Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 31 May 1991:
Vol. 252. no. 5010, pp. 1278 - 1284
DOI: 10.1126/science.1925539
Prev | Table of Contents | Next

Articles

Science, Vol 252, Issue 5010, 1278-1284
Copyright © 1991 by American Association for the Advancement of Science

articles

Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations

DK Wilson, FB Rudolph, and FA Quiocho

Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030.

The crystal structure of a murine adenosine deaminase complexed with 6-hydroxyl-1,6-dihydropurine ribonucleoside, a nearly ideal transition-state analog, has been determined and refined at 2.4 angstrom resolution. The structure is folded as an eight-stranded parallel alpha/beta barrel with a deep pocket at the beta-barrel COOH-terminal end wherein the inhibitor and a zinc are bound and completely sequestered. The presence of the zinc cofactor and the precise structure of the bound analog were not previously known. The 6R isomer of the analog is very tightly held in place by the coordination of the 6-hydroxyl to the zinc and the formation of nine hydrogen bonds. On the basis of the structure of the complex a stereoselective addition-elimination or SN2 mechanism of the enzyme is proposed with the zinc atom and the Glu and Asp residues playing key roles. A molecular explanation of a hereditary disease caused by several point mutations of an enzyme is also presented.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Identification and characterization of a salivary adenosine deaminase from the sand fly Phlebotomus duboscqi, the vector of Leishmania major in sub-Saharan Africa.
H. Kato, R. C. Jochim, P. G. Lawyer, and J. G. Valenzuela (2007)
J. Exp. Biol. 210, 733-740
   Abstract »    Full Text »    PDF »
A Catalytic Mechanism Revealed by the Crystal Structures of the Imidazolonepropionase from Bacillus subtilis.
Y. Yu, Y.-H. Liang, E. Brostromer, J.-M. Quan, S. Panjikar, Y.-H. Dong, and X.-D. Su (2006)
J. Biol. Chem. 281, 36929-36936
   Abstract »    Full Text »    PDF »
TrzN from Arthrobacter aurescens TC1 Is a Zinc Amidohydrolase..
N. Shapir, C. Pedersen, O. Gil, L. Strong, J. Seffernick, M. J. Sadowsky, and L. P. Wackett (2006)
J. Bacteriol. 188, 5859-5864
   Abstract »    Full Text »    PDF »
Membrane Association, Mechanism of Action, and Structure of Arabidopsis Embryonic Factor 1 (FAC1).
B. W. Han, C. A. Bingman, D. K. Mahnke, R. M. Bannen, S. Y. Bednarek, R. L. Sabina, and G. N. Phillips Jr. (2006)
J. Biol. Chem. 281, 14939-14947
   Abstract »    Full Text »    PDF »
Crystal Structures of HIV-1 Tat-derived Nonapeptides Tat-(1-9) and Trp2-Tat-(1-9) Bound to the Active Site of Dipeptidyl-peptidase IV (CD26).
W. A. Weihofen, J. Liu, W. Reutter, W. Saenger, and H. Fan (2005)
J. Biol. Chem. 280, 14911-14917
   Abstract »    Full Text »    PDF »
Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins.
L.-M. Ting, W. Shi, A. Lewandowicz, V. Singh, A. Mwakingwe, M. R. Birck, E. A. T. Ringia, G. Bench, D. C. Madrid, P. C. Tyler, et al. (2005)
J. Biol. Chem. 280, 9547-9554
   Abstract »    Full Text »    PDF »
Crystal Structure of CD26/Dipeptidyl-peptidase IV in Complex with Adenosine Deaminase Reveals a Highly Amphiphilic Interface.
W. A. Weihofen, J. Liu, W. Reutter, W. Saenger, and H. Fan (2004)
J. Biol. Chem. 279, 43330-43335
   Abstract »    Full Text »    PDF »
Evolution of Enzymes for the Metabolism of New Chemical Inputs into the Environment.
L. P. Wackett (2004)
J. Biol. Chem. 279, 41259-41262
