Disease relevance of NSC612237

• These assays further showed that borrelidin is a noncompetitive tight binding inhibitor of E. coli ThrRS with respect to threonine and ATP [1].
• Biosynthesis of the angiogenesis inhibitor borrelidin by Streptomyces parvulus Tü4055: insights into nitrile formation [2].
• Borrelidin also inhibited spontaneous lung metastasis of B16-BL6 melanoma at the same dose that inhibited angiogenesis [3].

High impact information on NSC612237

• Increased levels of threonyl-tRNA synthetase in a borrelidin-resistant Chinese hamster ovary cell line [4].
• Borrelidin-resistant clones have been isolated after ethyl methanesulfonate mutagenesis [4].
• Isolation of a cDNA clone for human threonyl-tRNA synthetase: amplification of the structural gene in borrelidin-resistant cell lines [5].
• A unique hydrophobic cluster near the active site contributes to differences in borrelidin inhibition among threonyl-tRNA synthetases [1].
• Insertional inactivation of two genes in the borrelidin gene cluster, borI (coding for a cytochrome P450 monooxygenase) and borJ (coding for an aminotransferase), generated borrelidin non-producing mutants [2].

Biological context of NSC612237

• Genetics of borrelidin resistant mutants of Saccharomyces cerivisiae and properties of their threonyl-tRNA-synthetase [6].
• Borrelidin remarkably disrupted capillary tubes in a dose-dependent manner, by inducing apoptosis of the tube-forming cells [7].
• In addition, borrelidin arrests both haploid and diploid cells in G1 phase at the point indistinguishable from that of alpha-mating pheromone, at concentrations not affecting the gross protein synthesis [8].
• A 50% inhibition concentration (IC50) of borrelidin for Cdc28/Cln2 was 24 microM [8].

Anatomical context of NSC612237

• We found that a high concentration of threonine (1 mM) attenuated the ability of borrelidin to inhibit both capillary tube formation in the rat aorta culture model and human umbilical vein endothelial cells (HUVEC) proliferation, yet did not affect the ability of borrelidin to collapse formed capillary tubes or to induce apoptosis in HUVEC [9].

Associations of NSC612237 with other chemical compounds

• Homoserine and threonine pools of borrelidin resistant Saccharomyces cerevisiae mutants with an altered aspartokinase [10].

Gene context of NSC612237

• In the first group borrelidin resistance is coupled to the gene HOM3 coding for aspartokinase, in the second group to the gene LEU1 [6].
• However the mutants of group three exhibit a structurally altered ThrRS, which is no longer inhibited by borrelidin [6].
• Borrelidin induces the transcription of amino acid biosynthetic enzymes via a GCN4-dependent pathway [11].
• Borrelidin inhibits a cyclin-dependent kinase (CDK), Cdc28/Cln2, of Saccharomyces cerevisiae [8].
• The activity of ThrRS from Sulfolobus solfataricus and Halobacterium sp. NRC-1 was inhibited by borrelidin, whereas ThrRS enzymes from Methanocaldococcus jannaschii and Archaeoglobus fulgidus were not [1].

Analytical, diagnostic and therapeutic context of NSC612237

• Sequence analysis indicates that the macrolide ring of borrelidin is formed by a modular polyketide synthase (PKS) (borA1-A6), a result that was confirmed by disruption of borA3 [12].
• By using a HPLC UV/Vis absorbance spectral library we could confirm that this compound was identical with the macrolide antibiotic borrelidin [13].

References