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.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 11 July 1997:
Vol. 277. no. 5323, pp. 202 - 206
DOI: 10.1126/science.277.5323.202
Prev | Table of Contents | Next

Research Articles

Orbital Steering in the Catalytic Power of Enzymes: Small Structural Changes with Large Catalytic Consequences

Andrew D. Mesecar, Barry L. Stoddard, Daniel E. Koshland Jr.

Small structural perturbations in the enzyme isocitrate dehydrogenase (IDH) were made in order to evaluate the contribution of precise substrate alignment to the catalytic power of an enzyme. The reaction trajectory of IDH was modified (i) after the adenine moiety of nicotinamide adenine dinucleotide phosphate was changed to hypoxanthine (the 6-amino was changed to 6-hydroxyl), and (ii) by replacing Mg2+, which has six coordinating ligands, with Ca2+, which has eight coordinating ligands. Both changes make large (10-3 to 10-5) changes in the reaction velocity but only small changes in the orientation of the substrates (both distance and angle) as revealed by cryocrystallographic trapping of active IDH complexes. The results provide evidence that orbital overlap produced by optimal orientation of reacting orbitals plays a major quantitative role in the catalytic power of enzymes.

A. D. Mesecar and D. E. Koshland Jr. are in the Department of Molecular and Cell Biology, Stanley Hall, University of California, Berkeley, CA 94720, and Center for Advanced Materials, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. B. L. Stoddard is at the Division of Basic Sciences, Program in Structural Biology, Fred Hutchinson Cancer Research Center, 1124 Columbia Street A3-023, Seattle, WA 98104, USA.

