1nbh › Citations

Catalytic mechanism of glycine N-methyltransferase.

Takata Y, Huang Y, Komoto J, Yamada T, Konishi K, Ogawa H, Gomi T, Fujioka M, Takusagawa F
Biochemistry 42 8394-402 (2003)
Cited: 47 times
EuropePMC logo PMID: 12859184

Abstract

Methyltransfer reactions are some of the most important reactions in biological systems. Glycine N-methyltransferase (GNMT) catalyzes the S-adenosyl-l-methionine- (SAM-) dependent methylation of glycine to form sarcosine. Unlike most SAM-dependent methyltransferases, GNMT has a relatively high value and is weakly inhibited by the product S-adenosyl-l-homocysteine (SAH). The major role of GNMT is believed to be the regulation of the cellular SAM/SAH ratio, which is thought to play a key role in SAM-dependent methyltransfer reactions. Crystal structures of GNMT complexed with SAM and acetate (a potent competitive inhibitor of Gly) and the R175K mutated enzyme complexed with SAM were determined at 2.8 and 3.0 A resolutions, respectively. With these crystal structures and the previously determined structures of substrate-free enzyme, a catalytic mechanism has been proposed. Structural changes occur in the transitions from the substrate-free to the binary complex and from the binary to the ternary complex. In the ternary complex stage, an alpha-helix in the N-terminus undergoes a major conformational change. As a result, the bound SAM is firmly connected to protein and a "Gly pocket" is created near the bound SAM. The second substrate Gly binds to Arg175 and is brought into the Gly pocket. Five hydrogen bonds connect the Gly in the proximity of the bound SAM and orient the lone pair orbital on the amino nitrogen (N) of Gly toward the donor methyl group (C(E)) of SAM. Thermal motion of the enzyme leads to a collision of the N and C(E) so that a S(N)2 methyltransfer reaction occurs. The proposed mechanism is supported by mutagenesis studies.

Articles - 1nbh mentioned but not cited (8)

  1. Structural insights into the mechanism and evolution of the vaccinia virus mRNA cap N7 methyl-transferase. De la Peña M, Kyrieleis OJ, Cusack S. EMBO J 26 4913-4925 (2007)
  2. Insights on the Origin of Catalysis on Glycine N-Methyltransferase from Computational Modeling. Świderek K, Tuñón I, Williams IH, Moliner V. J Am Chem Soc 140 4327-4334 (2018)
  3. Convergent Mechanistic Features between the Structurally Diverse N- and O-Methyltransferases: Glycine N-Methyltransferase and Catechol O-Methyltransferase. Zhang J, Klinman JP. J Am Chem Soc 138 9158-9165 (2016)
  4. Structural insights into the catalytic mechanism of Synechocystis magnesium protoporphyrin IX O-methyltransferase (ChlM). Chen X, Wang X, Feng J, Chen Y, Fang Y, Zhao S, Zhao A, Zhang M, Liu L. J Biol Chem 289 25690-25698 (2014)
  5. Structure-function studies of tetrahydroprotoberberine N-methyltransferase reveal the molecular basis of stereoselective substrate recognition. Lang DE, Morris JS, Rowley M, Torres MA, Maksimovich VA, Facchini PJ, Ng KKS. J Biol Chem 294 14482-14498 (2019)
  6. Burkholderia glumae ToxA Is a Dual-Specificity Methyltransferase That Catalyzes the Last Two Steps of Toxoflavin Biosynthesis. Fenwick MK, Philmus B, Begley TP, Ealick SE. Biochemistry 55 2748-2759 (2016)
  7. Phosphoproteomic analysis of Methanohalophilus portucalensis FDF1(T) identified the role of protein phosphorylation in methanogenesis and osmoregulation. Wu WL, Lai SJ, Yang JT, Chern J, Liang SY, Chou CC, Kuo CH, Lai MC, Wu SH. Sci Rep 6 29013 (2016)
  8. Structural Analysis of Glycine Sarcosine N-methyltransferase from Methanohalophilus portucalensis Reveals Mechanistic Insights into the Regulation of Methyltransferase Activity. Lee YR, Lin TS, Lai SJ, Liu MS, Lai MC, Chan NL. Sci Rep 6 38071 (2016)


Reviews citing this publication (8)

