Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase.

Trapoxin (cyclo-(L-phenylalanyl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8- oxo-9,10-epoxy-decanoyl)) is a fungal product that induces morphological reversion from transformed to normal in sis-transformed NIH3T3 fibroblasts. Trapoxin was found to cause accumulation of highly acetylated core histones in a variety of mammalian cell lines. In vitro experiments using partially purified mouse histone deacetylase showed that a low concentration of trapoxin irreversibly inhibited deacetylation of acetylated histone molecules. Chemical reduction of an epoxide group in trapoxin completely abolished the inhibitory activity, suggesting that trapoxin binds covalently to the histone deacetylase via the epoxide. In contrast, inhibition by trichostatin A, a known potent inhibitor of histone deacetylase, was reversible. Despite the different mode of inhibition, trapoxin and trichostatin A induced almost the same biological effects on the cell cycle and differentiation. These results strongly suggest that the in vivo effects commonly induced by these agents can be attributed to histone hyperacetylation resulting from the inhibition of histone deacetylase.

• Publication year

  1993

• Venue

  Journal of Biological Chemistry

• Publication date

  1993-10-25

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/s0021-9258(18)41547-5PMID 8226751
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Trichostatin A inhibited histone deacetylase reversibly, yet produced nearly the same cell-cycle and differentiation effects as trapoxin.

  Confidence 0.93

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review
• Chemical reduction of the epoxide group completely abolished trapoxin's inhibitory activity, consistent with covalent binding to histone deacetylase through that moiety.

  Confidence 0.96

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review
• Low concentrations of trapoxin irreversibly inhibited deacetylation by partially purified mouse histone deacetylase.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review
• Trapoxin induced accumulation of highly acetylated core histones in multiple mammalian cell lines.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review

• core histones

  protein

  The nucleosomal histone proteins whose acetylation state was examined in treated mammalian cells.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review
• epoxide group

  chemical group

  The epoxide moiety within trapoxin that was chemically reduced in the structure-activity test.

  Aliases: epoxide

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review
• histone deacetylase

  enzyme

  The mammalian enzyme preparation that removes acetyl groups from histones in the in vitro assay.

  Aliases: HDAC

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review
• histone hyperacetylation

  molecular state

  A state of elevated acetylation of core histones measured in the treated cells.

  Aliases: highly acetylated core histones

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review
• trapoxin

  compound

  A fungal cyclic tetrapeptide studied here as an antitumor compound and histone deacetylase inhibitor.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review
• trichostatin a

  compound

  A known potent histone deacetylase inhibitor used as a comparator compound in the experiments.

  Aliases: TSA

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAK (4715169a40) reviewGahyoun (29ua5897xm) review

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