02559nas a2200265   4500008004100000022001400041245014200055210006900197260000900266300001100275490000800286520163300294653002301927653002201950653003401972653002102006653002602027100002002053700002102073700001902094700002202113700001702135700002002152856012102172       2024                        eng d  a0006-291X00aStructure of epoxide hydrolase 2 from Mangifera indica throws light on the substrate specificity determinants of plant epoxide hydrolases0 aStructure of epoxide hydrolase 2 from Mangifera indica throws li  cNOV   a1504440 v7333 a<p>
	Epoxide hydrolases (EHs) are a group of ubiquitous enzymes that catalyze hydrolysis of chemically reactive epoxides to yield corresponding dihydrodiols. Despite extensive studies on EHs from different clades, generic rules governing their substrate specificity determinants have remained elusive. Here, we present structural, biochemical and molecular dynamics simulation studies on MiEH2, a plant epoxide hydrolase from Mangifera indica. Comparative structure-function analysis of nine homologs of MiEH2, which include a few AlphaFold structural models, show that the two conserved tyrosines (MiEH2Y152 and MiEH2Y232) from the lid domain dissect substrate binding tunnel into two halves, forming substrate-binding-pocket one (BP1) and two (BP2). This compartmentalization offers diverse binding modes to their substrates, as exemplified by the binding of smaller aromatic substrates, such as styrene oxide (SO). Docking and molecular dynamics simulations reveal that the linear epoxy fatty acid substrates predominantly occupy BP1, while the aromatic substrates can bind to either BP1 or BP2. Furthermore, SO preferentially binds to BP2, by stacking against catalytically important histidine (MiEH2H297) with the conserved lid tyrosines engaging its epoxide oxygen. Residue (MiEH2L263) next to the catalytic aspartate (MiEH2D262) modulates substrate binding modes. Thus, the divergent binding modes correlate with the differential affinities of the EHs for their substrates. Furthermore, long-range dynamical coupling between the lid and core domains critically influences substrate enantioselectivity in plant EHs.</p>
10aEnantioselectivity10aEpoxide hydrolase10amolecular dynamics simulation10aRegioselectivity10aX-ray crystallography1 aBhoite, Ashwini1 aGaur, Neeraj, K.1 aPalange, Megha1 aKontham, Ravindar1 aGupta, Vidya1 aKulkarni, Kiran  uhttps://library.ncl.res.in/content/structure-epoxide-hydrolase-2-mangifera-indica-throws-light-substrate-specificity