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Chemical Compound Review

HC-Toxin     (3S,6R,9S,12R)-6,9-dimethyl- 3-[6-(oxiran-2...

Synonyms: CHEBI:48028, AC1L32W5, 83209-65-8, Cyclo(aoe-pro-ala-ala)
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Disease relevance of HC-Toxin


High impact information on HC-Toxin

  • A gene, HDC1, related to the Saccharomyces cerevisiae histone deacetylase (HDAC) gene HOS2, was isolated from the filamentous fungus Cochliobolus carbonum, a pathogen of maize that makes the HDAC inhibitor HC-toxin [3].
  • An ortholog of SNF1, ccSNF1, was isolated from the maize pathogen Cochliobolus carbonum, and ccsnf1 mutants of HC toxin-producing (Tox2(+)) and HC toxin-nonproducing (Tox2(-)) strains were created by targeted gene replacement [4].
  • Race 1 isolates of the filamentous fungus Cochliobolus carbonum are exceptionally virulent on certain genotypes of maize due to production of a cyclic tetrapeptide, HC-toxin [5].
  • Two other genes known or thought to be important for HC-toxin biosynthesis, TOXA and TOXC, are also on the same chromosome in multiple copies [5].
  • HDs from chicken and the myxomycete Physarum polycephalum were also inhibited, indicating that the host selectivity of HC toxin is not determined by its inhibitory effect on HD [6].

Biological context of HC-Toxin

  • In vivo treatment of embryos with HC toxin caused the accumulation of highly acetylated histone H4 subspecies and elevated acetate incorporation into H4 in susceptible-genotype embryos but not in the resistant genotype [6].
  • Consistent with these results, we propose a model in which HC toxin promotes the establishment of pathogenic compatibility between C. carbonum and maize by interfering with reversible histone acetylation, which is implicated in the control of fundamental cellular processes, such as chromatin structure, cell cycle progression, and gene expression [6].
  • TOXE plays a specific regulatory role in HC-toxin production and, therefore, pathogenicity by C. carbonum [7].
  • Disruption of both copies at either site resulted in loss of ability to produce HC-toxin and loss of host-selective pathogenicity, but the mutants displayed different biochemical phenotypes depending on the site of disruption [8].
  • The cyclic peptide synthetase catalyzing HC-toxin production in the filamentous fungus Cochliobolus carbonum is encoded by a 15.7-kilobase open reading frame [9].

Anatomical context of HC-Toxin


Associations of HC-Toxin with other chemical compounds

  • The maize Hm1 gene encoding the NADPH-dependent HC-toxin reductase is capable of detoxifying HC-toxin of fungus Cochliobolus carbonum [11].
  • A high molecular weight complex (430,000) is sensitive to HC-toxin and trichostatin A and shows immunoreactivity with an antibody against Cochliobolus HDC2, an enzyme homologous to yeast RPD3 [12].
  • The antimitogenic activities of HC-toxin chloromethyl ketone (IC50 = 30-40 ng/mL) and chlamydocin chloromethyl ketone (IC50 = 3-10 ng/mL) were found to be 3-4-fold lower than those of the natural products themselves [13].
  • PCR products representing CPS genes from Diheterospora chlamydosporia, which makes the HC-toxin analog chlamydocin, Cylindrocladium macrosporum, which makes the analog Cyl-2, and C. victoriae, which makes the unrelated cyclic pentapeptide victorin, were cloned and analysed [14].

Gene context of HC-Toxin

  • In vivo treatment of meristematic tissue with the deacetylase inhibitor HC toxin does not affect the expression of the three maize histone deacetylases, whereas it causes downregulation of histone acetyltransferase B [15].
  • In MCF-7 cells that contain high level estrogen receptor, trichostatin A and HC-toxin brought about three-times more potent cell growth inhibitory effect than estrogen receptor negative MDA-MB-468 cells [16].
  • When fractionated by anion-exchange chromatography, extracts of resistant and sensitive isolates and species had two peaks of HDAC activity, one that was fully HC-toxin resistant and a second that was larger and sensitive [17].
  • The DNA sequence encodes tryptic peptides derived from two HC-toxin biosynthetic enzymes, HC-toxin synthetase 1 (HTS-1) and HC-toxin synthetase 2 (HTS-2), indicating that these two enzymes exist in vivo as part of a single polypeptide [9].
  • It is concluded that TOXG encodes an alanine racemase whose function is to synthesize D-Ala for incorporation into HC-toxin [18].

