title: Structural study reveals that Ser-354 determines substrate specificity on human histidine decarboxylase.
abstract: Histamine is an important chemical mediator for a wide variety of physiological reactions. L-histidine decarboxylase (HDC) is the primary enzyme responsible for histamine synthesis and produces histamine from histidine in a one-step reaction. In this study, we determined the crystal structure of human HDC (hHDC) complexed with the inhibitor histidine methyl ester. This structure shows the detailed features of the pyridoxal-5'-phosphate inhibitor adduct (external aldimine) at the active site of HDC. Moreover, a comparison of the structures of hHDC and aromatic L-amino acid (L-DOPA) decarboxylase showed that Ser-354 was a key residue for substrate specificity. The S354G mutation at the active site enlarged the size of the hHDC substrate-binding pocket and resulted in a decreased affinity for histidine, but an acquired ability to bind and act on L-DOPA as a substrate. These data provide insight into the molecular basis of substrate recognition among the group II pyridoxal-5'-phosphate-dependent decarboxylases.
authors: Department of Life Science, Graduate School of Life Science, University of Hyogo, 3-2-1 Koto, Kamigori-cho, Ako-gun, Hyogo 678-1297, Japan. komori@sci.u-hyogo.ac.jp
authors: Hirofumi
authors: H
authors: Komori
authors: Yoko
authors: Y
authors: Nitta
authors: Hiroshi
authors: H
authors: Ueno
authors: Yoshiki
authors: Y
authors: Higuchi
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D006639:Histidine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000502:physiology
chemical_list: D007980:Levodopa; D006639:Histidine; C022493:pyridoxal-5-phosphatase; D010744:Phosphoric Monoester Hydrolases; D006640:Histidine Decarboxylase