Department of Life Science, Graduate School of Life Science, University of Hyogo, 3-2-1 Koto, Kamigori-cho, Ako-gun, Hyogo 678-1297, Japan.
J Biol Chem. 2012 Aug 17;287(34):29175-83. doi: 10.1074/jbc.M112.381897. Epub 2012 Jul 5.
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.
组氨酸是多种生理反应的重要化学介质。L-组氨酸脱羧酶（HDC）是负责组氨酸合成的主要酶，它在一步反应中从组氨酸产生组氨酸。在这项研究中，我们确定了与人 HDC（hHDC）复合的抑制剂组氨酸甲酯的晶体结构。该结构显示了 HDC 活性位点处吡啶醛-5'-磷酸抑制剂加合物（外部醛亚胺）的详细特征。此外，hHDC 和芳香族 L-氨基酸（L-DOPA）脱羧酶结构的比较表明，Ser-354 是决定底物特异性的关键残基。活性位点的 S354G 突变增大了 hHDC 底物结合口袋的大小，导致对组氨酸的亲和力降低，但获得了结合和作用于 L-DOPA 作为底物的能力。这些数据提供了组 II 依赖吡啶醛-5'-磷酸的脱羧酶之间底物识别的分子基础的深入了解。
