Abstract
An important step towards a comprehensive description of the structure-function properties of AChE has been made with the elucidation of the three dimensional structure of Torpedo californica AChE (TcAChE)1. Alignment of amino acid sequences of the cholinesterase family2 reveals over 56% sequence identity and 74% sequence homology1 between TcAChE and human AChE (HuAChE). The highest degree of conservation is in the active site “gorge” and in the residues which are probably involved in maintaining the overall structural integrity of the protein. These observations, together with the nearly identical activity profiles of the two enzymes led us to construct a HuAChE molecular model using the TcAChE structure as a template. Such models are useful for rationalizing the structural and functional effects of site directed mutagenesis3–6 as well as for probing the molecular basis for HuAChE reactivity. Here we provide another example for the use of this model for the analysis of the marked enantioselectivity exhibited by AChE towards organophophorous compounds7. In the case of isopropyl methylphosphonates (IMP) the ratio of bimolecular rate constants of inhibition (ki) for Sp-IMP vs Rp-IMP is in the range of 3 orders of magnitude’. This chiral selectivity is most likely a consequence of the steric requirements of the nucleophilic displacement reaction at the phosphorous atom in the enzyme environment. In order to test this assumption and also to test and refine our model, we have constructed the phosphonylation products of HuAChE, with Sp and Rp diastereoisomers of IMP.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
J.L. Sussman, M. Harel, F. Frolow, C. Oefner, A. Goldman, L. Toker, and I. Silman, Science 253, 872 (1991).
M.K. Gentry, and B.P. Doctor, in: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology. J. Massoulie, F. Bacou, E.A. Barnard, B.P. Doctor, and D.M. Quinn, eds., Am. Chem. Soc Washington (1991), pp. 394.
B. Velan, H. Grosfeld, C. Kronman, M. Leitner, Y. Gozes, A. Lazar, Y. Flashner, D. Markus, S. Cohen, and A. Shafferman, J. Biol. Chem., 266, 23977 (1991).
A. Shafferman, C. Kronman, Y. Flashner, M. Leitner, H. Grosfeld, A. Ordentlich, Y. Gozes, S.Cohen, N. Ariel, D. Barak, M. Harel, I. Silman, J.L. Sussman, and B. Velan, J. Biol. Chem.,in press.
A. Shafferman, B. Velan, A. Ordentlich, C. Kronman, H. Grosfeld, M. Leitner, Y. Flashner, S. Cohen, D. Barak, and N. Ariel, Submitted (1992).
A. Shafferman, B.Velan, A. Ordentlich, C. Kronman, H. Grosfeld, M. Leitner, Y. Flashner, S. Cohen, D. Barak, and N. Ariel, This volume.
H.P. Benschop, and L.P.A. De Jong, Acc. Chem. Res. 21, 368 (1988)
H.L. Boter, L.P.A. De Jong, and H. Kienhuis, in: Interactions of Chemical Agents with Cholinergic Mechanisms,Israel Ins. Biol. Res. 16th Annual Biology Conference (1971).
M. Harel, C.T. Su, F. Frolow, Y. Ashani, I. Silman, and J.L. Sussman, J. Mol. Biol.. 221, 909 (1991).
I.M. Kovach, and D. Huhta, Teochem.,234, 335 (1991).
J. Greer, Proteins,7, 317 (1990)
D.L. 011is, E. Cheah, M. Cygler, B. Dijkstra, F. Frolow, M.S. Franken, M. Harel, S.J. Remington, I. Silman, J. Schrag, J.L. Sussman, K.H.G. Verschueren, and A. Goldman, Prot. Eng.,in press.
H.A. Berman, and K. Leonard, J. Biol. Chem., 264, 3942 (1989).
J. Järv, Bioorg. Chem., 12, 259 (1984).
M. Harel, I. Silman, and J.L. Sussman, This volume.
H.A. Berman, and M.M. Decker, J. Biol. Chem., 264, 3951 (1989).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1992 Springer Science+Business Media New York
About this chapter
Cite this chapter
Barak, D., Ariel, N., Velan, B., Shafferman, A. (1992). Molecular Models for Human AChE and its Phosphonylation Products. In: Shafferman, A., Velan, B. (eds) Multidisciplinary Approaches to Cholinesterase Functions. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3046-6_26
Download citation
DOI: https://doi.org/10.1007/978-1-4615-3046-6_26
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6328-6
Online ISBN: 978-1-4615-3046-6
eBook Packages: Springer Book Archive