Pubblicazioni

Autori:

Baine, Jonathan M.; Duhoo, Yoan; Doukov, Tzanko; Desfosses, Ambroise; Bisello, Giovanni; Beio, Matthew L.; Bauer, Olivia; Perduca, Massimiliano; Bacia-Verloop, Maria; Bertoldi, Mariarita; Phillips, Robert S.; Gutsche, Irina; Berkowitz, David B.

Titolo:

α-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via “Catalytically Correct” Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery?

Anno:

2025

Tipologia prodotto:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Lingua:

Inglese

Formato:

A Stampa

Referee:

Sì

Nome rivista:

ACS CATALYSIS

ISSN Rivista:

2155-5435

N° Volume:

15

Intervallo pagine:

8204-8218

Parole chiave:

PLP-hydrazones, α-hydrazino acid, PLP enzyme inhibitors, ketoenamine tautomer, carbidopa, human DOPA decarboxylase, lysine decarboxylase, cryo-electron microscopy

Breve descrizione dei contenuti:

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 Hafnia alvei 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 H. alvei 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.

Id prodotto:

145467

Handle IRIS:

11562/1161147

ultima modifica:

5 maggio 2025

Citazione bibliografica:

Baine, Jonathan M.; Duhoo, Yoan; Doukov, Tzanko; Desfosses, Ambroise; Bisello, Giovanni; Beio, Matthew L.; Bauer, Olivia; Perduca, Massimiliano; Bacia-Verloop, Maria; Bertoldi, Mariarita; Phillips, Robert S.; Gutsche, Irina; Berkowitz, David B., α-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via “Catalytically Correct” Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery? «ACS CATALYSIS» , vol. 15 , 2025 , pp. 8204-8218

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