title: Aminooxy analog of histamine is an efficient inhibitor of mammalian L-histidine decarboxylase: combined in silico and experimental evidence.
abstract: Histamine plays highlighted roles in the development of many common, emergent and rare diseases. In mammals, histamine is formed by decarboxylation of L-histidine, which is catalyzed by pyridoxal-5'-phosphate (PLP) dependent histidine decarboxylase (HDC, EC 4.1.1.22). The limited availability and stability of the protein have delayed the characterization of its structure-function relationships. Our previous knowledge on mammalian HDC, derived from both in silico and experimental approaches, indicates that an effective competitive inhibitor should be capable to form an "external aldimine-like structure" and have an imidazole group, or its proper mimetic, which provides additional affinity of PLP-inhibitor adduct to the HDC active center. This is confirmed using HEK-293 cells transfected to express human HDC and the aminooxy analog of histidine, 4(5)-aminooxymethylimidazole (O-IMHA, IC₅₀ ≈ 2 × 10(-7) M) capable to form a PLP-inhibitor complex (oxime) in the enzyme active center. Taking advantage of the availability of the human HDC X-ray structure, we have also determined the potential interactions that could stabilize this oxime in the active site of mammalian HDC.
authors.affiliation: Faculty of Sciences, Universidad de Málaga, Málaga, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Castro-Oropeza
authors.forename: A
authors.initials: A
authors.lastname: Pino-Ángeles
authors.forename: M A
authors.initials: MA
authors.lastname: Khomutov
authors.forename: J L
authors.initials: JL
authors.lastname: Urdiales
authors.forename: A A
authors.initials: AA
authors.lastname: Moya-García
authors.forename: J
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: L
authors.initials: L
authors.lastname: Persson
authors.forename: F
authors.initials: F
authors.lastname: Sarabia
authors.forename: A
authors.initials: A
authors.lastname: Khomutov
authors.forename: F
authors.initials: F
authors.lastname: Sánchez-Jiménez
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006898:Hydroxylamines / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000595074:4(5)-aminooxymethylimidazole; D004791:Enzyme Inhibitors; D006898:Hydroxylamines; D007093:Imidazoles; D011994:Recombinant Proteins; D006640:Histidine Decarboxylase