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.
Yang
Z
Z
Department of Biological Sciences, Columbia University, New York, New York, 10027, USA.
Batra
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Floyd
D L
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Hung
H C
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Chang
G G
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Tong
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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