Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs

Kannan R. Karukurichi; Philip A. Cole

doi:10.1016/j.bioorg.2010.10.004

Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs

Kannan R. Karukurichi, Philip A. Cole

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biological pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a negatively charged surface on the enzyme to interact with the histone tail.

Original language	English (US)
Pages (from-to)	42-47
Number of pages	6
Journal	Bioorganic Chemistry
Volume	39
Issue number	1
DOIs	https://doi.org/10.1016/j.bioorg.2010.10.004
State	Published - Feb 2011
Externally published	Yes

Keywords

Acetyltransferase
Enzyme inhibition

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Drug Discovery
Organic Chemistry

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10.1016/j.bioorg.2010.10.004

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title = "Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs",

abstract = "Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biological pathways. This study investigates the proposed Theorell-Chance or {"}hit-and-run{"} catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a negatively charged surface on the enzyme to interact with the histone tail.",

keywords = "Acetyltransferase, Enzyme inhibition",

author = "Karukurichi, {Kannan R.} and Cole, {Philip A.}",

note = "Funding Information: We thank NIH for funding this study. Also, we thank Dr. Ling Wang for her assistance with the purification of p300 HAT and HAT assays.",

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AU - Karukurichi, Kannan R.

AU - Cole, Philip A.

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N2 - Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biological pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a negatively charged surface on the enzyme to interact with the histone tail.

AB - Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biological pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a negatively charged surface on the enzyme to interact with the histone tail.

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KW - Enzyme inhibition

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Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs

Abstract

Keywords

ASJC Scopus subject areas

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