Pochodne fosforylowanych cukrów jako inhibitory syntazy GLcN-6-P

• Autorzy: Melcer A.

Warianty tytułu

EN

Derivatives of phosphorylated aminosugars as inhibitors of GLcN-6-synthase

• Języki publikacji: PL

Abstrakty

EN

A reaction catalyzed by glucosamine-6-phosphate synthase (L-glutamine: D-fructose-phosphate amidotransferase, Glms) is the first step committed to the amino-sugar biosynthetic pathway of all living organisms [1]. This is in particular the only endogeneous access to hexosamines which are absolutely required in the edification of microbial cell walls. Glucosamine-6-phosphate synthase was proposed as a target for antifungal chemotherapy and a search for its selective inhibitors as potential antifungals has been continued [2]. This enzyme catalyzes two coupled enzymatic reactions. The first is the hydrolysis of glutamine to yield glutamate and nascent ammonia, which is transferred to Fru-6-P. The second reaction is the isomerization of Fru-6-P to an aldose, corresponding to Heyns rearrangement (3, 4). Like other amidotransferases, GlmS is organized into two domains: the NH2-terminal glutamine amidotransferase domain, which catalyzes the hydrolysis of glutamine, and the COOH-terminal synthase domain, which catalyzes the isomerization (5-8). The glutamine hydrolysis reaction has been studied extensively and utilises the NH2-terminal cysteine thiol, which forms a g-glutamyl thioester intermediate during the reaction. This catalytic role was confirmed by conversion of the NH2-terminal cysteine to alanine using site-directed mutagenesis which abolished enzymatic activity [2]. The already known specific inhibitors of GlcN-6-P synthase belong to two different structural groups: L-glutamine mimics and analogues of the putative transition state intermediates. In general, glutamine amidotransferases are inactivated by glutamine afinity analogues such as 6-diazo-5-oxo-L-norleucine and 6-chloro-5-oxo-L-norleucine (chloroketone), which alkylate the essential cysteine residue (5, 6, 9). Indeed, many of the active site-directed irreversible inactivators developed for GlmS contain an electrophilic function at the ă -position of glutamate and react irreversibly with the NH2-terminal cysteine residue. More recently, attempts to develop carbohydrate-based inhibitors have been made with the hope of developing higher specificity (10-13). The second group of compounds comprises derivatives of phosphorylated aminosugars, including: 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP), arabinose-5-phosphate oxime and 5-methylenephosphono-D-arabinohydroximolactone, as the most powerful GlcN-6-P synthase inhibitors [11-15]. These compounds exhibit a very poor, if any, antifungal activity. This paper describes the inhibition of GlmS by several analogues of the cis-enolamine intermediate in an attempt to probe the structural requirements for potent inhibition of this enzyme. The energetic contribution of the 2-amino group to binding of the product and the cis-enolamine intermediate is determined.

Słowa kluczowe

PL

syntaza glukozamino-6-fosforan; inihibitory syntazy GlcN-6-P; właściwości przeciwgrzybicze; fosforylowane aminocukry; analogi cis-enolaminy

EN

Glucosamine-6-P synthase; inhibitors of GlcN-6-P; antifungals; phosphorylated aminosugars; analogues of the cis-enolamine

• Wydawca: Polskie Towarzystwo Chemiczne
• Czasopismo: Wiadomości Chemiczne
• Rocznik: 2010
• Tom: [Z] 64, 9-10
• Strony: 771--786
• Opis fizyczny: Bibliogr. 51 poz., schem.

Twórcy

autor

Melcer A.

• Politechnika Gdańska, Wydział Chemiczny, Katedra Aparatury i Maszynoznawstwa Chemicznego, ul G. Narutowicza 11/12, 80-233 Gdańsk Wrzeszcz

