Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).

Protein ubiquitination plays an important role in the regulation of almost every aspect of eukaryotic cellular function; therefore, its destabilization is often observed in most human diseases and cancers. Consequently, developing inhibitors of the ubiquitination system for the treatment of cancer h...

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Autores principales:	Dana Ungermannova, Seth J Parker, Christopher G Nasveschuk, Wei Wang, Bettina Quade, Gan Zhang, Robert D Kuchta, Andrew J Phillips, Xuedong Liu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2a8a5c698f3449d8a82141713b9f224b
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spelling	oai:doaj.org-article:2a8a5c698f3449d8a82141713b9f224b2021-11-18T07:30:00ZLargazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).1932-620310.1371/journal.pone.0029208https://doaj.org/article/2a8a5c698f3449d8a82141713b9f224b2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22279528/?tool=EBIhttps://doaj.org/toc/1932-6203Protein ubiquitination plays an important role in the regulation of almost every aspect of eukaryotic cellular function; therefore, its destabilization is often observed in most human diseases and cancers. Consequently, developing inhibitors of the ubiquitination system for the treatment of cancer has been a recent area of interest. Currently, only a few classes of compounds have been discovered to inhibit the ubiquitin-activating enzyme (E1) and only one class is relatively selective in E1 inhibition in cells. We now report that Largazole and its ester and ketone analogs selectively inhibit ubiquitin conjugation to p27(Kip1) and TRF1 in vitro. The inhibitory activity of these small molecules on ubiquitin conjugation has been traced to their inhibition of the ubiquitin E1 enzyme. To further dissect the mechanism of E1 inhibition, we analyzed the effects of these inhibitors on each of the two steps of E1 activation. We show that Largazole and its derivatives specifically inhibit the adenylation step of the E1 reaction while having no effect on thioester bond formation between ubiquitin and E1. E1 inhibition appears to be specific to human E1 as Largazole ketone fails to inhibit the activation of Uba1p, a homolog of E1 in Schizosaccharomyces pombe. Moreover, Largazole analogs do not significantly inhibit SUMO E1. Thus, Largazole and select analogs are a novel class of ubiquitin E1 inhibitors and valuable tools for studying ubiquitination in vitro. This class of compounds could be further developed and potentially be a useful tool in cells.Dana UngermannovaSeth J ParkerChristopher G NasveschukWei WangBettina QuadeGan ZhangRobert D KuchtaAndrew J PhillipsXuedong LiuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e29208 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dana Ungermannova Seth J Parker Christopher G Nasveschuk Wei Wang Bettina Quade Gan Zhang Robert D Kuchta Andrew J Phillips Xuedong Liu Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
description	Protein ubiquitination plays an important role in the regulation of almost every aspect of eukaryotic cellular function; therefore, its destabilization is often observed in most human diseases and cancers. Consequently, developing inhibitors of the ubiquitination system for the treatment of cancer has been a recent area of interest. Currently, only a few classes of compounds have been discovered to inhibit the ubiquitin-activating enzyme (E1) and only one class is relatively selective in E1 inhibition in cells. We now report that Largazole and its ester and ketone analogs selectively inhibit ubiquitin conjugation to p27(Kip1) and TRF1 in vitro. The inhibitory activity of these small molecules on ubiquitin conjugation has been traced to their inhibition of the ubiquitin E1 enzyme. To further dissect the mechanism of E1 inhibition, we analyzed the effects of these inhibitors on each of the two steps of E1 activation. We show that Largazole and its derivatives specifically inhibit the adenylation step of the E1 reaction while having no effect on thioester bond formation between ubiquitin and E1. E1 inhibition appears to be specific to human E1 as Largazole ketone fails to inhibit the activation of Uba1p, a homolog of E1 in Schizosaccharomyces pombe. Moreover, Largazole analogs do not significantly inhibit SUMO E1. Thus, Largazole and select analogs are a novel class of ubiquitin E1 inhibitors and valuable tools for studying ubiquitination in vitro. This class of compounds could be further developed and potentially be a useful tool in cells.
format	article
author	Dana Ungermannova Seth J Parker Christopher G Nasveschuk Wei Wang Bettina Quade Gan Zhang Robert D Kuchta Andrew J Phillips Xuedong Liu
author_facet	Dana Ungermannova Seth J Parker Christopher G Nasveschuk Wei Wang Bettina Quade Gan Zhang Robert D Kuchta Andrew J Phillips Xuedong Liu
author_sort	Dana Ungermannova
title	Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
title_short	Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
title_full	Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
title_fullStr	Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
title_full_unstemmed	Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
title_sort	largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/2a8a5c698f3449d8a82141713b9f224b
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Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).

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