Synthesis and Characterization of the N-succinyl-l,l-diaminopimelic Acid Desuccinylase (DapE) Alternate Substrate Analog N,N-dimethyl-l,l-SDAP

Authors

Zachary J. Liveris, Loyola University Chicago
Emma H. Kelley, Loyola University Chicago
Emma Simmons, Loyola University Chicago
Katherine Konczak, Loyola University Chicago
Marlon Lutz Jr., Loyola University Chicago
Miguel Ballicora, Loyola University ChicagoFollow
Ken W. Olsen, Loyola University ChicagoFollow
Daniel P. Becker Ph.D., Loyola University ChicagoFollow

Document Type

Article

Publication Date

8-15-2023

Publication Title

Bioorganic & Medicinal Chemistry

Volume

91

Pages

1-38

Publisher Name

Elsevier

Abstract

Growing antibiotic resistance by pathogenic bacteria has led to a global crisis. The bacterial enzyme N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) provides a very attractive target for the discovery of a new class of antibiotics, as it resides exclusively in many pathogenic bacterial strains and is a key enzyme in the lysine biosynthetic pathway. This pathway is responsible for the production of lysine as well as meso-diaminopimelate (m-DAP), both of which are required for peptidoglycan cell-wall synthesis, and lysine for peptide synthesis. The enzyme DapE catalyzes the hydrolysis of N-succinyl-l,l-diaminopimelic acid (l,l-SDAP) to succinate and l,l-diaminopimelic acid (l,l-DAP), and due to its absence in humans, inhibition of DapE avoids mechanism-based side effects. We have executed the asymmetric synthesis of N,N-dimethyl-SDAP, an l,l-SDAP substrate analog and an analog of the synthetic substrate of our previously described DapE assay. Previous modeling studies advocated that N,N-dimethyl-SDAP might function as an inhibitor, however the compound behaves as a substrate, and we have demonstrated the use of N,N-dimethyl-SDAP as the substrate in a modified ninhydrin-based DapE assay. Thermal shift experiments of DapE in the presence of N,N-dimethyl-SDAP are consistent with a melt temperature (Tm) shifted by succinate, the product of enzymatic hydrolysis.

Comments

Author Posting © Elsevier Ltd., 2023. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Bioorganic & Medicinal Chemistry, Volume 91, August 2023. https://doi.org/10.1016/j.bmc.2023.117415

Recommended Citation

Liveris, Zachary J.; Kelley, Emma H.; Simmons, Emma; Konczak, Katherine; Lutz Jr., Marlon; Ballicora, Miguel; Olsen, Ken W.; and Becker, Daniel P. Ph.D.. Synthesis and Characterization of the N-succinyl-l,l-diaminopimelic Acid Desuccinylase (DapE) Alternate Substrate Analog N,N-dimethyl-l,l-SDAP. Bioorganic & Medicinal Chemistry, 91, : 1-38, 2023. Retrieved from Loyola eCommons, Chemistry: Faculty Publications and Other Works, http://dx.doi.org/10.1016/j.bmc.2023.117415

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Copyright Statement

© Elsevier Ltd., 2023.