analysis predict the N5 nitrogen of flavin as
a proton source during the reductive deiodination, while the anisotropic
charge distribution on the halogen atom has negligible structural
and electronic effects. The present findings provide key insights
into the molecular basis of hIYD activity and lay the groundwork for
future research aimed at therapeutic interventions and industrial
applications.