Structure of a closed form of human malic enzyme and implications for catalytic mechanism.
Malic enzymes are widely distributed in nature and have many biological functions. The crystal structure of human mitochondrial NAD(P)+-dependent malic enzyme in a quaternary complex with NAD+, Mn++ and oxalate has been determined at 2.2 A resolution. The structures of the quaternary complex with NAD+, Mg++, tartronate or ketomalonate have been determined at 2.6 A resolution. The structures show the enzyme in a closed form in these complexes and reveal the binding modes of the cation and the inhibitors. The divalent cation is coordinated in an octahedral fashion by six ligating oxygens, two from the substrate/inhibitor, three from Glu 255, Asp 256 and Asp 279 of the enzyme, and one from a water molecule. The structural information has significant implications for the catalytic mechanism of malic enzymes and identifies Tyr 112 and Lys 183 as possible catalytic residues. Changes in tetramer organization of the enzyme are also observed in these complexes, which might be relevant for its cooperative behavior and allosteric control.
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Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Floyd
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Loeber
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Tong
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D000494:Allosteric Regulation; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008274:Magnesium / Q000378:metabolism; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008314:Malonates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008345:Manganese / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D019815:Oxalic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D013646:Tartronates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014867:Water / Q000378:metabolism
D008314:Malonates; D013646:Tartronates; D014867:Water; D009243:NAD; C032973:tartronic acid; D008345:Manganese; C008375:mesoxalic acid; D019815:Oxalic Acid; D008291:Malate Dehydrogenase; C046446:malate dehydrogenase-(oxaloacetate-decarboxylating) (NAD+); D008274:Magnesium; D010100:Oxygen