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Viral destruction of cell surface receptors.
A. D. Mesecar and K. Ratia (2008)
PNAS 105, 8807-8808
   Full Text »    PDF »
The difficult road from sequence to function..
R. H. White (2006)
J. Bacteriol. 188, 3431-3432
   Full Text »    PDF »
Severe acute respiratory syndrome coronavirus papain-like protease: Structure of a viral deubiquitinating enzyme.
K. Ratia, K. S. Saikatendu, B. D. Santarsiero, N. Barretto, S. C. Baker, R. C. Stevens, and A. D. Mesecar (2006)
PNAS 103, 5717-5722
   Abstract »    Full Text »    PDF »
Structure of the Pyrroloquinoline Quinone Radical in Quinoprotein Ethanol Dehydrogenase.
C. W. M. Kay, B. Mennenga, H. Gorisch, and R. Bittl (2006)
J. Biol. Chem. 281, 1470-1476
   Abstract »    Full Text »    PDF »
Characterization of GlaKP, a UDP-Galacturonic Acid C4-Epimerase from Klebsiella pneumoniae with Extended Substrate Specificity.
E. Frirdich and C. Whitfield (2005)
J. Bacteriol. 187, 4104-4115
   Abstract »    Full Text »    PDF »
Structures of Human Cytosolic NADP-dependent Isocitrate Dehydrogenase Reveal a Novel Self-regulatory Mechanism of Activity.
X. Xu, J. Zhao, Z. Xu, B. Peng, Q. Huang, E. Arnold, and J. Ding (2004)
J. Biol. Chem. 279, 33946-33957
   Abstract »    Full Text »    PDF »
Crystal Structure of WbpP, a Genuine UDP-N-acetylglucosamine 4-Epimerase from Pseudomonas aeruginosa: SUBSTRATE SPECIFICITY IN UDP-HEXOSE 4-EPIMERASES.
N. Ishiyama, C. Creuzenet, J. S. Lam, and A. M. Berghuis (2004)
J. Biol. Chem. 279, 22635-22642
   Abstract »    Full Text »    PDF »
Crystal Structure of the Bifunctional Chorismate Synthase from Saccharomyces cerevisiae.
S. Quevillon-Cheruel, N. Leulliot, P. Meyer, M. Graille, M. Bremang, K. Blondeau, I. Sorel, A. Poupon, J. Janin, and H. van Tilbeurgh (2004)
J. Biol. Chem. 279, 619-625
   Abstract »    Full Text »    PDF »
Crystal Structure of Escherichia coli PdxA, an Enzyme Involved in the Pyridoxal Phosphate Biosynthesis Pathway.
J. Sivaraman, Y. Li, J. Banks, D. E. Cane, A. Matte, and M. Cygler (2003)
J. Biol. Chem. 278, 43682-43690
   Abstract »    Full Text »    PDF »
Crystal Structure of the Monomeric Isocitrate Dehydrogenase in the Presence of NADP+: INSIGHT INTO THE COFACTOR RECOGNITION, CATALYSIS, AND EVOLUTION.
Y. Yasutake, S. Watanabe, M. Yao, Y. Takada, N. Fukunaga, and I. Tanaka (2003)
J. Biol. Chem. 278, 36897-36904
   Abstract »    Full Text »    PDF »
The Putative Catalytic Bases Have, at Most, an Accessory Role in the Mechanism of Arginine Kinase.
P. S. Pruett, A. Azzi, S. A. Clark, M. S. Yousef, J. L. Gattis, T. Somasundaram, W. R. Ellington, and M. S. Chapman (2003)
J. Biol. Chem. 278, 26952-26957
   Abstract »    Full Text »    PDF »
Structural Basis for Potent Slow Binding Inhibition of Human Matrix Metalloproteinase-2 (MMP-2).
G. Rosenblum, S. O. Meroueh, O. Kleifeld, S. Brown, S. P. Singson, R. Fridman, S. Mobashery, and I. Sagi (2003)
J. Biol. Chem. 278, 27009-27015
   Abstract »    Full Text »    PDF »
Engineering the Substrate Specificity of D-Amino-acid Oxidase.
S. Sacchi, S. Lorenzi, G. Molla, M. S. Pilone, C. Rossetti, and L. Pollegioni (2002)
J. Biol. Chem. 277, 27510-27516
   Abstract »    Full Text »    PDF »
Structure Prediction and Active Site Analysis of the Metal Binding Determinants in gamma -Glutamylcysteine Synthetase.
J. J. Abbott, J. Pei, J. L. Ford, Y. Qi, V. N. Grishin, L. A. Pitcher, M. A. Phillips, and N. V. Grishin (2001)
J. Biol. Chem. 276, 42099-42107
   Abstract »    Full Text »    PDF »
Toward a quantum-mechanical description of metal-assisted phosphoryl transfer in pyrophosphatase.
P. Heikinheimo, V. Tuominen, A.-K. Ahonen, A. Teplyakov, B. S. Cooperman, A. A. Baykov, R. Lahti, and A. Goldman (2001)
PNAS
   Abstract »    Full Text »
The x-ray structure of D-amino acid oxidase at very high resolution identifies the chemical mechanism of flavin-dependent substrate dehydrogenation.
S. Umhau, L. Pollegioni, G. Molla, K. Diederichs, W. Welte, M. S. Pilone, and S. Ghisla (2000)
PNAS 97, 12463-12468
   Abstract »    Full Text »    PDF »
Calcineurin: Form and Function.
F. Rusnak and P. Mertz (2000)
Physiol Rev 80, 1483-1521
   Abstract »    Full Text »    PDF »
Catalytic role of enzymes: Short strong H-bond-induced partial proton shuttles and charge redistributions.
K. S. Kim, K. S. Oh, and J. Y. Lee (2000)
PNAS 97, 6373-6378
   Abstract »    Full Text »    PDF »
Accurate protein crystallography at ultra-high resolution: Valence electron distribution in crambin.
C. Jelsch, M. M. Teeter, V. Lamzin, V. Pichon-Pesme, R. H. Blessing, and C. Lecomte (2000)
PNAS 97, 3171-3176
   Abstract »    Full Text »    PDF »
A Piston Model for Transmembrane Signaling of the Aspartate Receptor.
K. M. Ottemann, W. Xiao, Y. Shin, and D. E. Koshland Jr. (1999)
Science 285, 1751-1754
   Abstract »    Full Text »
Experimental Observation of Bonding Electrons in Proteins.
V. S. Lamzin, R. J. Morris, Z. Dauter, K. S. Wilson, and M. M. Teeter (1999)
J. Biol. Chem. 274, 20753-20755
   Abstract »    Full Text »    PDF »
Electrostatic Origin of the Catalytic Power of Enzymes and the Role of Preorganized Active Sites.
A. Warshel (1998)
J. Biol. Chem. 273, 27035-27038
   Full Text »    PDF »
Solvation, Reorganization Energy, and Biological Catalysis.
W. R. Cannon and S. J. Benkovic (1998)
J. Biol. Chem. 273, 26257-26260
   Full Text »    PDF »
New enzyme lineages by subdomain shuffling.
K.-P. Hopfner, E. Kopetzki, G.-B. Kresse, W. Bode, R. Huber, and R. A. Engh (1998)
PNAS 95, 9813-9818
   Abstract »    Full Text »    PDF »
Crystal Structures of Flavobacterium Glycosylasparaginase. AN N-TERMINAL NUCLEOPHILE HYDROLASE ACTIVATED BY INTRAMOLECULAR PROTEOLYSIS.
H.-C. Guo, Q. Xu, D. Buckley, and C. Guan (1998)
J. Biol. Chem. 273, 20205-20212
   Abstract »    Full Text »    PDF »
Transition state structure of arginine kinase: Implications for catalysis of bimolecular reactions.
G. Zhou, T. Somasundaram, E. Blanc, G. Parthasarathy, W. R. Ellington, and M. S. Chapman (1998)
PNAS 95, 8449-8454
   Abstract »    Full Text »    PDF »
X-ray Crystal Structure of C3d: A C3 Fragment and Ligand for Complement Receptor 2 .
B. Nagar, R. G. Jones, R. J. Diefenbach, D. E. Isenman, and J. M. Rini (1998)
Science 280, 1277-1281
   Abstract »    Full Text »
Immunological Origins of Binding and Catalysis in a Diels-Alderase Antibody.
F. E. Romesberg, B. Spiller, P. G. Schultz, and R. C. Stevens (1998)
Science 279, 1929-1933
   Abstract »    Full Text »
Role of Arginine 285 in the Active Site of Rhodotorula gracilis D-Amino Acid Oxidase. A SITE-DIRECTED MUTAGENESIS STUDY.
G. Molla, D. Porrini, V. Job, L. Motteran, C. Vegezzi, S. Campaner, M. S. Pilone, and L. Pollegioni (2000)
J. Biol. Chem. 275, 24715-24721
   Abstract »    Full Text »    PDF »
Toward a quantum-mechanical description of metal-assisted phosphoryl transfer in pyrophosphatase.
P. Heikinheimo, V. Tuominen, A.-K. Ahonen, A. Teplyakov, B. S. Cooperman, A. A. Baykov, R. Lahti, and A. Goldman (2001)
PNAS 98, 3121-3126
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

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