A New Inhibitor of γ-aminobutric Acid Aminotransferase from Streptomyces sp. ZZ035 Isolated from a Folk Medicinal Soil in China

Author(s): Xuejie Xu, Xuejiao Wu, Ganjun Yuan, Qiwang Zhong, Li Xu

Strain ZZ035 was isolated from a folk medicinal soil in China. Polyphasic taxonomy procedure indicated that this strain belonged to the genus Streptomyces and was closest to S. cinnamonensis with high similarities (99.2%) of 16S rDNA sequence. 1 was isolated from the broth of this strain and identified as 5-amonimethyl-2-iminoimidazolidine-4-carboxylic acid. Its chemical structure was established by its spectroscopic data, and 1H and 13C signals were assigned by its 1H, 13C, Dept and HSQC spectra. Considering that 1 was a γ-aminobutric acid (GABA) derivative, its inhibitory activity against GABA-aminotransferase (GABA-AT) was assayed, and the result showed that 1 can inhibit GABA-AT activity with the 50% inhibitory concentration of approximately 60 μM. As 1 was a 2,3-disubstituted GABA derivative not published before, the approximate GABA-AT inhibitory activity of 1 compared to positive control vigabatrin showed that 1 were worthy of further research and developing.

Actinomycete, Streptomyces sp. ZZ035, γ-Aminobutric acid derivative, γ-Aminobutric acid-aminotransferase, Inhibitor

