GTP-Dependent Regulation of CTP Synthase: Evolving Insights into Allosteric Activation and NH3 Translocation

doi:10.3390/biom12050647

	GTP-Dependent Regulation of CTP Synthase: Evolving Insights into Allosteric Activation and NH3 Translocation
	Bearne, Stephen L.1,2; Guo, Chen-Jun3 ; Liu, Ji-Long3,4
	2022-05
发表期刊	BIOMOLECULES (IF:4.8[JCR-2023],5.4[5-Year])
ISSN	2218-273X
EISSN	2218-273X
卷号	12 期号:5
发表状态	已发表
DOI	10.3390/biom12050647
摘要	Cytidine-5'-triphosphate (CTP) synthase (CTPS) is the class I glutamine-dependent amidotransferase (GAT) that catalyzes the last step in the de novo biosynthesis of CTP. Glutamine hydrolysis is catalyzed in the GAT domain and the liberated ammonia is transferred via an intramolecular tunnel to the synthase domain where the ATP-dependent amination of UTP occurs to form CTP. CTPS is unique among the glutamine-dependent amidotransferases, requiring an allosteric effector (GTP) to activate the GAT domain for efficient glutamine hydrolysis. Recently, the first cryo-electron microscopy structure of Drosophila CTPS was solved with bound ATP, UTP, and, notably, GTP, as well as the covalent adduct with 6-diazo-5-oxo-L-norleucine. This structural information, along with the numerous site-directed mutagenesis, kinetics, and structural studies conducted over the past 50 years, provide more detailed insights into the elaborate conformational changes that accompany GTP binding at the GAT domain and their contribution to catalysis. Interactions between GTP and the L2 loop, the L4 loop from an adjacent protomer, the L11 lid, and the L13 loop (or unique flexible wing region), induce conformational changes that promote the hydrolysis of glutamine at the GAT domain; however, direct experimental evidence on the specific mechanism by which these conformational changes facilitate catalysis at the GAT domain is still lacking. Significantly, the conformational changes induced by GTP binding also affect the assembly and maintenance of the NH 3 tunnel. Hence, in addition to promoting glutamine hydrolysis, the allosteric effector plays an important role in coordinating the reactions catalyzed by the GAT and synthase domains of CTPS.
关键词	CTP synthase allostery ammonia tunnel guanosine-5 '-triphosphate kinetics structure glutaminase guanosine-5′-triphosphate
URL	查看原文
收录类别	SCIE
语种	英语
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000801461700001
出版者	MDPI
原始文献类型	Review
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/243159
专题	生命科学与技术学院_硕士生生命科学与技术学院_PI研究组_刘冀珑组生命科学与技术学院_博士生
通讯作者	Bearne, Stephen L.; Liu, Ji-Long
作者单位	1.Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS B3H 4R2, Canada; 2.Dalhousie Univ, Dept Chem, Halifax, NS B3H 4R2, Canada; 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 4.Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Bearne, Stephen L.,Guo, Chen-Jun,Liu, Ji-Long. GTP-Dependent Regulation of CTP Synthase: Evolving Insights into Allosteric Activation and NH3 Translocation[J]. BIOMOLECULES,2022,12(5).
APA	Bearne, Stephen L.,Guo, Chen-Jun,&Liu, Ji-Long.(2022).GTP-Dependent Regulation of CTP Synthase: Evolving Insights into Allosteric Activation and NH3 Translocation.BIOMOLECULES,12(5).
MLA	Bearne, Stephen L.,et al."GTP-Dependent Regulation of CTP Synthase: Evolving Insights into Allosteric Activation and NH3 Translocation".BIOMOLECULES 12.5(2022).