   Full Text »    PDF »
The Functional Role of the Binuclear Metal Center in D-Aminoacylase: ONE-METAL ACTIVATION AND SECOND-METAL ATTENUATION.
W.-L. Lai, L.-Y. Chou, C.-Y. Ting, R. Kirby, Y.-C. Tsai, A. H.-J. Wang, and S.-H. Liaw (2004)
J. Biol. Chem. 279, 13962-13967
   Abstract »    Full Text »    PDF »
Ribavirin, viramidine and adenosine-deaminase-catalysed drug activation: implication for nucleoside prodrug design.
J. Z. Wu, C.-c. Lin, and Z. Hong (2003)
J. Antimicrob. Chemother. 52, 543-546
   Full Text »    PDF »
Crystal Structure of Yeast Cytosine Deaminase: INSIGHTS INTO ENZYME MECHANISM AND EVOLUTION.
T.-P. Ko, J.-J. Lin, C.-Y. Hu, Y.-H. Hsu, A. H.-J. Wang, and S.-H. Liaw (2003)
J. Biol. Chem. 278, 19111-19117
   Abstract »    Full Text »    PDF »
The Methanococcus jannaschii dCTP Deaminase Is a Bifunctional Deaminase and Diphosphatase.
H. Li, H. Xu, D. E. Graham, and R. H. White (2003)
J. Biol. Chem. 278, 11100-11106
   Abstract »    Full Text »    PDF »
Dihydropyrimidine amidohydrolases and dihydroorotases share the same origin and several enzymatic properties.
Z. Gojkovic, L. Rislund, B. Andersen, M. P. B. Sandrini, P. F. Cook, K. D. Schnackerz, and J. Piskur (2003)
Nucleic Acids Res. 31, 1683-1692
   Abstract »    Full Text »    PDF »
Crystal Structure of D-Aminoacylase from Alcaligenes faecalis DA1. A NOVEL SUBSET OF AMIDOHYDROLASES AND INSIGHTS INTO THE ENZYME MECHANISM.
S.-H. Liaw, S.-J. Chen, T.-P. Ko, C.-S. Hsu, C.-J. Chen, A. H.-J. Wang, and Y.-C. Tsai (2003)
J. Biol. Chem. 278, 4957-4962
   Abstract »    Full Text »    PDF »
Characterization of the Zinc-binding Site of the Histidine-Proline-rich Glycoprotein Associated with Rabbit Skeletal Muscle AMP Deaminase.
S. Mangani, W. Meyer-Klaucke, A. J. G. Moir, M. Ranieri-Raggi, D. Martini, and A. Raggi (2003)
J. Biol. Chem. 278, 3176-3184
   Abstract »    Full Text »    PDF »
Activation and Deactivation of a Broad-Spectrum Antiviral Drug by a Single Enzyme: Adenosine Deaminase Catalyzes Two Consecutive Deamination Reactions.
J. Z. Wu, H. Walker, J. Y. N. Lau, and Z. Hong (2003)
Antimicrob. Agents Chemother. 47, 426-431
   Abstract »    Full Text »    PDF »
Reduction of Arsenate to Arsenite in Hepatic Cytosol.
B. Nemeti and Z. Gregus (2002)
Toxicol. Sci. 70, 4-12
   Abstract »    Full Text »    PDF »
Clustered Charged Amino Acids of Human Adenosine Deaminase Comprise a Functional Epitope for Binding the Adenosine Deaminase Complexing Protein CD26/Dipeptidyl Peptidase IV.
E. Richard, S. M. Alam, F. X. Arredondo-Vega, D. D. Patel, and M. S. Hershfield (2002)
J. Biol. Chem. 277, 19720-19726
   Abstract »    Full Text »    PDF »
Adenosine deaminase-related growth factors stimulate cell proliferation in Drosophila by depleting extracellular adenosine.
M. Zurovec, T. Dolezal, M. Gazi, E. Pavlova, and P. J. Bryant (2002)
PNAS 99, 4403-4408
   Abstract »    Full Text »    PDF »
Adenosine deaminase deficiency with mosaicism for a "second-site suppressor" of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy.
F. X. Arredondo-Vega, I. Santisteban, E. Richard, P. Bali, M. Koleilat, M. Loubser, A. Al-Ghonaium, M. Al-Helali, and M. S. Hershfield (2002)
Blood 99, 1005-1013
   Abstract »    Full Text »    PDF »
Adenosine A2B Receptors Behave as an Alternative Anchoring Protein for Cell Surface Adenosine Deaminase in Lymphocytes and Cultured Cells.
C. Herrera, V. Casadó, F. Ciruela, P. Schofield, J. Mallol, C. Lluis, and R. Franco (2001)
Mol. Pharmacol. 59, 127-134
