S-(5'-Deoxy-5'-adenosyl)-1-aminoxy-4-(methylsulfonio)-2-cyclopentene (AdoMao): An Irreversible Inhibitor of S-Adenosylmethionine Decarboxylase with Potent in Vitro Antitrypanosomal Activity

Guo, Junqing; Wu, Yong; Rattendi, Donna; Bacchi, Cyrus J.; Woster, Patrick M.

doi:10.1021/jm00010a021

Cited by 28 publications

(19 citation statements)

References 14 publications

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“…the 2-pyrimidinone ring is positioned as the "flipped-out" target base and the methylsulfonium-adenosyl part is positioned as methylsulfonium-adenosyl parts of AdoMet. Interestingly, presented inhibitor is somewhat structurally similar to earlier described inhibitors of AdoMet decarboxylase [84][85][86].…”

Section: Novel Mechanism-based Inhibitors Can Mimic Accumulation Of Esupporting

confidence: 67%

Mammalian Cytosine DNA Methyltransferase Dnmt1: Enzymatic Mechanism, Novel Mechanism-Based Inhibitors, and RNA-directed DNA Methylation

Svedružić¹

2008

CMC

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This is a review of the enzymatic mechanism of DNA methyltransferase Dnmt1 and analysis of its implications on regulation of DNA methylation in mammalian cells and design of novel mechanism-based inhibitors. The methylation reaction by Dnmt1 has different phases that depend on DNA substrate and allosteric regulation. Consequently, depending on the phase, the differences in catalytic rates between unmethylated and pre-methylated DNA can vary between 30-40 fold, 3-6 fold or only 1 fold. The allosteric site and the active site can bind different molecules. Allosteric activity depends on DNA sequence, methylation pattern and DNA structure (single stranded vs. double stranded). Dnmt1 binds poly(ADP-ribose) and some RNA molecules. The results on kinetic preferences, allosteric activity and binding preference of Dnmt1 are combined together in one comprehensive model mechanism that can address regulation of DNA methylation in cells; namely, inhibition of DNA methylation by poly(ADP-ribose), RNA-directed DNA methylation by methylated and unmethylated non-coding RNA molecules, and transient interactions between Dnmt1 and genomic DNA. Analysis of reaction intermediates showed that equilibrium between base-flipping and base-restacking events can be the key mechanism in control of enzymatic activity. The two events have equal but opposite effect on accumulation of early reaction intermediates and methylation rates. The accumulation of early reaction intermediates can be exploited to improve the current inhibitors of Dnmt1 and achieve inhibition without toxic modifications in genomic DNA. [1,2-dihydropyrimidin-2-one]-5-methylene-(methylsulfonium)-adenosyl is described as the lead compound. Cell differentiation [1], oncogenic transformation [2], viral infection [3], and long term memory [4] are some of many physiological processes that have created a large interest in DNA methylation. DNA methylation is one of the first steps in epigenetic regulation [5]. Epigenetic regulation is a sequence of molecular events that controls chromatin structure and supports functional organization of eukaryotic genome through cell divisions [6]. DNA methylation is attractive as a fundamental mechanism in functional organization of the human genome, and also as a promising target in development of new drugs for cancer chemotherapy [7,8], suppression of viral infections [3] and possibly mental illness [9]. DNA methylation in mammalian cells is usually associated with five methyltransferases: Dnmt1, Dnmt2, Dnmt3a, Dnmt3b and Dnmt3L. This manuscript will cover Dnmt1, the most predominant DNA methyltransferase in the mammalian cells, and the major target of the current pharmaceutical interest.Dnmt1 is crucial for keeping genomic integrity in higher eukaryotes [6] by preserving existing methylation patterns or by participating in the creation of new methylation patterns. The molecular mechanism that guides these two types of DNA methylation events represent the two most basic questions in DNA methylation research: how new methylation sites are created...

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Section: Novel Mechanism-based Inhibitors Can Mimic Accumulation Of Esupporting

confidence: 67%

Mammalian Cytosine DNA Methyltransferase Dnmt1: Enzymatic Mechanism, Novel Mechanism-Based Inhibitors, and RNA-directed DNA Methylation

Svedružić¹

2008

CMC

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“…The AdoMet analogue AdoMao [ S -(5′-deoxy-5′-adenosyl)-1-aminoxy-4-(methylsulfonio)-2-cyclopentene] inhibits AdoMetDC irreversibly [38]. Of several diastereomeric forms synthesized, trans -1 S ,4 S -AdoMao proved to be the most promising in all respects.…”

Section: African Sleeping Sicknessmentioning

confidence: 99%

Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities

Birkholtz

Williams

Niemand

et al. 2011

Biochemical Journal

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New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (Sadenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies.

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“…The trans-1S,4S isomer of 19 ( Fig. 8) is an irreversible inactivator of mammalian and bacterial Sadenosylmethionine decarboxylase (AdoMet-DC), and also acts as a trypanocide with an IC 50 of 0.9 mM [76]. Another inhibitor of AdoMet-DC, AbeAdo 20, was a substrate for the P2 transporter in T. b. rhodesiense, exhibited a nanomolar IC 50 value [77] and was curative for T. b. rhodesiense infections in mice [36,78,79].…”

Section: Progress In Drug Research For Hat Chagas' Disease and Leishmentioning

confidence: 99%

Antiprotozoal/Antiparasitic Agents

Woster

2010

Burger's Medicinal Chemistry and Drug Discovery

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Collectively, diseases caused by parasitic protozoa, including human African trypanosomiasis ( HAT ), Chagas' disease and leishmaniasis, threaten more than 550 million people worldwide and cause nearly 150,000 deaths annually. The causative organisms for these diseases are unicellular trypanosomatid parasites of the genera Trypanosoma brucei , Trypanosoma cruzi , and Leishmania sp., respectively. Drug therapies available for these diseases have not changed significantly in the past 50 years, and currently used agents are far less than satisfactory due to extreme toxicity, and because resistant parasitic strains are becoming more prevalent. These diseases are confined to impoverished or rural areas of Mexico, Central America, South America, sub‐Saharan Africa, the Middle East, Indonesia, and India. As such, drug discovery efforts against trypanosomatid diseases are limited because patients in underdeveloped areas cannot afford therapy, and because the infected population is too small to justify the required research expenditures. In addition, antiparasitic research in Third World nations is often hampered by economic issues and political turmoil, virtually assuring that the world's most impoverished people will continue to bear the major burden of parasitic disease. Clearly, there is a need for new anti‐infective agents that are potent, nontoxic and inexpensive to manufacture. In this chapter, the etiology of these diseases and their current treatment are described. The chapter also deals with medicinal chemistry aspects of efforts to identify new drug targets for parasitic diseases, and to produce novel inhibitors of trypanosomatid growth for use as antiparasitic agents.

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S-(5'-Deoxy-5'-adenosyl)-1-aminoxy-4-(methylsulfonio)-2-cyclopentene (AdoMao): An Irreversible Inhibitor of S-Adenosylmethionine Decarboxylase with Potent in Vitro Antitrypanosomal Activity

Cited by 28 publications

References 14 publications

Mammalian Cytosine DNA Methyltransferase Dnmt1: Enzymatic Mechanism, Novel Mechanism-Based Inhibitors, and RNA-directed DNA Methylation

Mammalian Cytosine DNA Methyltransferase Dnmt1: Enzymatic Mechanism, Novel Mechanism-Based Inhibitors, and RNA-directed DNA Methylation

Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities

Antiprotozoal/Antiparasitic Agents

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