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Dawn M. Z. Schmidt

Bio: Dawn M. Z. Schmidt is an academic researcher from University of Illinois at Urbana–Champaign. The author has contributed to research in topics: Enolase superfamily & Monoamine oxidase. The author has an hindex of 11, co-authored 17 publications receiving 1232 citations. Previous affiliations of Dawn M. Z. Schmidt include University of Pennsylvania & Duke University.

Papers
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Journal ArticleDOI
TL;DR: Treatment of P19 embryonal carcinoma cells with tranylcypromine resulted in global increase in H3K4 methylation as well as transcriptional derepression of two BHC110 target genes, Egr1 and the pluripotent stem cell marker Oct4, attest to the effectiveness of tranyl Cypromine as a small molecular inhibitor of histone demethylation.

422 citations

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TL;DR: 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...

307 citations

Journal ArticleDOI
TL;DR: Single-site mutants of the (β/α)8-barrel domains in both the l-Ala-d/l-Glu epimerase from Escherichia coli (AEE) and the muconate lactonizing enzyme II from Pseudomonas sp.
Abstract: The members of the mechanistically diverse, (β/α)8-barrel fold-containing enolase superfamily evolved from a common progenitor but catalyze different reactions using a conserved partial reaction. The molecular pathway for natural divergent evolution of function in the superfamily is unknown. We have identified single-site mutants of the (β/α)8-barrel domains in both the l-Ala-d/l-Glu epimerase from Escherichia coli (AEE) and the muconate lactonizing enzyme II from Pseudomonas sp. P51 (MLE II) that catalyze the o-succinylbenzoate synthase (OSBS) reaction as well as the wild-type reaction. These enzymes are members of the MLE subgroup of the superfamily, share conserved lysines on opposite sides of their active sites, but catalyze acid- and base-mediated reactions with different mechanisms. A comparison of the structures of AEE and the OSBS from E. coli was used to design the D297G mutant of AEE; the E323G mutant of MLE II was isolated from directed evolution experiments. Although neither wild-type enzyme c...

170 citations

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TL;DR: A facile synthetic route to substituted trans-2-arylcyclopropylamines was developed to provide access to mechanism-based inhibitors of the human flavoenzyme oxidase lysine-specific histone demethylase LSD1 and related enzyme family members such as monoamine oxidases A and B.

112 citations

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TL;DR: YcjG from Escherichia coli and YkfB from Bacillus subtilis, proteins of previously unknown function, were discovered to be L-Ala-D/L-Glu epimerases, although they also catalyze the epimerization of other dipeptides.
Abstract: The members of the mechanistically diverse enolase superfamily catalyze different overall reactions by using a common catalytic strategy and structural scaffold. In the muconate lactonizing enzyme (MLE) subgroup of the superfamily, abstraction of a proton adjacent to a carboxylate group initiates reactions, including cycloisomerization (MLE), dehydration [o-succinylbenzoate synthase (OSBS)], and 1,1-proton transfer (catalyzed by an OSBS that also catalyzes a promiscuous N-acylamino acid racemase reaction). The realization that a member of the MLE subgroup could catalyze a 1,1-proton transfer reaction, albeit poorly, led to a search for other enzymes which might catalyze a 1,1-proton transfer as their physiological reaction. YcjG from Escherichia coli and YkfB from Bacillus subtilis, proteins of previously unknown function, were discovered to be l-Ala-d/l-Glu epimerases, although they also catalyze the epimerization of other dipeptides. The values of kcat/KM for l-Ala-d/l-Glu for both proteins are ∼104 M-1...

84 citations


Cited by
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TL;DR: This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.
Abstract: Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.

1,303 citations

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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.
Abstract: Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein-protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins.

1,184 citations

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TL;DR: The hypothesis that promiscuous enzymatic activities serve as evolutionary starting points and highlight the unique evolutionary features ofpromiscuous enzyme functions are addressed.
Abstract: Many, if not most, enzymes can promiscuously catalyze reactions, or act on substrates, other than those for which they evolved. Here, we discuss the structural, mechanistic, and evolutionary implications of this manifestation of infidelity of molecular recognition. We define promiscuity and related phenomena and also address their generality and physiological implications. We discuss the mechanistic enzymology of promiscuity—how enzymes, which generally exert exquisite specificity, catalyze other, and sometimes barely related, reactions. Finally, we address the hypothesis that promiscuous enzymatic activities serve as evolutionary starting points and highlight the unique evolutionary features of promiscuous enzyme functions.

1,153 citations

Journal ArticleDOI
TL;DR: The discovery of mutations in the epigenetic machinery and the approval of the first epigenetic drugs for the treatment of subtypes of leukemias and lymphomas has been an eye-opener for many biomedical scientists and clinicians.
Abstract: Epigenetics is one of the most promising and expanding fields in the current biomedical research landscape. Since the inception of epigenetics in the 1940s, the discoveries regarding its implications in normal and disease biology have not stopped, compiling a vast amount of knowledge in the past decade. The field has moved from just one recognized marker, DNA methylation, to a variety of others, including a wide spectrum of histone modifications. From the methodological standpoint, the successful initial single gene candidate approaches have been complemented by the current comprehensive epigenomic approaches that allow the interrogation of genomes to search for translational applications in an unbiased manner. Most important, the discovery of mutations in the epigenetic machinery and the approval of the first epigenetic drugs for the treatment of subtypes of leukemias and lymphomas has been an eye-opener for many biomedical scientists and clinicians. Herein, we will summarize the progress in the field of cancer epigenetics research that has reached mainstream oncology in the development of new biomarkers of the disease and new pharmacological strategies.

1,151 citations

Journal ArticleDOI
TL;DR: The enzymatic and structural basis for the mechanisms that these enzymes use to counteract histone methylation are examined and insights into their substrate specificity and biological function are provided.
Abstract: Histone methylation has important roles in regulating transcription, genome integrity and epigenetic inheritance. Historically, methylated histone arginine and lysine residues have been considered static modifications because of the low levels of methyl-group turnover in chromatin. The recent identification of enzymes that antagonize or remove histone methylation has changed this view and now the dynamic nature of these modifications is being appreciated. Here, we examine the enzymatic and structural basis for the mechanisms that these enzymes use to counteract histone methylation and provide insights into their substrate specificity and biological function.

838 citations