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1.
Eur J Med Chem ; 201: 112557, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32563813

RESUMO

The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific antiviral inhibitors and/or vaccines to fight these massive outbreaks is an urgent research priority. Enzymes involved in the capping pathway of viruses and more specifically RNA N7- or 2'O-methyltransferases (MTases) are now admitted as potential targets for antiviral chemotherapy. We designed bisubstrate inhibitors by mimicking the transition state of the 2'-O-methylation of the cap RNA in order to block viral 2'-O MTases. This work resulted in the synthesis of 16 adenine dinucleosides with both adenosines connected by various nitrogen-containing linkers. Unexpectedly, all the bisubstrate compounds were barely active against 2'-O MTases of several flaviviruses or SARS-CoV but surprisingly, seven of them showed efficient and specific inhibition against SARS-CoV N7-MTase (nsp14) in the micromolar to submicromolar range. The most active nsp14 inhibitor identified is as potent as but particularly more specific than the broad-spectrum MTase inhibitor, sinefungin. Molecular docking suggests that the inhibitor binds to a pocket formed by the S-adenosyl methionine (SAM) and cap RNA binding sites, conserved among SARS-CoV nsp14. These dinucleoside SAM analogs will serve as starting points for the development of next inhibitors for SARS-CoV-2 nsp14 N7-MTase.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Exorribonucleases/antagonistas & inibidores , Metiltransferases/antagonistas & inibidores , Nucleosídeos/química , Pneumonia Viral/tratamento farmacológico , Capuzes de RNA/metabolismo , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Adenina/química , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Exorribonucleases/metabolismo , Humanos , Metilação , Metiltransferases/metabolismo , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Capuzes de RNA/química , Capuzes de RNA/genética , RNA Viral/genética , RNA Viral/metabolismo , Proteínas não Estruturais Virais/metabolismo
2.
Chem Commun (Camb) ; 56(22): 3317-3320, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32077874

RESUMO

In this work, the preparation of new S-adenosyl-l-methionine (SAM) analogues for sequence specific DNA labeling is evaluated. These non-natural analogues, comprising cysteine rather than the natural homolog, were obtained in near quantitative conversions from readily available starting materials without relying on using an excess amount of labor intensive molecules. The synthetic strategy was used to generate fluorescent cofactors, with colours spanning the whole visible spectrum, and their applicability in methyltransferase based optical mapping is shown.


Assuntos
DNA/metabolismo , Metiltransferases/metabolismo , S-Adenosilmetionina/metabolismo , DNA/química , Corantes Fluorescentes/química , Plasmídeos/genética , Plasmídeos/metabolismo , S-Adenosilmetionina/análogos & derivados
3.
Chem Commun (Camb) ; 56(14): 2115-2118, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-31970375

RESUMO

Methyltransferases (MTases) modify a wide range of biomolecules using S-adenosyl-l-methionine (AdoMet) as the cosubstrate. Synthetic AdoMet analogues are powerful tools to site-specifically introduce a variety of functional groups and exhibit potential to be converted only by distinct MTases. Extending the size of the substituent at the sulfur/selenium atom provides selectivity among MTases but is insufficient to discriminate between promiscuous MTases. We present a panel of AdoMet analogues differing in the nucleoside moiety (NM-AdoMets). These NM-AdoMets were efficiently produced by a previously uncharacterized methionine adenosyltransferase (MAT) from methionine and ATP analogues, such as ITP and N6-propargyl-ATP. The N6-modification changed the relative activity of three representative MTases up to 13-fold resulting in discrimination of substrates for the methyl transfer and could also be combined with transfer of allyl and propargyl groups.


Assuntos
Metiltransferases/metabolismo , Nucleosídeos/metabolismo , S-Adenosilmetionina/metabolismo , Estrutura Molecular , Nucleosídeos/química , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/química
4.
Methods ; 156: 46-52, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30827466

RESUMO

Over 150 unique RNA modifications are now known including several nonstandard nucleotides present in the body of messenger RNAs. These modifications can alter a transcript's function and are collectively referred to as the epitrancriptome. Chemically modified nucleoside analogs are poised to play an important role in the study of these epitranscriptomic marks. Introduced chemical features on nucleic acid strands provide unique structures or reactivity that can be used for downstream detection or quantification. Three methods are used in the field to synthesize RNA containing chemically modified nucleoside analogs. Nucleoside analogs can be introduced by metabolic labeling, via polymerases with modified nucleotide triphosphates or via phosphoramidite-based chemical synthesis. In this review, these methods for incorporation of nucleoside analogs will be discussed with specific recently published examples pertaining to the study of the epitranscriptome.


