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Flexible loop in the structure of S-adenosylmethionine synthetase crystallized in the tetragonal modification.

Fu Z, Hu Y, Markham GD, Takusagawa F
J Biomol Struct Dyn 13 727-39 (1996)
Cited: 29 times
EuropePMC logo PMID: 8723769

Abstract

S-Adenosylmethionine synthetase (MAT, ATP:L-methionine S-adenosyltransferase, E.C.2.5.1.6.) plays a central metabolic role in all organisms. MAT catalyzes the two-step reaction which synthesizes S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi) from ATP and L-methionine. AdoMet is the primary methyl group donor in biological systems. MAT from Escherichia coli was crystallized in the tetragonal modification with space group P4(3)2(1)2 using the same conditions as previously yielded crystals of the hexagonal system [Takusagawa, et al., (1996), J. Biol. Chem. 171, 136-147], except for the crystallization temperature. The structure has been determined by molecular replacement at 3.2 A resolution. The overall structure of the tetrameric MAT in the tetragonal modification is essentially the same as the structure found in the hexagonal modification. However there are two remarkable differences between the structures of two modifications. One is the contents in the active sites (holoform vs. apo-form), and the other is the conformation of the flexible loop over the active site (open vs. closed). These differences in the crystal structures are caused solely by the difference in crystallization temperatures (26 degrees C vs. 4 degrees C). We have interpreted the structural data obtained from the X-ray analyses in conjunction with the results of the mechanistic and sequencing studies in terms of possible dynamic motion of the flexible loop. When a substrate/product binds in the active site (hexagonal modification), the loop becomes disordered, apparently due to flexibility at the entrance of the active site as if it acts as a "mobile loop" during the catalytic reaction. On the other hand, when the temperature is decreased, the dynamic motion of the flexible loop may be reduced, and the loop residues enter the active site and close its entrance (tetragonal modification). Thus, the active site of the tetragonal modification is empty despite the crystals being grown in mother liquor containing a large concentration of phosphate (100 mM). There is no significant displacement of amino acid residues in the active site between the holo and apo forms, suggesting that the flexible loop plays an important role in determination of the contents in the active site. Since the functionally important amino acid residues in the active site are all conserved throughout various species, the structures of the active sites and the mechanism of the catalysis are probably essentially identical in the enzymes from a wide range of organisms. However, the substrate KM and Vmax values of MATs from various species are distributed over a wide range. The amino acid residues in the flexible loop regions are poorly conserved throughout various species. Therefore, the wide differences in catalysis rates of MATs from various speeches may be due to the differences in the composition of the flexible loop.

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  1. S-Adenosylmethionine: a control switch that regulates liver function. Mato JM, Corrales FJ, Lu SC, Avila MA. FASEB J 16 15-26 (2002)

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  1. The crystal structure of tetrameric methionine adenosyltransferase from rat liver reveals the methionine-binding site. González B, Pajares MA, Hermoso JA, Alvarez L, Garrido F, Sufrin JR, Sanz-Aparicio J. J Mol Biol 300 363-375 (2000)
  2. Practical conversion from torsion space to Cartesian space for in silico protein synthesis. Parsons J, Holmes JB, Rojas JM, Tsai J, Strauss CE. J Comput Chem 26 1063-1068 (2005)
  3. Lysine 2,3-aminomutase from Clostridium subterminale SB4: mass spectral characterization of cyanogen bromide-treated peptides and cloning, sequencing, and expression of the gene kamA in Escherichia coli. Ruzicka FJ, Lieder KW, Frey PA. J Bacteriol 182 469-476 (2000)
  4. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas AL. Proc Natl Acad Sci U S A 113 2104-2109 (2016)
  5. Understanding molecular recognition of promiscuity of thermophilic methionine adenosyltransferase sMAT from Sulfolobus solfataricus. Wang F, Singh S, Zhang J, Huber TD, Helmich KE, Sunkara M, Hurley KA, Goff RD, Bingman CA, Morris AJ, Thorson JS, Phillips GN. FEBS J 281 4224-4239 (2014)
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  7. Folding of dimeric methionine adenosyltransferase III: identification of two folding intermediates. Sánchez del Pino MM, Pérez-Mato I, Sanz JM, Mato JM, Corrales FJ. J Biol Chem 277 12061-12066 (2002)
  8. Lysine acetylation regulates the activity of Escherichia coli S-adenosylmethionine synthase. Sun M, Guo H, Lu G, Gu J, Wang X, Zhang XE, Deng J. Acta Biochim Biophys Sin (Shanghai) 48 723-731 (2016)
  9. Structure of HOE/BAY 793 complexed to human immunodeficiency virus (HIV-1) protease in two different crystal forms--structure/function relationship and influence of crystal packing. Lange-Savage G, Berchtold H, Liesum A, Budt KH, Peyman A, Knolle J, Sedlacek J, Fabry M, Hilgenfeld R. Eur J Biochem 248 313-322 (1997)
  10. Creation of a functional S-nitrosylation site in vitro by single point mutation. Castro C, Ruiz FA, Pérez-Mato I, Sánchez del Pino MM, LeGros L, Geller AM, Kotb M, Corrales FJ, Mato JM. FEBS Lett 459 319-322 (1999)
  11. Conformational dynamics of the active site loop of S-adenosylmethionine synthetase illuminated by site-directed spin labeling. Taylor JC, Markham GD. Arch Biochem Biophys 415 164-171 (2003)
  12. Discovery of novel types of inhibitors of S-adenosylmethionine synthesis by virtual screening. Taylor JC, Bock CW, Takusagawa F, Markham GD. J Med Chem 52 5967-5973 (2009)
  13. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. Niland CN, Ghosh A, Cahill SM, Schramm VL. Biochemistry 60 791-801 (2021)
  14. Control and regulation of S-Adenosylmethionine biosynthesis by the regulatory β subunit and quinolone-based compounds. Panmanee J, Bradley-Clarke J, Mato JM, O'Neill PM, Antonyuk SV, Hasnain SS. FEBS J 286 2135-2154 (2019)
  15. Comparative protein modeling of methionine S-adenosyltransferase (MAT) enzyme from Mycobacterium tuberculosis: a potential target for antituberculosis drug discovery. Khedkar SA, Malde AK, Coutinho EC. J Mol Graph Model 23 355-366 (2005)
  16. 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)
  17. Molecular dynamics studies on the domain swapped Salmonella typhimurium survival protein SurE: insights on the possible reasons for catalytic cooperativity. Mathiharan YK, Murthy MRN. J Biomol Struct Dyn 36 2303-2311 (2018)


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