   Abstract »    Full Text »
The Binding Site of Human Adenosine Deaminase for Cd26/Dipeptidyl Peptidase IV: The Arg142gln Mutation Impairs Binding to Cd26 but Does Not Cause Immune Deficiency.
E. Richard, F. X. Arredondo-Vega, I. Santisteban, S. J. Kelly, D. D. Patel, and M. S. Hershfield (2000)
J. Exp. Med. 192, 1223-1236
   Abstract »    Full Text »    PDF »
Calcineurin: Form and Function.
F. Rusnak and P. Mertz (2000)
Physiol Rev 80, 1483-1521
   Abstract »    Full Text »    PDF »
Function and Mechanism of Zinc Metalloenzymes.
K. A. McCall, C.-c. Huang, and C. A. Fierke (2000)
J. Nutr. 130, 1437S-1446
   Abstract »    Full Text »
A T4-phage Deoxycytidylate Deaminase Mutant That No Longer Requires Deoxycytidine 5'-Triphosphate for Activation.
R. G. Keefe, G. F. Maley, R. L. Saxl, and F. Maley (2000)
J. Biol. Chem. 275, 12598-12602
   Abstract »    Full Text »    PDF »
An Adenosine Deaminase that Generates Inosine at the Wobble Position of tRNAs.
A. P. Gerber and W. Keller (1999)
Science 286, 1146-1149
   Abstract »    Full Text »
CD26 and Adenosine Deaminase Interaction: Its Role in the Fusion Between Horse Membrane Vesicles and Spermatozoa.
A. Minelli, C. Allegrucci, I. Mezzasoma, G. Ronquist, C. Lluis, and R. Franco (1999)
Biol Reprod 61, 802-808
   Abstract »    Full Text »
Reaction Mechanism of (6-4) Photolyase.
X. Zhao, J. Liu, D. S. Hsu, S. Zhao, J.-S. Taylor, and A. Sancar (1997)
J. Biol. Chem. 272, 32580-32590
   Abstract »    Full Text »    PDF »
Adenosine Deaminase Deficiency in Adults.
H. Ozsahin, F. X. Arredondo-Vega, I. Santisteban, H. Fuhrer, P. Tuchschmid, W. Jochum, A. Aguzzi, H. M. Lederman, A. Fleischman, J. A. Winkelstein, et al. (1997)
Blood 89, 2849-2855
   Abstract »    Full Text »    PDF »
Novel Zinc-containing Ferredoxin Family in Thermoacidophilic Archaea.
T. Iwasaki, T. Suzuki, T. Kon, T. Imai, A. Urushiyama, D. Ohmori, and T. Oshima (1997)
J. Biol. Chem. 272, 3453-3458
   Abstract »    Full Text »    PDF »
Studies on Identifying the Catalytic Role of Glu-204 in the Active Site of Yeast Invertase.
A. Reddy and F. Maley (1996)
J. Biol. Chem. 271, 13953-13958
   Abstract »    Full Text »    PDF »
Identification of an Essential Second Metal Ion in the Reaction Mechanism of Escherichia coli Adenylosuccinate Synthetase.
C. Kang and H. J. Fromm (1995)
J. Biol. Chem. 270, 15539-15544
   Abstract »    Full Text »    PDF »
Mutagenesis of apobec-1, the Catalytic Subunit of the Mammalian Apolipoprotein B mRNA Editing Enzyme, Reveals Distinct Domains That Mediate Cytosine Nucleoside Deaminase, RNA Binding, and RNA Editing Activity.
A. J. MacGinnitie, S. Anant, and N. O. Davidson (1995)
J. Biol. Chem. 270, 14768-14775
   Abstract »    Full Text »    PDF »
The crystal structure of urease from Klebsiella aerogenes.
E Jabri, M. Carr, R. Hausinger, and P. Karplus (1995)
Science 268, 998-1004
   Abstract »    PDF »
An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications.
D. Wilson, K. Bohren, K. Gabbay, and F. Quiocho (1992)
Science 257, 81-84
   Abstract »    PDF »
The Binding of Substrate Analogs to Phosphotriesterase.
M. M. Benning, S.-B. Hong, F. M. Raushel, and H. M. Holden (2000)
J. Biol. Chem. 275, 30556-30560
   Abstract »    Full Text »    PDF »
Adenosine deaminase-related growth factors stimulate cell proliferation in Drosophila by depleting extracellular adenosine.
M. Zurovec, T. Dolezal, M. Gazi, E. Pavlova, and P. J. Bryant (2002)
PNAS 99, 4403-4408
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)