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Structure of a closed form of human malic enzyme and implications for catalytic mechanism

Nature Structural Biology volume 7, pages 251–257 (2000)Cite this article

Abstract

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 Å resolution. The structures of the quaternary complex with NAD+, Mg++, tartronate or ketomalonate have been determined at 2.6 Å 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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Figure 1: Overall structure of human malic enzyme.
Figure 2: The active site of human malic enzyme.
Figure 3: A possible catalytic mechanism for malic enzymes.
Figure 4: The tetramer of human malic enzyme.

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Acknowledgements

We thank C. Ogata for setting up the beam line, Y. Xu and R. Khayat for help with data collection at NSLS, W. W. Cleland for many helpful discussions, and H. Wu for comments on the manuscript. This work was supported by a grant from the National Science Foundation to L.T.

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Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, New York, 10027, New York, USA

    Zhiru Yang, Daniel L. Floyd & Liang Tong

  2. Boehringer Ingelheim Austria Research and Development, Vienna, A-1121, Dr.Boehringer-Gasse 5-11, Austria

    Gerhard Loeber

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  1. Zhiru Yang
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  2. Daniel L. Floyd
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  3. Gerhard Loeber
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  4. Liang Tong
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Correspondence to Liang Tong.

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Yang, Z., Floyd, D., Loeber, G. et al. Structure of a closed form of human malic enzyme and implications for catalytic mechanism. Nat Struct Mol Biol 7, 251–257 (2000). https://doi.org/10.1038/73378

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