Regulation of Glutarate Catabolism by GntR Family Regulator CsiR and LysR Family Regulator GcdR in Pseudomonas putida KT2440
Regulation of Glutarate Catabolism by GntR Family Regulator CsiR and LysR Family Regulator GcdR in Pseudomonas putida KT2440
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GntR 家族调节剂 CsiR 和 LysR 家族调节剂 GcdR 对恶臭假单胞菌 KT2440 中戊二酸分解代谢的调节
作者：
Zhang Manman;Kang Zhaoqi;Guo Xiaoting;Guo Shiting;Xiao Dan;Liu Yidong;Ma Cuiqing;Xu Ping;Gao Chao
戊二酸是一种极具吸引力的二元羧酸盐，具有多种用途。阐明戊二酸分解代谢的调控机制有助于阻断戊二酸分解代谢途径，从而通过生物技术途径提高戊二酸的产量。戊二酸是人体内的一种有毒代谢物，它的蓄积导致遗传性代谢紊乱，即戊二酸尿I型。阐明CSIR和GCDR作为戊二酸反应调节因子的功能有助于设计用于戊二酸尿I型患者戊二酸快速检测的戊二酸生物传感器。此外，CSIR还被确定为调节L-2-HG代谢的调节器。将CSIR定位为L-2-HG的调节因子，有助于发现和研究参与L-2-HG分解代谢的其他调节蛋白。摘要恶臭假单胞菌KT2440中的戊二酸是几种氨基酸和芳香族化合物分解代谢的中间产物，可通过戊二酸羟化途径和戊二酰辅酶A脱氢途径降解。调控机制的阐明将极大地帮助设计用于戊二酸生产的生物技术替代品。本研究发现，GntR家族蛋白CSIR和LysR家族蛋白GcdR分别通过抑制戊二酸羟化途径中两个关键基因CSID和lhgO的转录，以及激活戊二醛-辅酶A脱氢途径中两个关键基因gcdH和GCOT的转录，来调节戊二酸的分解代谢。我们的数据表明，CSIR和GcdR是独立的，两条途径之间没有交叉调节。L-2-羟基戊二酸(L-2-HG)是戊二酸分解代谢的中间产物，具有多种生理功能，但其代谢调节机制尚未阐明。在这里，我们揭示了两个分子，戊二酸和L-2-HG，作为CSIR的效应器，恶臭假单胞菌KT2440利用CSIR来感知戊二酸和L-2-HG并有效地利用它们。这份报告拓宽了我们对戊二酸和L-2-HG分解代谢的细菌调控机制的理解，并可能有助于在其他物种中识别L-2-HG分解代谢的调控因子。重要意义戊二酸酯是一种极具吸引力的二元羧酸盐，具有多种用途。阐明戊二酸分解代谢的调控机制有助于阻断戊二酸分解代谢途径，从而通过生物技术途径提高戊二酸的产量。戊二酸是人体内的一种有毒代谢物，它的蓄积导致遗传性代谢紊乱，即戊二酸尿I型。阐明CSIR和GCDR作为戊二酸反应调节因子的功能有助于设计用于戊二酸尿I型患者戊二酸快速检测的戊二酸生物传感器。此外，CSIR还被确定为调节L-2-HG代谢的调节器。将CSIR定位为L-2-HG的调节因子，有助于发现和研究参与L-2-HG分解代谢的其他调节蛋白。
Glutarate is an attractive dicarboxylate with various applications. Clarification of the regulatory mechanism of glutarate catabolism could help to block the glutarate catabolic pathways, thereby improving glutarate production through biotechnological routes. Glutarate is a toxic metabolite in humans, and its accumulation leads to a hereditary metabolic disorder, glutaric aciduria type I. The elucidation of the functions of CsiR and GcdR as regulators that respond to glutarate could help in the design of glutarate biosensors for the rapid detection of glutarate in patients with glutaric aciduria type I. In addition, CsiR was identified as a regulator that also regulates l-2-HG metabolism. The identification of CsiR as a regulator that responds to l-2-HG could help in the discovery and investigation of other regulatory proteins involved in l-2-HG catabolism. ABSTRACT Glutarate, a metabolic intermediate in the catabolism of several amino acids and aromatic compounds, can be catabolized through both the glutarate hydroxylation pathway and the glutaryl-coenzyme A (glutaryl-CoA) dehydrogenation pathway in Pseudomonas putida KT2440. The elucidation of the regulatory mechanism could greatly aid in the design of biotechnological alternatives for glutarate production. In this study, it was found that a GntR family protein, CsiR, and a LysR family protein, GcdR, regulate the catabolism of glutarate by repressing the transcription of csiD and lhgO, two key genes in the glutarate hydroxylation pathway, and by activating the transcription of gcdH and gcoT, two key genes in the glutaryl-CoA dehydrogenation pathway, respectively. Our data suggest that CsiR and GcdR are independent and that there is no cross-regulation between the two pathways. l-2-Hydroxyglutarate (l-2-HG), a metabolic intermediate in the glutarate catabolism with various physiological functions, has never been elucidated in terms of its metabolic regulation. Here, we reveal that two molecules, glutarate and l-2-HG, act as effectors of CsiR and that P. putida KT2440 uses CsiR to sense glutarate and l-2-HG and to utilize them effectively. This report broadens our understanding of the bacterial regulatory mechanisms of glutarate and l-2-HG catabolism and may help to identify regulators of l-2-HG catabolism in other species. IMPORTANCE Glutarate is an attractive dicarboxylate with various applications. Clarification of the regulatory mechanism of glutarate catabolism could help to block the glutarate catabolic pathways, thereby improving glutarate production through biotechnological routes. Glutarate is a toxic metabolite in humans, and its accumulation leads to a hereditary metabolic disorder, glutaric aciduria type I. The elucidation of the functions of CsiR and GcdR as regulators that respond to glutarate could help in the design of glutarate biosensors for the rapid detection of glutarate in patients with glutaric aciduria type I. In addition, CsiR was identified as a regulator that also regulates l-2-HG metabolism. The identification of CsiR as a regulator that responds to l-2-HG could help in the discovery and investigation of other regulatory proteins involved in l-2-HG catabolism.
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DOI：
10.1073/pnas.1614102114
发表时间：
2017-02-07
影响因子：
11.1
作者：
Li, Hongde;Chawla, Geetanjali;Tennessen, Jason M.
通讯作者：
Tennessen, Jason M.
影响因子：
6.4
作者：
Tsuge Y;Kawaguchi H;Sasaki K;Kondo A
通讯作者：
Kondo A
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
K. Livak;Thomas D. Schmittgen
通讯作者：
K. Livak;Thomas D. Schmittgen
影响因子：
9.9
作者：
Moroni, I;Bugiani, M;Uziel, G
通讯作者：
Uziel, G
影响因子：
3.2
作者：
Aguilera, Laura;Campos, Evangelina;Baldoma, Laura
通讯作者：
Baldoma, Laura