OleD Loki as a Catalyst for Hydroxamate Glycosylation

Ryan R. Hughes; Khaled A. Shaaban; Larissa V. Ponomareva; Jamie Horn; Chunhui Zhang; Chang Guo Zhan; S. Randal Voss; Markos Leggas; Jon S. Thorson

doi:10.1002/cbic.201900601

OleD Loki as a Catalyst for Hydroxamate Glycosylation

Ryan R. Hughes, Khaled A. Shaaban, Larissa V. Ponomareva, Jamie Horn, Chunhui Zhang, Chang Guo Zhan, S. Randal Voss, Markos Leggas, Jon S. Thorson

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

5 Scopus citations

Abstract

Herein we describe the ability of the permissive glycosyltransferase (GT) OleD Loki to convert a diverse set of >15 histone deacetylase (HDAC) inhibitors (HDACis) into their corresponding hydroxamate glycosyl esters. Representative glycosyl esters were subsequently evaluated in assays for cancer cell line cytotoxicity, chemical and enzymatic stability, and axolotl embryo tail regeneration. Computational substrate docking models were predictive of enzyme-catalyzed turnover and suggest certain HDACis may form unproductive, potentially inhibitory, complexes with GTs.

Original language	English
Pages (from-to)	952-957
Number of pages	6
Journal	ChemBioChem
Volume	21
Issue number	7
DOIs	https://doi.org/10.1002/cbic.201900601
State	Published - Apr 1 2020

Bibliographical note

Funding Information:
This work was supported in part by US National Institutes of Health (NIH) grants R37 AI52218 (J.S.T.) and R24 OD21479 (S.R.V. and J.S.T.), the National Center for Advancing Translational Sciences (UL1 TR000117 and UL1 TR001998), and the University of Kentucky College of Pharmacy. We thank the College of Pharmacy NMR Center (University of Kentucky) for NMR support.

Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

HDAC
glucosylation
glycosyltransferase
histone deacetylase

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/cbic.201900601

Cite this

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title = "OleD Loki as a Catalyst for Hydroxamate Glycosylation",

abstract = "Herein we describe the ability of the permissive glycosyltransferase (GT) OleD Loki to convert a diverse set of >15 histone deacetylase (HDAC) inhibitors (HDACis) into their corresponding hydroxamate glycosyl esters. Representative glycosyl esters were subsequently evaluated in assays for cancer cell line cytotoxicity, chemical and enzymatic stability, and axolotl embryo tail regeneration. Computational substrate docking models were predictive of enzyme-catalyzed turnover and suggest certain HDACis may form unproductive, potentially inhibitory, complexes with GTs.",

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note = "Funding Information: This work was supported in part by US National Institutes of Health (NIH) grants R37 AI52218 (J.S.T.) and R24 OD21479 (S.R.V. and J.S.T.), the National Center for Advancing Translational Sciences (UL1 TR000117 and UL1 TR001998), and the University of Kentucky College of Pharmacy. We thank the College of Pharmacy NMR Center (University of Kentucky) for NMR support. Publisher Copyright: {\textcopyright} 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

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doi = "10.1002/cbic.201900601",

language = "English",

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T1 - OleD Loki as a Catalyst for Hydroxamate Glycosylation

AU - Hughes, Ryan R.

AU - Shaaban, Khaled A.

AU - Ponomareva, Larissa V.

AU - Horn, Jamie

AU - Zhang, Chunhui

AU - Zhan, Chang Guo

AU - Voss, S. Randal

AU - Leggas, Markos

AU - Thorson, Jon S.

N1 - Funding Information: This work was supported in part by US National Institutes of Health (NIH) grants R37 AI52218 (J.S.T.) and R24 OD21479 (S.R.V. and J.S.T.), the National Center for Advancing Translational Sciences (UL1 TR000117 and UL1 TR001998), and the University of Kentucky College of Pharmacy. We thank the College of Pharmacy NMR Center (University of Kentucky) for NMR support. Publisher Copyright: © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Herein we describe the ability of the permissive glycosyltransferase (GT) OleD Loki to convert a diverse set of >15 histone deacetylase (HDAC) inhibitors (HDACis) into their corresponding hydroxamate glycosyl esters. Representative glycosyl esters were subsequently evaluated in assays for cancer cell line cytotoxicity, chemical and enzymatic stability, and axolotl embryo tail regeneration. Computational substrate docking models were predictive of enzyme-catalyzed turnover and suggest certain HDACis may form unproductive, potentially inhibitory, complexes with GTs.

AB - Herein we describe the ability of the permissive glycosyltransferase (GT) OleD Loki to convert a diverse set of >15 histone deacetylase (HDAC) inhibitors (HDACis) into their corresponding hydroxamate glycosyl esters. Representative glycosyl esters were subsequently evaluated in assays for cancer cell line cytotoxicity, chemical and enzymatic stability, and axolotl embryo tail regeneration. Computational substrate docking models were predictive of enzyme-catalyzed turnover and suggest certain HDACis may form unproductive, potentially inhibitory, complexes with GTs.

KW - HDAC

KW - glucosylation

KW - glycosyltransferase

KW - histone deacetylase

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JO - ChemBioChem

JF - ChemBioChem

IS - 7

ER -

OleD Loki as a Catalyst for Hydroxamate Glycosylation

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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