Potent and competitive inhibition of malic enzymes by lanthanide ions

The catalytic activity of malic enzyme (ME), a member of a new class of oxi dative decarboxylases, requires the presence of divalent cations (Mn2+, Mg2 +, and others). The crystal structure at 2.9 Angstrom resolution of human m itochondrial NAD(+)-dependent malic enzyme in a ternary complex with NAD(+) and the lanthanide ion Lu3+, Which has similar radius as Mn2+, reveals a n ew conformation of the enzyme. The active site in this ternary complex is i n an open form, while the organization of the tetramer of the enzyme actual ly resembles that with a closed active site. The Lu3+ ion is bound to the e nzyme at the same site as Mn2+. Kinetic studies showed that Lu3+ is a poten t inhibitor of both the human NAD(P)(+)-dependent ME and the NADP(+)-depend ent ME from pigeon liver, and is competitive with respect to the divalent c ation, consistent with the structural information. (C) 2000 Academic Press.