1. Yuan G, Li P, Yang H, et al. Chemical screening of sixty-one actinomycete strains and anti-methicillin- -resistant Staphylococcus aureus assays of target strains [J]. Chin J Nat Med, 2012, 10(2): 155-160.
2. Xu L, Yuan G, Zeng Q, et al. Antimicrobial activity and identification of actinomycete strains from a folk medicinal soil in China [J]. Appli Micro Open Access, 2015, 1: 105. doi:10.4172/2471-9315.1000105
3. Yogeeswari P, Sriram D, Vaigundaragavendran J. The GABA shunt: An attractive and potential therapeutic target in the treatment of epileptic disorders [J]. Curr Drug Metab, 2005, 6(2): 127-139.
4. Kawato M, Shinobu R. On Streptomyces herbaricolor sp. nov., supplement: a simple technique for microscopical observation [J]. Mem Osaka Univ Lib Arts Educ B Nat Sci, 1959, 8: 114-119.
5. Holt JG, Krieg NR, Sneath PHA, et al. Bergey's Manual of Determinative Bacteriology, ninth ed. [M]. Baltimore: Williams and Wilkins Co., 1994: 625-703.
6. Lechevalier MP, DeBievre C, Lechevalier HA. Chemotaxonomy of aerobic actinomycetes: phospholipid composition [J]. Biochem Syst Ecol, 1977, 5(4): 249-260.
7. Staneck JL, Roberts GD. Simplified approach to identification of aerobic actinomycetes by thin-layer chromatography [J]. Appl Microbiol, 1974, 28(2): 226-231.
8. Lane DJ. 16S/23S rRNA sequencing. In: Stackebrandt, E., Goodfellow, M. (Eds.), Nucleic acid techniques in bacterial systematics [M]. New York: John Wiley & Sons, 1991: 115-148.
9. Thompson JD, Gibson TJ, Plewniak F, et al. The CLUSTAL-_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools [J]. Nucleic Acids Res, 1997, 25(24): 4876-4882.
10. Tamura K, Dudley J, Nei M, et al. MEGA 4: Molecular evolutionary genetics analysis (MEGA) software version 4.0 [J]. Mol Biol Evol, 2007, 24(8): 1596-1599.
11. Saitou N, Nei M. The Neighbor-Joining Method—a new method for reconstructing phylogenetic trees [J]. Mol Bio Evol, 1987, 4(4): 406-425.
12. Felsenstein J. Confidence limits on phylogenies: an approach using the bootstrap [J]. Evolution, 1985, 39(4): 783-791.
13. Churchich JE, Moses U. 4-Aminobutyrate aminotransferase: the presence of nonequivalent binding sites [J]. J Biol Chem, 1981, 256(3): 1101-1104.
14. Chambliss KL, Gibson KM. Succinic semialdehyde dehydrogenase from mammalian brain: subunit analysis using polyclonal antiserum [J]. Int J Biochem, 1992, 24(9): 1493-1499.
15. Choi S, Silverman RB. Inactivation and inhibition of γ-aminobutyric acid aminotransferase by conformationally restricted vigabatrin analogues [J]. J Med Chem, 2002, 45(20): 4531-4539.
16. Qiu J, Pingsterhaus JM, Silverman RB. Inhibition and substrate activity of conformationally rigid vigabatrin analogues with γ-aminobutyric acid aminotransferase [J]. J Med Chem,1999, 42(22): 4725-4728.
17. Napolitano JG, Gavín JA, García C, et al. On the configuration of five-membered rings: A spin-spin coupling constant approach [J]. Chemistry, 2011, 17(23): 6338-6347.
18. Lippert B, Metcalf BW, Jung MJ, et al. 4-Amino-hex-5-enoic acid, a selective catalytic inhibitor of 4-aminobutyric-acid aminotransferase in mammalian brain [J]. Eur J Biochem, 1977, 74(3): 441-445.
19. Choi S, Storici P, Schirmer T, et al. Design of a conformationally restricted analogue of the antiepilepsy drug vigabatrin that directs its mechanism of inactivation of γ-aminobutyric acid aminotransferase [J]. J Am Chem Soc, 2002, 124(8):1620-1624.
20. Clift MD, Silverman RB. Synthesis and evaluation of novel aromatic substrates and competitive inhibitors of GABA-aminotransferase [J]. Bioorg Med Chem Lett, 2008, 18(10): 3122-3125.
21. Hawker DD, Silverman RB. Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase [J]. Bioorg Med Chem, 2012, 20(19): 5763-5773.
22. Johnson TR, Silverman RB. Syntheses of (Z)- and (E)-4-amino-2-(trifluoromethyl)-2-butenoic acid and their inactivation of γ-aminobutyric acid aminotransferase [J]. Bioorgan Med Chem, 1999, 7(8): 1625-1636.
23. Le HV, Hawker DD, Wu R, et al. Design and mechanism of tetrahydrothiophene-based γ-aminobutyric acid aminotransferase inactivators [J], J Am Chem Soc, 2015, 137(13): 4525-4533.
24. Pan Y, Qiu J, Silverman RB. Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent γ-aminobutyric acid aminotransferase inhibitor [J]. J Med Chem, 2003, 46(25): 5292-5293.
25. Pinto A, Tamborini L, Pennacchietti E, et al. Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase [J]. J Enzyme Inhib Med Chem, 2016, 31(2): 295-301.
26. Silverman RB. The 2011 E. B. Hershberg Award for important discoveries in medicinally active substances: (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a GABA aminotransferase inactivator and new treatment for drug addiction and infantile spasms [J]. J Med Chem, 2012, 55(2): 567-575.
27. Wang Z, Silverman R. Syntheses and evaluation of fluorinated conformationally restricted analogues of GABA as potential inhibitors of GABA aminotransferase [J]. Bioorg Med Chem, 2006, 14(7): 2242-2252.
28. Kobayashi K, Miyazawa S, Endo A. Isolation and inhibitory activity of gabaculine, a new potent inhibitor of γ-aminobutyrate aminotransferase produced by a Streptomyces [J]. FEBS Lett, 1977, 76(2): 207-210.
29. Nguyen E, Picklo Sr. MJ. Inhibition of succinic semialdehyde dehydrogenase activity by alkenal products of lipid peroxidation [J]. Biochim Biophys Acta, 2003, 1637(1):107-112.