Analytical, diagnostic and therapeutic context of HC-Toxin


  1. Expression of 15-lipoxygenase-1 is regulated by histone acetylation in human colorectal carcinoma. Kamitani, H., Taniura, S., Ikawa, H., Watanabe, T., Kelavkar, U.P., Eling, T.E. Carcinogenesis (2001) [Pubmed]
  2. Antiproliferative effect of trichostatin A and HC-toxin in T47D human breast cancer cells. Joung, K.E., Kim, D.K., Sheen, Y.Y. Arch. Pharm. Res. (2004) [Pubmed]
  3. A gene related to yeast HOS2 histone deacetylase affects extracellular depolymerase expression and virulence in a plant pathogenic fungus. Baidyaroy, D., Brosch, G., Ahn, J.H., Graessle, S., Wegener, S., Tonukari, N.J., Caballero, O., Loidl, P., Walton, J.D. Plant Cell (2001) [Pubmed]
  4. The Cochliobolus carbonum SNF1 gene is required for cell wall-degrading enzyme expression and virulence on maize. Tonukari, N.J., Scott-Craig, J.S., Walton, J.D. Plant Cell (2000) [Pubmed]
  5. Chromosomal organization of TOX2, a complex locus controlling host-selective toxin biosynthesis in Cochliobolus carbonum. Ahn, J.H., Walton, J.D. Plant Cell (1996) [Pubmed]
  6. Inhibition of maize histone deacetylases by HC toxin, the host-selective toxin of Cochliobolus carbonum. Brosch, G., Ransom, R., Lechner, T., Walton, J.D., Loidl, P. Plant Cell (1995) [Pubmed]
  7. Regulation of cyclic peptide biosynthesis in a plant pathogenic fungus by a novel transcription factor. Pedley, K.F., Walton, J.D. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  8. A cyclic peptide synthetase gene required for pathogenicity of the fungus Cochliobolus carbonum on maize. Panaccione, D.G., Scott-Craig, J.S., Pocard, J.A., Walton, J.D. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  9. The cyclic peptide synthetase catalyzing HC-toxin production in the filamentous fungus Cochliobolus carbonum is encoded by a 15.7-kilobase open reading frame. Scott-Craig, J.S., Panaccione, D.G., Pocard, J.A., Walton, J.D. J. Biol. Chem. (1992) [Pubmed]
  10. Histone deacetylase inhibitor FK228 is a potent inducer of human fetal hemoglobin. Cao, H., Stamatoyannopoulos, G. Am. J. Hematol. (2006) [Pubmed]
  11. Enhanced dihydroflavonol-4-reductase activity and NAD homeostasis leading to cell death tolerance in transgenic rice. Hayashi, M., Takahashi, H., Tamura, K., Huang, J., Yu, L.H., Kawai-Yamada, M., Tezuka, T., Uchimiya, H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. An inhibitor-resistant histone deacetylase in the plant pathogenic fungus Cochliobolus carbonum. Brosch, G., Dangl, M., Graessle, S., Loidl, A., Trojer, P., Brandtner, E.M., Mair, K., Walton, J.D., Baidyaroy, D., Loidl, P. Biochemistry (2001) [Pubmed]
  13. Analogues of the cytostatic and antimitogenic agents chlamydocin and HC-toxin: synthesis and biological activity of chloromethyl ketone and diazomethyl ketone functionalized cyclic tetrapeptides. Shute, R.E., Dunlap, B., Rich, D.H. J. Med. Chem. (1987) [Pubmed]
  14. Identification of peptide synthetase-encoding genes from filamentous fungi producing host-selective phytotoxins or analogs. Nikolskaya, A.N., Panaccione, D.G., Walton, J.D. Gene (1995) [Pubmed]
  15. RPD3-type histone deacetylases in maize embryos. Lechner, T., Lusser, A., Pipal, A., Brosch, G., Loidl, A., Goralik-Schramel, M., Sendra, R., Wegener, S., Walton, J.D., Loidl, P. Biochemistry (2000) [Pubmed]
  16. Estrogen receptor enhances the antiproliferative effects of trichostatin A and HC-toxin in human breast cancer cells. Min, K.N., Cho, M.J., Kim, D.K., Sheen, Y.Y. Arch. Pharm. Res. (2004) [Pubmed]
  17. Characterization of inhibitor-resistant histone deacetylase activity in plant-pathogenic fungi. Baidyaroy, D., Brosch, G., Graessle, S., Trojer, P., Walton, J.D. Eukaryotic Cell (2002) [Pubmed]
  18. A eukaryotic alanine racemase gene involved in cyclic peptide biosynthesis. Cheng, Y.Q., Walton, J.D. J. Biol. Chem. (2000) [Pubmed]
  19. An extended physical map of the TOX2 locus of Cochliobolus carbonum required for biosynthesis of HC-toxin. Ahn, J.H., Cheng, Y.Q., Walton, J.D. Fungal Genet. Biol. (2002) [Pubmed]
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