Bibliografia

• [1] D. Mengin-Lecreulx, J. Van Heijenoort, J. Bacteriol., 1994, 176, 5788.
• [2] E. Borowski, Il Farmaco., 2000, 55, 206.
• [3] J.M. Kort, Adv. Carbohydr. Chem. Biochem., 1970, 25, 311.
• [4] B. Golinelli-Pimpaneau., F. Le Goffic, J. Am. Chem. Soc., 1989, 111, 3029.
• [5] F. Massiere, M.A. Badet-Denisot, Cell. Mol. Life. Sci., 1998, 54, 205.
• [6] H. Zalkin, Adv. Enzymol., 1993, 66, 203.
• [7] B. Mei, H. Zalkin, J. Bacteriol., 1990, 172, 3512.
• [8] M.A. Denisot, F. Le Goffic, B. Badet, Arch. Biochem. Biophys., 1991, 288, 225.
• [9] J.M. Buchanan, Adv. Enzymol., 1973, 39, 91.
• [10] V. Corizzi, B. Badet, M.A. Badet-Denisot, J. Chem. Soc. Chem. Commun., 1992, 189.
• [11] M.A. Badet-Denisot, C. Leriche, F. Massiere, B. Badet, Bioorg. Med. Chem. Lett., 1995, 5, 815.
• [12] S.L. Bearne, J. Biol. Chem., 1996, 271, 3052.
• [13] C. Leriche, M.-A. Badet-Denisot, B. Badet, Eur. J. Biochem., 1997, 245, 418.
• [14] C. Le Camus, M.-A. Badet-Denisot, B. Badet, Tetrahedron Lett., 1998, 39, 2571.
• [15] C. Le Camus, A. Chassange, M.A. Badet-Denisot, B. Badet, Tetrahedron Lett., 1998, 39, 287.
• [16] H. Chmara, E. Borowski, Biochim. Biophys. Chem. Comun., 1973, 52, 1381.
• [17] H. Chmara, E. Borowski, Biochim. Biophys. Chem. Comun., 1973, 55, 1147.
• [18] J.M. Buchmanan, Areas. Mol. Biol., 1973, 39, 91.
• [19] S. Milewski, H. Chmara, E. Borowski, Acta Microbiol., 1986, 145, 234.
• [20] E. Borowski, 2nd European Symposium on Antimicrobial Agents, XXIII Supplementum, 1998, 12.
• [21] E. Borowski, R. Andruszkiewicz, M. Bontemps-Gracz, H. Chmara, S. Milewski, M. Zaremba, 6th Meditterranean Congress of Chemotherapy, Taormina 88, Abstrakt Book, 1998, 164.
• [22] B. Badet, M.A. Badet-Denisot, B. Rene, Bull. Soc. Chim, Fr., 1993,130, 155.
• [23] C. Leriche, M.A. Badet-Denisot, B. Badet, J. Am. Chem. Soc., 1996, 118, 1797.
• [24] H. Chmara, H. Zahner, Biochem. Biophys. Acta, 1984, 787, 45.
• [25] H. Chmara, R. Adruszkiewicz, E. Borowski, Biochem. Biophys. Acta, 1986, 870, 357.
• [26] A. Teplyakow, G. Obmolova, M.A. Badet-Denisot, B. Badet, Protein Sci., 1999, 8, 596.
• [27] B. Badet. P. Vermoote, P.Y. Haumont, F. Lederer, F. Le Goffic, Biochemistry, (1987), 26, 1940.
• [28] B. Golinelli-Pimpaneau, B. Badet. Eur. J. Biochem., 1991, 201, 175.
• [29] A. Teplyakow, G. Obmolova, M.A. Badet-Denisot, Structure, 1998, 6, 1047.
• [30] H. Zalkin, Meth. Enzymol., 1985, 113, 263.
• [31] B. Mei, H. Zalkin, J. Biol. Chem., 1998, 264, 16613.
• [32] J.A. Branningan, G. Dodson, P.C.E. Moody, J.L. Smith, D.R. Tomchick, Nature, 1995, 378, 416.
• [33] M.G.J. Richards, S.M. Schuster, FEBS., 1992, 313, 98.
• [34] C. Leriche, M.A. Badet-Denisot, B. Badet, Eur. J. Biochem., 1997, 245, 418.
• [35] N. Kucharczyk, M.A. Badet-Denisot, F. Le Goffic, B. Badet, Biochemistry, 1990, 29, 3668.
• [36] M. Tarnowska, S. Ołdziej, A. Liwo, Z. Grzonka, E. Borowski, Eur. Biophys. J., 1992, 21, 273.
• [37] M.A. Badet-Denisot, B. Badet, Arch. Biochem. Biophys., 1992, 292, 475.
• [38] J.L. Smith. Biochem. Soc. Trans., 1995, 23, 894.
• [39] J.G. Tesamer, T.J. Klem, M.L. Deras, V.J. Davisson, J.L. Smith, Nature Struct. Biology, 1996, 74.
• [40] M.A. Badet-Denisot, C. Leriche, F. Massiere, B. Badet, Bioorg. Med. Chem. Lett., 1995, 5, 815.
• [41] P. Le Maréchal, C. Froussios, M. Level, R. Azard, Carbohydr. Res., 1981, 94, 1.
• [42] S. Milewski, Biochim. Biophys. Acta, 2002, 1597, 173.
• [43] C. Le Camus, A. Chassange, M.A. Badet-Denisot, Tetrahedron Lett., 1998, 39, 287.
• [44] C.E. McKenna, M.T. Higa, N.H. Cheung, M.C. McKenna, Tetrahedron Lett., 1977, 155.
• [45] S.L. Bearne, O. Hekmat, J.E. MacDonnel, Biochem. J. 2001, 223.
• [46] A. Janiak, B. Cybulska, J. Szlinder-Richert, E. Borowski, S. Milewski, Acta Biochim. Polon., 2002, 49, 77.
• [47] S.L. Bearne, J. Biol. Chem., 1996, 271, 3052.
• [48] J. Grzybowska, P. Sowiñski, J. Gumieniak, T. Zieniawa, E. Borowski, J. Antibiot., 1997, 6, 115.
• [49] A.M. Janiak, M. Hoffmann, M.J. Milewska, S. Milewski, Bioorg. Med. Chem. 2003, 11,1653.
• [50] B. Liberek, A. Melcer, A. Osuch, R. Wakieæ, S. Milewski, A. Wioeniewski, Carbohydr. Res., 2005, 17, 6
• [51] A. Melcer, I. Łącka, I. Gabriel, M. Wojciechowski, B. Liberek, A. Wioeniewski, S. Milewski, Bioorg. Med. Chem. Lett.,2007, 17, 6602.