A conserved active site tyrosine residue of proline dehydrogenase helps enforce the preference for proline over hydroxyproline as the substrate.

Biochemistry
Elizabeth L OstranderJohn J Tanner

Abstract

Proline dehydrogenase (PRODH) catalyzes the oxidation of l-proline to Delta-1-pyrroline-5-carboxylate. PRODHs exhibit a pronounced preference for proline over hydroxyproline (trans-4-hydroxy-l-proline) as the substrate, but the basis for specificity is unknown. The goal of this study, therefore, is to gain insight into the structural determinants of substrate specificity of this class of enzyme, with a focus on understanding how PRODHs discriminate between the two closely related molecules, proline and hydroxyproline. Two site-directed mutants of the PRODH domain of Escherichia coli PutA were created: Y540A and Y540S. Kinetics measurements were performed with both mutants. Crystal structures of Y540S complexed with hydroxyproline, proline, and the proline analogue l-tetrahydro-2-furoic acid were determined at resolutions of 1.75, 1.90, and 1.85 A, respectively. Mutation of Tyr540 increases the catalytic efficiency for hydroxyproline 3-fold and decreases the specificity for proline by factors of 20 (Y540S) and 50 (Y540A). The structures show that removal of the large phenol side chain increases the volume of the substrate-binding pocket, allowing sufficient room for the 4-hydroxyl of hydroxyproline. Furthermore, the introduced s...Continue Reading

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Citations

Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Dhiraj SrivastavaJohn J Tanner
Nov 26, 2010·The Journal of Biological Chemistry·Thomas M TomasiakTina M Iverson
Jun 10, 2011·The Journal of Biological Chemistry·Mahmood MohammadiMichel Sylvestre
Jul 31, 2013·PloS One·Lisvane Silva PaesAriel Mariano Silber
Dec 29, 2011·Frontiers in Bioscience (Landmark Edition)·Ranjan K Singh, John J Tanner
May 11, 2010·Archives of Biochemistry and Biophysics·Srimevan WanduragalaDonald F Becker
Apr 5, 2016·Biochimica Et Biophysica Acta·Bruno C MarreirosManuela M Pereira
Jan 4, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·David A KorasickJohn J Tanner
Oct 11, 2017·Antioxidants & Redox Signaling·John J Tanner
May 21, 2019·Applied Microbiology and Biotechnology·Ryotaro HaraKuniki Kino
Dec 7, 2020·The International Journal of Biochemistry & Cell Biology·Michelle MereisFrancois H van der Westhuizen
Jun 21, 2018·Biophysical Journal·David A KorasickJohn J Tanner
Apr 13, 2018·Biochemistry·John J TannerDonald F Becker

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