Journal ArticleDOI
trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1.
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TLDR
It is shown that 2-PCPA is a time-dependent, mechanism-based irreversible inhibitor of LSD1 with a KI of 242 microM and a kinact of 0.0106 s-1, which will provide a foundation for the design of cyclopropylamine-based inhibitors that are selective for LSD1 to probe its role in vivo.Abstract:
The catalytic domain of the flavin-dependent human histone demethylase lysine-specific demethylase 1 (LSD1) belongs to the family of amine oxidases including polyamine oxidase and monoamine oxidase (MAO). We previously assessed monoamine oxidase inhibitors (MAOIs) for their ability to inhibit the reaction catalyzed by LSD1 [Lee, M. G., et al. (2006) Chem. Biol. 13, 563−567], demonstrating that trans-2-phenylcyclopropylamine (2-PCPA, tranylcypromine, Parnate) was the most potent with respect to LSD1. Here we show that 2-PCPA is a time-dependent, mechanism-based irreversible inhibitor of LSD1 with a KI of 242 μM and a kinact of 0.0106 s-1. 2-PCPA shows limited selectivity for human MAOs versus LSD1, with kinact/KI values only 16-fold and 2.4-fold higher for MAO B and MAO A, respectively. Profiles of LSD1 activity and inactivation by 2-PCPA as a function of pH are consistent with a mechanism of inactivation dependent upon enzyme catalysis. Mass spectrometry supports a role for FAD as the site of covalent mod...read more
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Journal ArticleDOI
Epigenetic protein families: a new frontier for drug discovery
Cheryl H. Arrowsmith,C. Bountra,Paul V. Fish,Kevin Lee,Kevin Lee,Matthieu Schapira,Matthieu Schapira +6 more
TL;DR: The key protein families that mediate epigenetic signalling through the acetylation and methylation of histones are reviewed, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones.
Journal ArticleDOI
The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation
Jing Wang,Sarah Hevi,Julia K. Kurash,Hong Lei,Jeffrey Bajko,Hui Su,Weitao Sun,Hua Chang,Guoliang Xu,François Gaudet,En Li,Taiping Chen +11 more
TL;DR: It is suggested that LSD1 demethylates and stabilizes Dnmt1, thus providing a previously unknown mechanistic link between the histone and DNA methylation systems.
Journal ArticleDOI
Reversal of Histone Methylation: Biochemical and Molecular Mechanisms of Histone Demethylases
Nima Mosammaparast,Yang Shi +1 more
TL;DR: The evidence strongly supports a key role for histone demethylases in eukaryotic transcription and other chromatin-dependent processes as well as their biochemistry, structure, and enzymology.
Journal ArticleDOI
Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers.
Shinya Hayami,John D. Kelly,Hyun-Soo Cho,Masanori Yoshimatsu,Motoko Unoki,Tatsuhiko Tsunoda,Helen I. Field,David E. Neal,Hiroki Yamaue,Bruce A.J. Ponder,Yusuke Nakamura,Ryuji Hamamoto,Ryuji Hamamoto +12 more
TL;DR: Investigation of exogenous LSD1 expression promoted cell cycle progression of human embryonic kidney fibroblast cells and showed that LSD1 could affect the expression of genes involved in various chromatin‐modifying pathways such as chromatin remodeling at centromere, centromeric heterochromatin formation and chromatin assembly, indicating its essential roles in carcinogenesis through chromatin modification.
Journal ArticleDOI
Histone lysine demethylases as targets for anticancer therapy
TL;DR: Key biological findings demonstrating the roles of members of the histone lysine demethylase class of enzymes in the development of cancers are highlighted, the potential and challenges of therapeutically targeting them are discussed, and emerging small-molecule inhibitors of these enzymes are highlighted.
References
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Journal ArticleDOI
The language of covalent histone modifications.
Brian D. Strahl,C D Allis +1 more
TL;DR: It is proposed that distinct histone modifications, on one or more tails, act sequentially or in combination to form a ‘histone code’ that is, read by other proteins to bring about distinct downstream events.
Journal ArticleDOI
Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process
TL;DR: The functional properties of the protein demonstrating that histone demethylation involves the flavin‐catalysed oxidation of the methylated lysine are addressed and the nature of the substrate that acts as the electron acceptor required to complete the catalytic cycle was investigated.
Journal ArticleDOI
Human Histone Demethylase LSD1 Reads the Histone Code
TL;DR: It is shown that LSD1 does not have a strong preference for mono- or dimethylated Lys4 of H3, and its ability to demethylate Lys4 in presence of a second modification on the same peptide substrate is probed.
Journal ArticleDOI
Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations A COMPARISON OF POLYAMINE OXIDASE AND MONOAMINE OXIDASE
Journal ArticleDOI
Mechanism of inactivation of monoamine oxidase by trans-2-phenylcyclopropylamine and the structure of the enzyme-inactivator adduct.
TL;DR: A mechanism of inactivation of monoamine oxidase by 2-phenylcyclopropylamine and the structure of the enzyme-inactivator adduct are proposed.
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