  1. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Stipanuk MH. Annu Rev Nutr 24 539-577 (2004)
  2. Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. Luka Z, Mudd SH, Wagner C. J Biol Chem 284 22507-22511 (2009)
  3. Metabolic defects provide a spark for the epigenetic switch in cancer. Hitchler MJ, Domann FE. Free Radic Biol Med 47 115-127 (2009)
  4. Methoxistasis: integrating the roles of homocysteine and folic acid in cardiovascular pathobiology. Joseph J, Loscalzo J. Nutrients 5 3235-3256 (2013)
  5. The role of genetics in the establishment and maintenance of the epigenome. Huidobro C, Fernandez AF, Fraga MF. Cell Mol Life Sci 70 1543-1573 (2013)
  6. Environmental epigenetics in zebrafish. Cavalieri V, Spinelli G. Epigenetics Chromatin 10 46 (2017)
  7. One-Carbon Metabolism Links Nutrition Intake to Embryonic Development via Epigenetic Mechanisms. Wu S, Zhang J, Li F, Du W, Zhou X, Wan M, Fan Y, Xu X, Zhou X, Zheng L, Zhou Y. Stem Cells Int 2019 3894101 (2019)
  8. Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players. Siblini Y, Namour F, Oussalah A, Guéant JL, Chéry C. Cells 11 3607 (2022)

Articles citing this publication (31)

