Potent and competitive inhibition of malic enzymes by lanthanide ions.
The catalytic activity of malic enzyme (ME), a member of a new class of oxidative decarboxylases, requires the presence of divalent cations (Mn(2+), Mg(2+), and others). The crystal structure at 2.9 A resolution of human mitochondrial NAD(+)-dependent malic enzyme in a ternary complex with NAD(+) and the lanthanide ion Lu(3+), which has similar radius as Mn(2+), reveals a new conformation of the enzyme. The active site in this ternary complex is in an open form, while the organization of the tetramer of the enzyme actually resembles that with a closed active site. The Lu(3+) ion is bound to the enzyme at the same site as Mn(2+). Kinetic studies showed that Lu(3+) is a potent inhibitor of both the human NAD(P)(+)-dependent ME and the NADP(+)-dependent ME from pigeon liver, and is competitive with respect to the divalent cation, consistent with the structural information.
Department of Biological Sciences, Columbia University, New York, New York, 10027, USA.
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Yang
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D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects*; D010856:Columbidae; D018360:Crystallography, X-Ray; D006801:Humans; D008187:Lutetium / Q000737:chemistry / Q000494:pharmacology; D008274:Magnesium / Q000737:chemistry; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008345:Manganese / Q000737:chemistry; D008674:Metals, Rare Earth / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry; D011487:Protein Conformation / Q000187:drug effects
D008674:Metals, Rare Earth; D009243:NAD; D008345:Manganese; D008187:Lutetium; D008291:Malate Dehydrogenase; D008274:Magnesium