Structural basis for the inactivation of Thermus thermophilus proline dehydrogenase by N-propargylglycine.

Biochemistry
Tommi A WhiteJohn J Tanner

Abstract

The flavoenzyme proline dehydrogenase catalyzes the first step of proline catabolism, the oxidation of proline to pyrroline-5-carboxylate. Here we report the first crystal structure of an irreversibly inactivated proline dehydrogenase. The 1.9 A resolution structure of Thermus thermophilus proline dehydrogenase inactivated by the mechanism-based inhibitor N-propargylglycine shows that N5 of the flavin cofactor is covalently connected to the -amino group of Lys99 via a three-carbon linkage, consistent with the mass spectral analysis of the inactivated enzyme. The isoalloxazine ring has a butterfly angle of 25 degrees , which suggests that the flavin cofactor is reduced. Two mechanisms can account for these observations. In both, N-propargylglycine is oxidized to N-propargyliminoglycine. In one mechanism, this alpha,beta-unsaturated iminium compound is attacked by the N5 atom of the now reduced flavin to produce a 1,4-addition product. Schiff base formation between Lys99 and the imine of the 1,4-addition product releases glycine and links the enzyme to the modified flavin. In the second mechanism, hydrolysis of N-propargyliminoglycine yields propynal and glycine. A 1,4-addition reaction with propynal coupled with Schiff base form...Continue Reading

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Citations

Mar 29, 2008·Amino Acids·John J Tanner
Oct 22, 2008·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Jonathan P SchuermannJohn J Tanner
Dec 29, 2011·Frontiers in Bioscience (Landmark Edition)·Benjamin W ArentsonDonald F Becker
Dec 29, 2011·Frontiers in Bioscience (Landmark Edition)·Ranjan K Singh, John J Tanner
Feb 20, 2014·Proceedings of the National Academy of Sciences of the United States of America·Harkewal SinghJohn J Tanner
Jan 18, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mieke M E HuijbersWillem J H van Berkel
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
Jul 16, 2017·The FEBS Journal·David A KorasickJohn J Tanner
Mar 12, 2020·ACS Chemical Biology·Ashley C CampbellJohn J Tanner
Jun 21, 2018·Biophysical Journal·David A KorasickJohn J Tanner
Apr 13, 2018·Biochemistry·John J TannerDonald F Becker
Sep 21, 2021·ACS Chemical Biology·Ashley C CampbellJohn J Tanner

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