Assuntos
Edição de RNA , RNA de Cadeia Dupla/química , Ribonucleotídeos/química , S-Adenosilmetionina/metabolismo , Coloração e Rotulagem/métodos , Transcriptoma , Adenosina/análogos & derivados , Adenosina/química , Adenosina/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Animais , Humanos , Inosina/metabolismo , Conformação de Ácido Nucleico , Compostos Organofosforados/química , Compostos Organofosforados/metabolismo , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/metabolismo , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ribonucleotídeos/metabolismo , S-Adenosilmetionina/análogos & derivados , Selênio/química , Selênio/metabolismo
5.
Int J Mol Sci ; 20(5)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871110

RESUMO

We first demonstrated that long-term increased polyamine (spermine, spermidine, putrescine) intake elevated blood spermine levels in mice and humans, and lifelong consumption of polyamine-rich chow inhibited aging-associated increase in aberrant DNA methylation, inhibited aging-associated pathological changes, and extend lifespan of mouse. Because gene methylation status is closely associated with aging-associated conditions and polyamine metabolism is closely associated with regulation of gene methylation, we investigated the effects of extracellular spermine supplementation on substrate concentrations and enzyme activities involved in gene methylation. Jurkat cells and human mammary epithelial cells were cultured with spermine and/or D,L-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase. Spermine supplementation inhibited enzymatic activities of adenosylmethionine decarboxylase in both cells. The ratio of decarboxylated S-adenosylmethionine to S-adenosyl-L-methionine increased by DFMO and decreased by spermine. In Jurkat cells cultured with DFMO, the protein levels of DNA methyltransferases (DNMTs) 1, 3A and 3B were not changed, however the activity of the three enzymes markedly decreased. The protein levels of these enzymes were not changed by addition of spermine, DNMT 3A and especially 3B were activated. We show that changes in polyamine metabolism dramatically affect substrate concentrations and activities of enzymes involved in gene methylation.


Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Espermina/metabolismo , Adenosilmetionina Descarboxilase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Metilação de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Eflornitina/metabolismo , Células Epiteliais/metabolismo , Humanos , Células Jurkat , Glândulas Mamárias Humanas/metabolismo , Ornitina Descarboxilase/metabolismo , Poliaminas/metabolismo , Putrescina/metabolismo , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Espermidina/metabolismo
7.
Biochemistry ; 58(6): 665-678, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30525512

RESUMO

Nonribosomal peptide synthetases use tailoring domains to incorporate chemical diversity into the final natural product. A structurally unique set of tailoring domains are found to be stuffed within adenylation domains and have only recently begun to be characterized. PchF is the NRPS termination module in pyochelin biosynthesis and includes a stuffed methyltransferase domain responsible for S-adenosylmethionine (AdoMet)-dependent N-methylation. Recent studies of stuffed methyltransferase domains propose a model in which methylation occurs on amino acids after adenylation and thiolation rather than after condensation to the nascent peptide chain. Herein, we characterize the adenylation and stuffed methyltransferase didomain of PchF through the synthesis and use of substrate analogues, steady-state kinetics, and onium chalcogen effects. We provide evidence that methylation occurs through an SN2 reaction after thiolation, condensation, cyclization, and reduction of the module substrate cysteine and is the penultimate step in pyochelin biosynthesis.


Assuntos
Proteínas de Bactérias/química , Metiltransferases/química , Peptídeo Sintases/química , Fenóis/química , Tiazóis/química , Proteínas de Bactérias/isolamento & purificação , Catálise , Catecol O-Metiltransferase/química , Escherichia coli/genética , Cinética , Methanocaldococcus/enzimologia , Metionina Adenosiltransferase/química , Metionina Adenosiltransferase/isolamento & purificação , Metilação , Metiltransferases/isolamento & purificação , Peptídeo Sintases/isolamento & purificação , Fenóis/síntese química , Domínios Proteicos , Pseudomonas aeruginosa/enzimologia , S-Adenosilmetionina/análogos & derivados , Tiazóis/síntese química
8.
Chem Rec ; 18(12): 1660-1671, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30324709

RESUMO

Physiological regulatory mechanisms of protein, RNA, and DNA functions include small chemical modifications, such as methylation, which are introduced or removed in a highly chemo-, regio-, and site-selective manner by methyltransferases and demethylases, respectively. However, mimicking or controlling these modifications by using labeling reagents and inhibitors remains challenging. In this Personal Account, we introduce our nascent interdisciplinary collaboration between chemists and biologists aimed at developing a basic strategy to analyse and control the methylation reactions regulated by protein methyltransferases (PMTs). We focus in particular on the structural development of chaetocin and S-adenosylmethionine to obtain PMT inhibitors and PMT substrate detectors.


