9dui
From Proteopedia
Re-refined of Crystal structure of dopa decarboxylase in complex with the inhibitor carbidopa (1JS3) with ketoenamine form of carbidopa
Structural highlights
FunctionDDC_PIG Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Publication Abstract from PubMedWe present evidence that supports a 'correct hydrazone tautomer/Dunathan alignment model' for how alpha-hydrazino analogues of alpha-amino acids inhibit PLP enzymes. Described is the asymmetric synthesis of l- and d-alpha-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 alpha-carboxylate groups, though insulated, aligning with the PLP-pi-system in a Dunathan-model-like orientation. High-resolution cryo-EM structures of the H. alvei LdcI holoenzyme (pdb 9E0M-2.1A) and LdcI-bound l- and d-hydrazones (pdb 9E0O-2.0 A; pdb 9E0Q-2.3A) and the first X-ray crystal structure of hDdc-bound carbidopa (pdb 9GNS-1.93A) support this 'correct tautomer' model. These insights are expected to guide future PLP enzyme inhibitor development. alpha-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via "Catalytically Correct" Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery?,Baine JM, Duhoo Y, Doukov T, Desfosses A, Bisello G, Beio ML, Bauer O, Perduca M, Bacia-Verloop M, Bertoldi M, Phillips RS, Gutsche I, Berkowitz DB ACS Catal. 2025 May 2;15(10):8204-8218. doi: 10.1021/acscatal.5c00326. , eCollection 2025 May 16. PMID:40401103[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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