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Azaserine

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Subramanyam Muthangi – 1st expert on this subject based on the ideXlab platform

  • survival of silk worm bombyx mori in Azaserine induced oxidative stress
    Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2020
    Co-Authors: Venkatesh Mandyam D, Subramanyam Muthangi

    Abstract:

    Abstract Cells under stress generate reactive oxygen species (ROS) in excess, which causes mitochondrial dysfunction and stimulates the apoptotic cascade. However, mild stress or pre-conditioning lead to the evasion of apoptosis by activating mitogenic signaling, including the signaling of inhibitors of apoptosis proteins (IAPs), or by inactivating certain apoptotic molecules. The silkworm (Bombyx mori) is an important economic insect which serves as a model organism in biological research. Bombyx mori apoptotic protease inducing factor (BmApaf1), a death-related ced-3/Nedd2-like protein (BmDredd), and BmSurvivin-2 (BmSvv2) are known to play significant roles in metamorphosis. Azaserine is an analogue of glutamine and irreversibly inhibits glutamine-utilizing enzymes and cysteine-glutamate transporter genes EAAT2. In the present study, we experimentally demonstrated stress induced by Azaserine along with the capacity of antioxidants to modulate apoptotic/anti-apoptotic gene expression in determining the fate of the larvae. We observed higher larval survival with higher Azaserine dosages and attributed this to the quantum of ROS generated and AOEs response, which favoured the BmSvv2 expression. Meanwhile higher levels of ROS with concomitant changes in AOEs were found to be responsible for BmApaf1 and BmDredd expression, which reflected a higher mortality rate.

Venkatesh Mandyam D – 2nd expert on this subject based on the ideXlab platform

  • survival of silk worm bombyx mori in Azaserine induced oxidative stress
    Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2020
    Co-Authors: Venkatesh Mandyam D, Subramanyam Muthangi

    Abstract:

    Abstract Cells under stress generate reactive oxygen species (ROS) in excess, which causes mitochondrial dysfunction and stimulates the apoptotic cascade. However, mild stress or pre-conditioning lead to the evasion of apoptosis by activating mitogenic signaling, including the signaling of inhibitors of apoptosis proteins (IAPs), or by inactivating certain apoptotic molecules. The silkworm (Bombyx mori) is an important economic insect which serves as a model organism in biological research. Bombyx mori apoptotic protease inducing factor (BmApaf1), a death-related ced-3/Nedd2-like protein (BmDredd), and BmSurvivin-2 (BmSvv2) are known to play significant roles in metamorphosis. Azaserine is an analogue of glutamine and irreversibly inhibits glutamine-utilizing enzymes and cysteine-glutamate transporter genes EAAT2. In the present study, we experimentally demonstrated stress induced by Azaserine along with the capacity of antioxidants to modulate apoptotic/anti-apoptotic gene expression in determining the fate of the larvae. We observed higher larval survival with higher Azaserine dosages and attributed this to the quantum of ROS generated and AOEs response, which favoured the BmSvv2 expression. Meanwhile higher levels of ROS with concomitant changes in AOEs were found to be responsible for BmApaf1 and BmDredd expression, which reflected a higher mortality rate.

Hidehiko Kumagai – 3rd expert on this subject based on the ideXlab platform

  • crystal structures of escherichia coli gamma glutamyltranspeptidase in complex with Azaserine and acivicin novel mechanistic implication for inhibition by glutamine antagonists
    Journal of Molecular Biology, 2008
    Co-Authors: Kei Wada, Hidehiko Kumagai, Hideyuki Suzuki, Jun Hiratake, Machiko Irie, Toshihiro Okada, Chiaki Yamada, Keiichi Fukuyama

    Abstract:

    Abstract γ-Glutamyltranspeptidase (GGT) catalyzes the cleavage of such γ-glutamyl compounds as glutathione, and the transfer of their γ-glutamyl group to water or to other amino acids and peptides. GGT is involved in a number of biological phenomena such as drug resistance and metastasis of cancer cells by detoxification of xenobiotics. Azaserine and acivicin are classical and irreversible inhibitors of GGT, but their binding sites and the inhibition mechanisms remain to be defined. We have determined the crystal structures of GGT from Escherichia coli in complex with Azaserine and acivicin at 1.65 A resolution. Both inhibitors are bound to GGT at its substrate-binding pocket in a manner similar to that observed previously with the γ-glutamyl-enzyme intermediate. They form a covalent bond with the O γ atom of Thr391, the catalytic residue of GGT. Their α-carboxy and α-amino groups are recognized by extensive hydrogen bonding and charge interactions with the residues that are conserved among GGT orthologs. The two amido nitrogen atoms of Gly483 and Gly484, which form the oxyanion hole, interact with the inhibitors directly or via a water molecule. Notably, in the Azaserine complex the carbon atom that forms a covalent bond with Thr391 is sp 3 -hybridized, suggesting that the carbonyl of Azaserine is attacked by Thr391 to form a tetrahedral intermediate, which is stabilized by the oxyanion hole. Furthermore, when acivicin is bound to GGT, a migration of the single and double bonds occurs in its dihydroisoxazole ring. The structural characteristics presented here imply that the unprecedented binding modes of Azaserine and acivicin are conserved in all GGTs from bacteria to mammals and give a new insight into the inhibition mechanism of glutamine amidotransferases by these glutamine antagonists.

  • the liv i ls system as a determinant of Azaserine sensitivity of escherichia coli k 12
    Fems Microbiology Letters, 2004
    Co-Authors: Takashi Koyanagi, Takane Katayama, Hideyuki Suzuki, Hidehiko Kumagai

    Abstract:

    The growth of Escherichia coli is inhibited by an antibiotic compound, Azaserine (O-diazoacetyl-l-serine). Previous studies revealed the biochemical properties of Azaserine, which involves inhibition of various enzymatic reactions as well as introduction of DNA breakage. However, genetically, nothing has been elucidated except that all the Azaserine-resistant strains isolated so far carry lesions in the aroP gene as a primary determinant. Here, we demonstrate that, in addition to AroP, the LIV-I/LS system, an ATP-binding cassette type transporter, is involved in Azaserine sensitivity of E. coli, by genetic analysis and transport studies, in which Ki value for Azaserine was determined to be ∼10−3 M.