Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius J N, Malashkevich V N
M.E. Müller Institute for Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
Nat Struct Biol. 2001 Nov;8(11):963-7. doi: 10.1038/nsb1101-963.
DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin via decarboxylation of L-3,4-dihydroxyphenylalanine (L-DOPA) and L-5-hydroxytryptophan, respectively. DDC has been implicated in a number of clinic disorders, including Parkinson's disease and hypertension. Peripheral inhibitors of DDC are currently used to treat these diseases. We present the crystal structures of ligand-free DDC and its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catechol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with better pharmacological characteristics.
多巴脱羧酶（DDC）分别通过L-3,4-二羟基苯丙氨酸（L-DOPA）和L-5-羟色氨酸的脱羧作用，负责合成关键神经递质多巴胺和血清素。DDC与多种临床疾病有关，包括帕金森病和高血压。目前，DDC的外周抑制剂被用于治疗这些疾病。我们展示了无配体DDC及其与抗帕金森药物卡比多巴复合物的晶体结构。该抑制剂通过与辅因子形成腙键与酶结合，其儿茶酚环深埋在活性位点裂隙中。这些结构为开发具有更好药理学特性的新型DDC抑制剂提供了分子基础。
