Abstract
N-acetylglutamate kinase (NAGK) catalyzes the phosphorylation of N-acetylglutamate. In many bacteria, NAGK catalysis is the rate controlling step in the L-arginine biosynthesis pathway from glutamate to L-arginine and is allosterically inhibited by L-arginine. Many data show that conformational dynamics of NAGKs are essential for their function. The demonstration of the conformational mechanism provides a potential way to improve the yield of arginine. Due to the lack of NAGK catalysis step in arginine synthesis route of mammals, the elucidation of the dynamic mechanism can also provide a way to design a new antivirus drug. This paper reviews how the dynamics affect the activity of NAGKs and are controlled by the effectors. X-ray crystallography and modeling data have shown that in NAGKs, the structural elements required for inhibitor and substrate binding, catalysis and product release, are highly mobile. It is possible to eliminate the inhibition of the arginine and/or block the synthesis of arginine by disturbing the flexibility of the NAGKs. Amino acid kinase family is thought to share some common dynamic features; the flexible structural elements of NAGKs have been identified, but the details of the dynamics and the signal transfer pathways are yet to be elucidated.
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References
Batra VK, Beard WA, Pedersen LC, Wilson SH (2016) Structures of DNA polymerase mispaired DNA termini transitioning to pre-catalytic complexes support an induced-fit fidelity mechanism. Structure 24:1863–1875. doi:10.1016/j.str.2016.08.006
Boehr DD, McElheny D, Dyson HJ, Wright PE (2006a) The dynamic energy landscape of dihydrofolate reductase catalysis. Science 313:1638–1642. doi:10.1126/science.1130258
Boehr DD, Dyson HJ, Wright PE (2006b) An NMR perspective on enzyme dynamics. Chem Rev 106:3055–3079. doi:10.1021/cr050312q
Cunin R, Glansdorff N, Pierard A, Stalon V (1986) Biosynthesis and metabolism of arginine in bacteria. Microbiol Rev 50:314–352
Eyal E, Yang LW, Bahar I (2006) Anisotropic network model: systematic evaluation and a new web interface. Bioinformatics 22:2619–2627. doi:10.1093/bioinformatics/btl448
Fernandez-Murga ML, Rubio V (2008) Basis of arginine sensitivity of microbial N-acetyl-L-glutamate kinase: mutagenesis and protein engineering study with the Pseudomonas aeruginosa and Escherichia coli enzymes. J Bacteriol 190:3018–3025. doi:10.1128/JB.01831-07
Fernandez-Murga ML, Gil-Ortiz F, Llacer JL, Rubio V (2004) Arginine biosynthesis in Thermotoga maritima: characterization of the arginine-sensitive N-acetyl-L-glutamate kinase. J Bacteriol 186:6142–6149. doi:10.1128/JB.186.18.6142-6149.2004
Gil-Ortiz F, Ramon-Maiques S, Fernandez-Murga ML, Fita I, Rubio V (2010) Two crystal structures of Escherichia coli N-acetyl-L-glutamate kinase demonstrate the cycling between open and closed conformations. J Mol Biol 399:476–490. doi:10.1016/j.jmb.2010.04.025
Henzler-Wildman K, Kern D (2007) Dynamic personalities of proteins. Nature 450:964–972. doi:10.1038/nature06522
Huang Y, Zhang H, Tian H, Li C, Han S, Lin Y, Zheng S (2015) Mutational analysis to identify the residues essential for the inhibition of N-acetyl glutamate kinase of Corynebacterium glutamicum. Appl Microbiol Biotechnol 99:7527–7537. doi:10.1007/s00253-015-6469-5
Huang Y, Li C, Zhang H, Liang S, Han S, Lin Y, Yang X, Zheng S (2016) Monomeric Corynebacterium glutamicum N-acetyl glutamate kinase maintains sensitivity to L-arginine but has a lower intrinsic catalytic activity. Appl Microbiol Biotechnol 100:1789–1798. doi:10.1007/s00253-015-7065-4
Korzhnev DM, Karlsson BG, Orekhov VY, Billeter M (2003) NMR detection of multiple transitions to low-populated states in azurin. Protein Sci 12:56–65. doi:10.1110/ps.0225403
Korzhnev DM, Kloiber K, Kanelis V, Tugarinov V, Kay LE (2004) Probing slow dynamics in high molecular weight proteins by methyl-TROSY NMR spectroscopy: application to a 723 residue enzyme. J Am Chem Soc 126:3964–3973. doi:10.1021/ja039587i
Kumar CJ, Nussinov TR (2000) Factors enhancing protein thermostability. Protein Eng 13:179–191
Loria JP, Berlow RB, Watt ED (2008) Characterization of enzyme motions by solution NMR relaxation dispersion. Acc Chem Res 41:214–221. doi:10.1021/ar700132n
Marcos E, Crehuet R, Bahar I (2010) On the conservation of the slow conformational dynamics within the amino acid kinase family: NAGK the paradigm. PLoS Comput Biol 6:e1000738. doi:10.1371/journal.pcbi.1000738
Marcos E, Crehuet R, Bahar I (2011) Changes in dynamics upon oligomerization regulate substrate binding and allostery in amino acid kinase family members. PLoS Comput Biol 7:e1002201. doi:10.1371/journal.pcbi.1002201
Michel D (2016) Conformational selection or induced fit? New insights from old principles. Biochimie 128-129:48–54. doi:10.1016/j.biochi.2016.06.012
Mittermaier AK, Kay LE (2009) Observing biological dynamics at atomic resolution using NMR. Trends Biochem Sci 34:601–611. doi:10.1016/j.tibs.2009.07.004
