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Zhou XE, Suino-Powell K, Schultz CR, et al. Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane. Biochem J. 2021;478(23):4137-4149doi: 10.1042/BCJ20210647.
Zhou, X. E., Suino-Powell, K., Schultz, C. R., Aleiwi, B., Brunzelle, J. S., Lamp, J., Vega, I. E., Ellsworth, E., Bachmann, A. S., & Melcher, K. (2021). Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane. The Biochemical journal, 478(23), 4137-4149. https://doi.org/10.1042/BCJ20210647
Zhou, X Edward, et al. "Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane." The Biochemical journal vol. 478,23 (2021): 4137-4149. doi: https://doi.org/10.1042/BCJ20210647
Zhou XE, Suino-Powell K, Schultz CR, Aleiwi B, Brunzelle JS, Lamp J, Vega IE, Ellsworth E, Bachmann AS, Melcher K. Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane. Biochem J. 2021 Dec 10;478(23):4137-4149. doi: 10.1042/BCJ20210647. PMID: 34796899.
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Biochem J. 2021 Dec 10;478(23):4137-4149. doi: 10.1042/BCJ20210647.

Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane.

The Biochemical journal

X Edward Zhou, Kelly Suino-Powell, Chad R Schultz, Bilal Aleiwi, Joseph S Brunzelle, Jared Lamp, Irving E Vega, Edmund Ellsworth, André S Bachmann, Karsten Melcher

Affiliations

  1. Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan 49503, U.S.A.
  2. Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49546, U.S.A.
  3. Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, U.S.A.
  4. Northwestern University Synchrotron Research Center, Life Sciences Collaborative Access Team, Northwestern University, Argonne, Illinois 60439, U.S.A.
  5. Department of Translational Neuroscience, Integrated Mass Spectrometry Unit, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, U.S.A.

PMID: 34796899 DOI: 10.1042/BCJ20210647

Abstract

Ornithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA). A previous crystal structure of an ODC-APA complex indicated that APA non-covalently binds ODC and its cofactor pyridoxal 5-phosphate (PLP) and functions by competing with the ODC substrate ornithine for binding to the catalytic site. We have revisited the mechanism of APA binding and ODC inhibition through a new crystal structure of APA-bound ODC, which we solved at 2.49 Å resolution. The structure unambiguously shows the presence of a covalent oxime between APA and PLP in the catalytic site, which we confirmed in solution by mass spectrometry. The stable oxime makes extensive interactions with ODC but cannot be catabolized, explaining APA's high potency in ODC inhibition. In addition, we solved an ODC/PLP complex structure with citrate bound at the substrate-binding pocket. These two structures provide new structural scaffolds for developing more efficient pharmaceutical ODC inhibitors.

© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Keywords: crystallography; ornithine decarboxylase; polyamines

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