Kalnins Gints, Kuka Janis, Grinberga Solveiga, Makrecka-Kuka Marina, Liepinsh Edgars, Dambrova Maija, Tars Kaspars
From the Latvian Biomedical Research and Study Center, LV-1067 Riga,
the Latvian Institute of Organic Synthesis, LV-1006 Riga, and.
J Biol Chem. 2015 Aug 28;290(35):21732-40. doi: 10.1074/jbc.M115.670471. Epub 2015 Jul 17.
CutC choline trimethylamine-lyase is an anaerobic bacterial glycyl radical enzyme (GRE) that cleaves choline to produce trimethylamine (TMA) and acetaldehyde. In humans, TMA is produced exclusively by the intestinal microbiota, and its metabolite, trimethylamine oxide, has been associated with a higher risk of cardiovascular diseases. Therefore, information about the three-dimensional structures of TMA-producing enzymes is important for microbiota-targeted drug discovery. We have cloned, expressed, and purified the CutC GRE and the activating enzyme CutD from Klebsiella pneumoniae, a representative of the human microbiota. We have determined the first crystal structures of both the choline-bound and choline-free forms of CutC and have discovered that binding of choline at the ligand-binding site triggers conformational changes in the enzyme structure, a feature that has not been observed for any other characterized GRE.
CutC胆碱三甲胺裂解酶是一种厌氧细菌甘氨酰自由基酶（GRE），它能裂解胆碱生成三甲胺（TMA）和乙醛。在人类中，TMA仅由肠道微生物群产生，其代谢产物氧化三甲胺与心血管疾病的较高风险有关。因此，有关产生TMA的酶的三维结构信息对于以微生物群为靶点的药物发现很重要。我们已经从人类微生物群的代表肺炎克雷伯菌中克隆、表达并纯化了CutC GRE和激活酶CutD。我们确定了CutC与胆碱结合和未结合胆碱形式的首个晶体结构，并发现胆碱在配体结合位点的结合会触发酶结构的构象变化，这一特征在任何其他已表征的GRE中均未观察到。