Mizuno Y, Moorhead GB, Ng KK (2007) Structural basis for the regulation of N-acetylglutamate kinase by PII in Arabidopsis thaliana. J Biol Chem 282:35733–35740. doi:10.1074/jbc.M707127200
Monod J, Wyman J, Changeux JP (1965) On the nature of allosteric transitions: a plausible model. J Mol Biol 12:88–118
Moustafa IM, Korneeva VS, Arnold JJ, Smidansky ED, Marcotte LL, Gohara DW, Yang X, Sánchez-Farrán MA, Filman D, Maranas JK, Boehr DD, Hogle JM, Colina CM, Cameron CE (2014) Structural dynamics as a contributor to error-prone replication by a RNA-dependent RNA polymerase. J Biol Chem 289:36229–36248. doi:10.1074/jbc.M114.616193
Nuermaimaiti A, S-Falk V, Cramer JL, Svane KL, Hammer B, Gothelf KV, Linderoth TR (2016) Selection of conformational states in surface self-assembly for a molecule with eight possible pairs of surface enantiomers. Chem Commun (Camb) 52:14023–14026. doi:10.1039/c6cc06876f
Ramon-Maiques S, Marina A, Gil-Ortiz F, Fita I, Rubio V (2002) Structure of acetylglumatae kinase, a key enzyme for arginine biosynthesis and a prototype for the amino acid kinase enzyme family, during catalysis. Structure 10:329–342
Ramon-Maiques S, Fernandez-Murga ML, Gil-Ortiz F, Vagin A, Fita I, Rubio V (2006) Structural bases of feed-back control of arginine biosynthesis, revealed by the structures of two hexameric N-acetylglutamate kinases, from Thermotoga maritima and Pseudomonas aeruginosa. J Mol Biol 356:695–713. doi:10.1016/j.jmb.2005.11.079
Riccardi L, Mereghetti P (2016) Induced fit in protein multimerization: the HFBI case. PLoS Comput Biol 12:e1005202. doi:10.1371/journal.pcbi.1005202
Shargool PD, Jain JC, McKay G (1988) Ornithine biosynthesis, and arginine biosynthesis and degradation in plant cells. Phytochemistry 27(6):1571–1574. doi:10.1016/0031-9422(88)80404-7
Sundaresan R, Ragunathan P, Kuramitsu S, Yokoyama S, Kumarevel T, Ponnuraj K (2012) The structure of putative N-acetyl glutamate kinase from Thermus thermophiles reveals an intermediate active site conformation of the enzyme. Biochem Biophys Res Commun 420:692–697. doi:10.1016/j.bbrc.2012.03.072
Tama F, Sanejouand YH (2001) Conformational change of proteins arising from normal mode calculations. Protein Eng 14:1–6
Tsai CJ, Ma B, Sham YY, Kumar S, Nussinov R (2001) Structured disorder and conformational selection. Proteins 44:418–427
Visek WJ (1986) Arginine needs, physiological state and usual diets. A reevaluation. J Nutr 116:36–46
Weikl TR, Boehr DD (2012) Conformational selection and induced changes along the catalytic cycle of Escherichia coli dihydrofolate reductase. Proteins 80:2369–2383. doi:10.1002/prot.24123
Woods KN, Pfeffer J, Dutta A, Klein-Seetharaman J (2016) Vibrational resonance, allostery, and activation in rhodopsin-like G protein-coupled receptors. Sci Rep 6:37290. doi:10.1038/srep37290
Xu M, Rao Z, Dou W, Yang J, Jin J, Xu Z (2012) Site-directed mutagenesis and feedback-resistant N-acetyl-L-glutamate kinase (NAGK) increase Corynebacterium crenatum L-arginine production. Amino Acids 43:255–266. doi:10.1007/s00726-011-1069-x
Yang X, Welch JL, Arnold JJ, Boehr DD (2010) Long-range interaction networks in the function and fidelity of poliovirus RNA-dependent RNA polymerase studied by nuclear magnetic resonance. Biochemistry 49:9361–9371. doi:10.1021/bi100833r
Yang X, Smidansky ED, Maksimchuk KR, Lum D, Welch JL, Arnold JJ, Cameron CE, Boehr DD (2012) Motif D of viral RNA-dependent RNA polymerases determines efficiency and fidelity of nucleotide addition. Structure 20:1519–1527. doi:10.1016/j.str.2012.06.012
Zhang B, Wan F, Qiu YL, Chen XL, Tang L, Chen JC, Xiong YH (2015) Increased L-arginine production by site-directed mutagenesis of N-acetyl-L-glutamate kinase and proB gene deletion in Corynebacterium crenatum. Biomed Environ Sci 28:864–874. doi:10.3967/bes2015.120
Zhuravleva AV, Korzhnev DM, Kupce E, Arseniev AS, Billeter M, Orekhov VY (2004) Gated electron transfers and electron pathways in azurin: a NMR dynamic study at multiple fields and temperatures. J Mol Biol 342:1599–1611. doi:10.1016/j.jmb.2004.08.001
Acknowledgments
Financial support from the National Natural Science Foundation of China (No. 41673074), Guangzhou Science and Technology and Innovation Commission (No. 201607010073), Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, and the Key Laboratory of Renewable Energy, Chinese Academy of Sciences (No. y507k81001) is gratefully acknowledge. The author also acknowledges the significant contribution to the scientific quality of this work made by the anonymous reviewers.
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Yang, X. Conformational dynamics play important roles upon the function of N-acetylglutamate kinase. Appl Microbiol Biotechnol 101, 3485–3492 (2017). https://doi.org/10.1007/s00253-017-8237-1
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DOI: https://doi.org/10.1007/s00253-017-8237-1