Assuntos
Metiltransferases de Proteína/metabolismo , Proteínas/metabolismo , S-Adenosilmetionina/análogos & derivados , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Metilação , Piperazinas/química , Piperazinas/metabolismo , Metiltransferases de Proteína/antagonistas & inibidores , Proteômica , S-Adenosilmetionina/metabolismo
10.
Nature ; 547(7661): 109-113, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28658205

RESUMO

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.


Assuntos
Adenosilmetionina Descarboxilase/metabolismo , Complexos Multiproteicos/metabolismo , Poliaminas/metabolismo , Neoplasias da Próstata/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adenosilmetionina Descarboxilase/imunologia , Animais , Proliferação de Células , Ativação Enzimática , Everolimo/uso terapêutico , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Metabolômica , Camundongos , Complexos Multiproteicos/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Estabilidade Proteica , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores
11.
Biochem Biophys Res Commun ; 490(3): 861-867, 2017 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-28648602

RESUMO

Helicobacter pylori is the primary pathogen associated to gastritis and gastric cancer. Growth of H. pylori depends on the availability of spermidine in vivo. Interestingly, the genome of H. pylori contains an incomplete set of genes for the classical pathway of spermidine biosynthesis. It is thus not clear whether some other genes remained in the pathway would have any functions in spermidine biosynthesis. Here, we study spermidine synthase, which is responsible for the final catalytic process in the classical route. Protein sequence alignment reveals that H. pylori SpeE (HpSpeE) lacks key residues for substrate binding. By using isothermal titration calorimetry, we show that purified recombinant HpSpeE does not interact with the putative substrates putrescine and decarboxylated S-adenosylmethionine, and the product spermidine. High performance liquid chromatography analysis further demonstrates that HpSpeE has no detectable in vitro enzymatic activity. Additionally, intracellular spermidine level in speE-null mutant strain is comparable to that in the wild type strain. Collectively, our results suggest that HpSpeE is functionally distinct from spermidine production. H. pylori may instead employ the alternative pathway for spermidine synthesis which is dominantly exploited by other human gut microbes.


Assuntos
Helicobacter pylori/enzimologia , Helicobacter pylori/metabolismo , Espermidina Sintase/metabolismo , Espermidina/metabolismo , Sequência de Aminoácidos , Infecções por Helicobacter/microbiologia , Helicobacter pylori/química , Humanos , Putrescina/metabolismo , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Alinhamento de Sequência , Espermidina Sintase/química , Especificidade por Substrato
12.
Subcell Biochem ; 83: 185-194, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28271477

RESUMO

Protein arginine methyltransferase 5 (PRMT5) plays multiple roles in cellular processes at different stages of the cell cycle in a tissue specific manner. PRMT5 in complex with MEP50/p44/WDR77 associates with a plethora of partner proteins to symmetrically dimethylate arginine residues on target proteins in both the nucleus and the cytoplasm. Overexpression of PRMT5 has been observed in several cancers, making it an attractive drug target. The structure of the 453 kDa heterooctameric PRMT5:MEP50 complex bound to an S-adenosylmethionine analog and a substrate peptide provides valuable insights into this intriguing target.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Proteína-Arginina N-Metiltransferases/química , Proteína-Arginina N-Metiltransferases/metabolismo , Arginina/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/metabolismo , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Especificidade por Substrato
13.
Angew Chem Int Ed Engl ; 55(36): 10899-903, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27511141

RESUMO

The 5'-cap is a hallmark of eukaryotic mRNAs and plays fundamental roles in RNA metabolism, ranging from quality control to export and translation. Modifying the 5'-cap may thus enable modulation of the underlying processes and investigation or tuning of several biological functions. A straightforward approach is presented for the efficient production of a range of N7-modified caps based on the highly promiscuous methyltransferase Ecm1. We show that these, as well as N(2) -modified 5'-caps, can be used to tune translation of the respective mRNAs both in vitro and in cells. Appropriate modifications allow subsequent bioorthogonal chemistry, as demonstrated by intracellular live-cell labeling of a target mRNA. The efficient and versatile N7 manipulation of the mRNA cap makes mRNAs amenable to both modulation of their biological function and intracellular labeling, and represents a valuable addition to the chemical biology toolbox.


Assuntos
Capuzes de RNA/química , RNA Mensageiro/química , Química Click , Encephalitozoon cuniculi/enzimologia , Eucariotos/genética , Proteínas Fúngicas/metabolismo , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Metiltransferases/metabolismo , Microscopia Confocal , Capuzes de RNA/metabolismo , RNA Mensageiro/metabolismo , S-Adenosilmetionina/análogos & derivados
14.
Curr Opin Biotechnol ; 42: 189-197, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27506965

RESUMO

S-Adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. In recent years, technologies enabling the synthesis and utilization of novel functional AdoMet surrogates have rapidly advanced. Developments highlighted within this brief review include improved syntheses of AdoMet analogs, unique S-adenosyl-l-methionine isosteres with enhanced stability, and corresponding applications in epigenetics, proteomics and natural product/small molecule diversification ('alkylrandomization').


