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Cavitation as a Mechanism of Substrate Discrimination by Adenylosuccinate Synthetases

Iancu, Cristina V. and Zhou, Yang and Borza, Tudor and Fromm, Herbert J. and Honzatko, Richard B. (2006) Cavitation as a Mechanism of Substrate Discrimination by Adenylosuccinate Synthetases. Biochemistry, 45 (38). pp. 11703-11711. ISSN 0006-2960. https://resolver.caltech.edu/CaltechAUTHORS:20170131-140942966

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Abstract

Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, coupling l-aspartate and IMP to form adenylosuccinate. Km values of IMP and 2‘-deoxy-IMP are nearly identical with each substrate supporting comparable maximal velocities. Nonetheless, the Km value for l-aspartate and the Ki value for hadacidin (a competitive inhibitor with respect to l-aspartate) are 29−57-fold lower in the presence of IMP than in the presence of 2‘-deoxy-IMP. Crystal structures of the synthetase ligated with hadacidin, GDP, and either 6-phosphoryl-IMP or 2‘-deoxy-6-phosphoryl-IMP are identical except for the presence of a cavity normally occupied by the 2‘-hydroxyl group of IMP. In the presence of 6-phosphoryl-IMP and GDP (hadacidin absent), the l-aspartate pocket can retain its fully ligated conformation, forming hydrogen bonds between the 2‘-hydroxyl group of IMP and sequence-invariant residues. In the presence of 2‘-deoxy-6-phosphoryl-IMP and GDP, however, the l-aspartate pocket is poorly ordered. The absence of the 2‘-hydroxyl group of the deoxyribonucleotide may destabilize binding of the ligand to the l-aspartate pocket by disrupting hydrogen bonds that maintain a favorable protein conformation and by the introduction of a cavity into the fully ligated active site. At an approximate energy cost of 2.2 kcal/mol, the unfavorable thermodynamics of cavity formation may be the major factor in destabilizing ligands at the l-aspartate pocket.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/bi0607498DOIArticle
http://pubs.acs.org/doi/abs/10.1021/bi0607498PublisherArticle
ORCID:
AuthorORCID
Iancu, Cristina V.0000-0002-7352-9226
Additional Information:© 2006 American Chemical Society. Received 18 April 2006. Published online 2 September 2006. Published in print 1 September 2006. This work was supported by National Institutes of Health Grant NS 10546.
Funders:
Funding AgencyGrant Number
NIHNS 10546
Issue or Number:38
Record Number:CaltechAUTHORS:20170131-140942966
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170131-140942966
Official Citation:Cavitation as a Mechanism of Substrate Discrimination by Adenylosuccinate Synthetases Cristina V. Iancu, Yang Zhou, Tudor Borza, Herbert J. Fromm, and Richard B. Honzatko Biochemistry 2006 45 (38), 11703-11711 DOI: 10.1021/bi0607498
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73897
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:01 Feb 2017 00:36
Last Modified:03 Oct 2019 16:32

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