  1. Structure and mechanism of mRNA cap (guanine-N7) methyltransferase. Fabrega C, Hausmann S, Shen V, Shuman S, Lima CD. Mol Cell 13 77-89 (2004)
  2. Single cell genome amplification accelerates identification of the apratoxin biosynthetic pathway from a complex microbial assemblage. Grindberg RV, Ishoey T, Brinza D, Esquenazi E, Coates RC, Liu WT, Gerwick L, Dorrestein PC, Pevzner P, Lasken R, Gerwick WH. PLoS One 6 e18565 (2011)
  3. Structural and functional analysis of the pyocyanin biosynthetic protein PhzM from Pseudomonas aeruginosa. Parsons JF, Greenhagen BT, Shi K, Calabrese K, Robinson H, Ladner JE. Biochemistry 46 1821-1828 (2007)
  4. Actin-binding protein ABP140 is a methyltransferase for 3-methylcytidine at position 32 of tRNAs in Saccharomyces cerevisiae. Noma A, Yi S, Katoh T, Takai Y, Suzuki T, Suzuki T. RNA 17 1111-1119 (2011)
  5. The structure of two N-methyltransferases from the caffeine biosynthetic pathway. McCarthy AA, McCarthy JG. Plant Physiol 144 879-889 (2007)
  6. Structural insights of the specificity and catalysis of a viral histone H3 lysine 27 methyltransferase. Qian C, Wang X, Manzur K, Sachchidanand, Farooq A, Zeng L, Wang R, Zhou MM. J Mol Biol 359 86-96 (2006)
  7. Structure and reaction mechanism of phosphoethanolamine methyltransferase from the malaria parasite Plasmodium falciparum: an antiparasitic drug target. Lee SG, Kim Y, Alpert TD, Nagata A, Jez JM. J Biol Chem 287 1426-1434 (2012)
  8. A novel tumor suppressor function of glycine N-methyltransferase is independent of its catalytic activity but requires nuclear localization. DebRoy S, Kramarenko II, Ghose S, Oleinik NV, Krupenko SA, Krupenko NI. PLoS One 8 e70062 (2013)
  9. Structural bases for 16 S rRNA methylation catalyzed by ArmA and RmtB methyltransferases. Schmitt E, Galimand M, Panvert M, Courvalin P, Mechulam Y. J Mol Biol 388 570-582 (2009)
  10. Structure and function of the glycopeptide N-methyltransferase MtfA, a tool for the biosynthesis of modified glycopeptide antibiotics. Shi R, Lamb SS, Zakeri B, Proteau A, Cui Q, Sulea T, Matte A, Wright GD, Cygler M. Chem Biol 16 401-410 (2009)
  11. Elevated physiological levels of folic acid can increase in vitro growth and invasiveness of prostate cancer cells. Petersen LF, Brockton NT, Bakkar A, Liu S, Wen J, Weljie AM, Bismar TA. BJU Int 109 788-795 (2012)
  12. The reaction mechanism of phenylethanolamine N-methyltransferase: a density functional theory study. Georgieva P, Wu Q, McLeish MJ, Himo F. Biochim Biophys Acta 1794 1831-1837 (2009)
  13. Effect of naturally occurring mutations in human glycine N-methyltransferase on activity and conformation. Luka Z, Wagner C. Biochem Biophys Res Commun 312 1067-1072 (2003)
  14. Structural and Functional Studies of Pavine N-Methyltransferase from Thalictrum flavum Reveal Novel Insights into Substrate Recognition and Catalytic Mechanism. Torres MA, Hoffarth E, Eugenio L, Savtchouk J, Chen X, Morris JS, Facchini PJ, Ng KK. J Biol Chem 291 23403-23415 (2016)
  15. Glycine N-methyltransferases: a comparison of the crystal structures and kinetic properties of recombinant human, mouse and rat enzymes. Pakhomova S, Luka Z, Grohmann S, Wagner C, Newcomer ME. Proteins 57 331-337 (2004)
  16. Identification of phosphorylation sites in glycine N-methyltransferase from rat liver. Luka Z, Ham AJ, Norris JL, Yeo EJ, Yermalitsky V, Glenn B, Caprioli RM, Liebler DC, Wagner C. Protein Sci 15 785-794 (2006)
  17. Thermodynamic evaluation of ligand binding in the plant-like phosphoethanolamine methyltransferases of the parasitic nematode Haemonchus contortus. Lee SG, Haakenson W, McCarter JP, Williams DJ, Hresko MC, Jez JM. J Biol Chem 286 38060-38068 (2011)
  18. Structure of the Q237W mutant of HhaI DNA methyltransferase: an insight into protein-protein interactions. Dong A, Zhou L, Zhang X, Stickel S, Roberts RJ, Cheng X. Biol Chem 385 373-379 (2004)
  19. The crystal structure of M. leprae ML2640c defines a large family of putative S-adenosylmethionine-dependent methyltransferases in mycobacteria. Graña M, Haouz A, Buschiazzo A, Miras I, Wehenkel A, Bondet V, Shepard W, Schaeffer F, Cole ST, Alzari PM. Protein Sci 16 1896-1904 (2007)
  20. Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate. Luka Z, Loukachevitch LV, Wagner C. Biochim Biophys Acta 1784 1342-1346 (2008)
  21. The carboxyl-terminal extension of yeast tRNA m5C methyltransferase enhances the catalytic efficiency of the amino-terminal domain. Walbott H, Auxilien S, Grosjean H, Golinelli-Pimpaneau B. J Biol Chem 282 23663-23671 (2007)
  22. Conformational changes in the di-domain structure of Arabidopsis phosphoethanolamine methyltransferase leads to active-site formation. Lee SG, Jez JM. J Biol Chem 292 21690-21702 (2017)
  23. Destabilization of human glycine N-methyltransferase by H176N mutation. Luka Z, Pakhomova S, Luka Y, Newcomer ME, Wagner C. Protein Sci 16 1957-1964 (2007)
  24. Differences in folate-protein interactions result in differing inhibition of native rat liver and recombinant glycine N-methyltransferase by 5-methyltetrahydrofolate. Luka Z, Pakhomova S, Loukachevitch LV, Newcomer ME, Wagner C. Biochim Biophys Acta 1824 286-291 (2012)
  25. Small methyltransferase RlmH assembles a composite active site to methylate a ribosomal pseudouridine. Koh CS, Madireddy R, Beane TJ, Zamore PD, Korostelev AA. Sci Rep 7 969 (2017)
  26. Altered dynamics upon oligomerization corresponds to key functional sites. Mishra SK, Sankar K, Jernigan RL. Proteins 85 1422-1434 (2017)
  27. Exogenous glycine partially attenuates homocysteine-induced apoptosis and membrane peroxidation in chick embryos. Miller RR, Hay CM, Striegnitz TR, Honsey LE, Coykendall CE, Blacquiere KD. Comp Biochem Physiol C Toxicol Pharmacol 144 25-33 (2006)
  28. Dichloroacetate improves systemic energy balance and feeding behavior during sepsis. Oh TS, Zabalawi M, Jain S, Long D, Stacpoole PW, McCall CE, Quinn MA. JCI Insight 7 e153944 (2022)
  29. Structure and mechanism of an antibiotics-synthesizing 3-hydroxykynurenine C-methyltransferase. Chen SC, Huang CH, Lai SJ, Liu JS, Fu PK, Tseng ST, Yang CS, Lai MC, Ko TP, Chen Y. Sci Rep 5 10100 (2015)
  30. Global and Complement Gene-Specific DNA Methylation in Grass Carp after Grass Carp Reovirus (GCRV) Infection. Xiong L, He L, Luo L, Li Y, Liao L, Huang R, Zhu Z, Wang Y. Int J Mol Sci 19 E1110 (2018)
  31. High-Throughput Screening and Directed Evolution of Methionine Adenosyltransferase from Escherichia coli. Cao C, Nie K, Xu H, Liu L. Appl Biochem Biotechnol 195 4053-4066 (2023)


Quick links