α-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via “Catalytically Correct” Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery?
We present evidence that supports a 'correct hydrazone tautomer/Dunathan alignment model' for how α-hydrazino analogues of α-amino acids inhibit PLP enzymes. Described is the asymmetric synthesis of l- and d-α-hydrazino acid l-lysine analogues and their inhibition of <i>Hafnia alvei</i> lysine decarboxylase (LdcI) via kinetic analysis, stopped-flow spectrophotometry, and cryo-EM. We describe a similar investigation of the important anti-Parkinsonism drug, carbidopa, with its human DOPA decarboxylase (hDdc) target. Evidence is consistent with these three hydrazino analogues forming the catalytically relevant ketoenamine PLP-hydrazone tautomer in their target active sites, with the α-carboxylate groups, though insulated, aligning with the PLP-π-system in a Dunathan-model-like orientation. High-resolution cryo-EM structures of the <i>H. alvei</i> LdcI holoenzyme (pdb 9E0M-2.1Å) and LdcI-bound l- and d-hydrazones (pdb 9E0O-2.0 Å; pdb 9E0Q-2.3Å) and the first X-ray crystal structure of hDdc-bound carbidopa (pdb 9GNS-1.93Å) support this 'correct tautomer' model. These insights are expected to guide future PLP enzyme inhibitor development.
Authors
- Jonathan M. Baine
- Matthew L. Beio
- Irina Gutsche
- Giovanni Bisello (ORCID: https://orcid.org/0000-0002-3803-9555)
- Robert S. Phillips
- David B. Berkowitz (ORCID: https://orcid.org/0000-0001-7550-0112)
- Ambroise Desfosses (ORCID: https://orcid.org/0000-0002-6525-5042)
- Tzanko Doukov (ORCID: https://orcid.org/0000-0001-8625-2572)
- Mariarita Bertoldi (ORCID: https://orcid.org/0000-0002-2337-9928)
- Olivia Bauer (ORCID: https://orcid.org/0000-0001-5759-5461)
- Massimiliano Perduca (ORCID: https://orcid.org/0000-0001-8291-0523)
- Yoan Duhoo (ORCID: https://orcid.org/0000-0002-6643-1693)
- Maria Bacia‐Verloop
Institutions
- University of Verona (IT)
- Centre National de la Recherche Scientifique (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- CEA Grenoble (FR)
- Stanford Synchrotron Radiation Lightsource (US)
- Institut de Biologie Structurale (FR)
- Université Grenoble Alpes (FR)
- Umeå University (SE)
- Stanford University (US)
Publication Details
- Journal
- ACS Catalysis
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1021/acscatal.5c00326
- Primary Topic
- Enzyme Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche
- European Synchrotron Radiation Facility
- Fondation pour la Recherche Médicale
- Région Auvergne-Rhône-Alpes
- Ministero dell'Università e della Ricerca
- National Institutes of Health
- Horizon 2020 Framework Programme
- European Regional Development Fund