title: Activation of p300 histone acetyltransferase by small molecules altering enzyme structure: probed by surface-enhanced Raman spectroscopy.
abstract: Reversible acetylation of nucleosomal histones and nonhistone proteins play pivotal roles in the regulation of all the DNA templated phenomenon. Dysfunction of the enzymes involved in the acetylation/deacetylation leads to several diseases. Therefore, these enzymes are the targets for new generation therapeutics. Here, we report the synthesis of trifluoromethyl phenyl benzamides and their effect on histone acetyltransferase (HAT) activity of p300. One of these benzamides, CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), was discovered as a potent activator of the p300 HAT activity. We have found that pentadecyl hydrocarbon chain of CTPB is required to activate the HAT only under certain context. Furthermore, our results show that the relative position of -CF3 and -Cl in CTB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide) is also very critical for the activation. Surface-enhanced Raman spectroscopy (SERS) of p300 and the HAT activator complexes evidently suggest that the activation of HAT activity is achieved by the alteration of p300 structure. Therefore, apart from elucidating the chemical basis for small molecule mediated activation of p300, this report also describes, for the first time, Raman spectroscopic analysis of the complexes of histone-modifying enzymes and their modulators, which may be highly useful for therapeutic applications.
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore-64, India.
authors.forename: K
authors.initials: K
authors.lastname: Mantelingu
authors.forename: A Hari
authors.initials: AH
authors.lastname: Kishore
authors.forename: K
authors.initials: K
authors.lastname: Balasubramanyam
authors.forename: G V Pavan
authors.initials: GV
authors.lastname: Kumar
authors.forename: M
authors.initials: M
authors.lastname: Altaf
authors.forename: S Nanjunda
authors.initials: SN
authors.lastname: Swamy
authors.forename: Ruthrotha
authors.initials: R
authors.lastname: Selvi
authors.forename: Chandrima
authors.initials: C
authors.lastname: Das
authors.forename: Chandrabhas
authors.initials: C
authors.lastname: Narayana
authors.forename: K S
authors.initials: KS
authors.lastname: Rangappa
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
mesh_terms: D048729:Anacardic Acids / Q000737:chemistry; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry; D007700:Kinetics; D015394:Molecular Structure; D020156:Salicylic Acid / Q000737:chemistry; D013059:Spectrum Analysis, Raman; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D048729:Anacardic Acids; D001549:Benzamides; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D006838:Hydrocarbons; D020156:Salicylic Acid; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C475167:N-(4-chloro-3-trifluoromethylphenyl)-2-ethoxy-6-pentadecylbenzamide; C088115:anacardic acid