Aminooxy analog of histamine is an efficient inhibitor of mammalian l-histidine decarboxylase: combined in silico and experimental evidence

作者：Castro Oropeza R; Pino Angeles A; Khomutov M A; Urdiales J L; Moya Garcia A A; Vepsalainen J; Persson L; Sarabia F; Khomutov A; Sanchez Jimenez F^*

来源：Amino Acids, 2014, 46(3): 621-631.

DOI：10.1007/s00726-013-1589-7

• Histidine decarboxylase
• Substrate analogs
• Histamine
• Drug discovery

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%26apos;-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 %26quot;external aldimine-like structure%26quot; 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 a parts per thousand 2 x 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.

• 出版日期2014-3