Assuntos
S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/síntese química , S-Adenosilmetionina/farmacologia , Biologia Sintética/tendências , Animais , Biocatálise , Catálise , Humanos , Cinética , Engenharia Metabólica/métodos , Engenharia Metabólica/tendências , Metionina/análogos & derivados , Especificidade por Substrato , Biologia Sintética/métodos
15.
Org Biomol Chem ; 14(26): 6189-92, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27270873

RESUMO

SalL, an enzyme that catalyzes the synthesis of SAM from l-methionine and 5'-chloro-5'-deoxyoadenosine, is shown to accept 5'-chloro-5'-deoxythienoadenosine as a substrate and facilitate the synthesis of a synthetic SAM analog with an unnatural nucleobase. This synthetic cofactor is demonstrated to replace SAM in the DNA methylation reaction with M.TaqI.


Assuntos
Metiltransferases/metabolismo , S-Adenosilmetionina/metabolismo , Adenosina/análogos & derivados , Adenosina/química , Adenosina/metabolismo , Biocatálise , Metionina/química , Metionina/metabolismo , Metiltransferases/química , Estrutura Molecular , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/química
16.
Methods ; 107: 3-9, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-26884260

RESUMO

This paper outlines chemically and enzymatically synthesized S-adenosylmethionine (AdoMet) analogs and their use in the site-specific modification of RNA by methyltransferases, enabling the facile attachment of clickable moieties to the nucleic acid. We then focus on methodological aspects of setting up a methyltransferase-based enzymatic cascade reaction starting from methionine analogs. This strategy is applied to the one-pot modification of the mRNA cap which is subsequently derivatized in copper-free and copper-catalyzed click reactions. We show that high transfer efficiencies to the cap are obtained using Se-propargyl-, hexenynyl- and azido-bearing methionine analogs. By switching to other methyltransferases our one-pot modification approach should be directly applicable to the regiospecific modification of other target molecules including nucleic acids, proteins and small molecules.


Assuntos
Química Click/métodos , Metionina/química , RNA Mensageiro/química , S-Adenosilmetionina/química , Sítios de Ligação , Metionina/genética , Metiltransferases/química , Metiltransferases/genética , RNA Mensageiro/genética , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/síntese química
17.
J Vis Exp ; (107)2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26780155

RESUMO

Phosphatidylethanolamine methyltransferases are biosynthetic enzymes that catalyze the transfer of one or more methyl group(s) from S-adenosyl-L-methionine onto phosphatidylethanolamine, monomethyl-phosphatidylethanolamine, or dimethyl-phosphatidylethanolamine to give either monomethyl-phosphatidylethanolamine, dimethyl-phosphatidylethanolamine or phosphatidylcholine. These enzymes are ubiquitous in animal cells, fungi, and are also found in approximately 10% of bacteria. They fulfill various important functions in cell physiology beyond their direct role in lipid metabolism such as in insulin resistance, diabetes, atherosclerosis, cell growth, or virulence. The present manuscript reports on a simple cell-free enzymatic assay that measures the transfer of tritiated methyl group(s) from S-[Methyl-(3)H]adenosyl-L-methionine onto phosphatidylethanolamine using whole cell extracts as an enzyme source. The resulting methylated forms of phosphatidylethanolamine are hydrophobic and thus, can be separated from water soluble S-[Methyl-(3)H]adenosyl-L-methionine by organic extraction. This assay can potentially be applied to any other cell types and used to test inhibitors/drugs specific to a phosphatidylethanolamine methyltransferase of interest without the need to purify the enzyme.


Assuntos
Fosfatidiletanolamina N-Metiltransferase/metabolismo , Animais , Técnicas In Vitro , Leishmania/enzimologia , Metilação , Fosfatidiletanolamina N-Metiltransferase/análise , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Trítio
18.
Biochimie ; 126: 6-13, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26805382

RESUMO

Many pathogenic missense mutations in human cystathionine beta-synthase (CBS) cause misfolding of the mutant enzyme resulting in aggregation or rapid degradation of the protein. Subsequent loss of CBS function leads to CBS-deficient homocystinuria (CBSDH). CBS contains two sets of binding sites for S-adenosylmethionine (SAM) that independently regulate the enzyme activity and kinetically stabilize its regulatory domain. In the present study, we examined the hypothesis that CBS activation may be decoupled from kinetic stabilization and thus CBS regulatory domain can serve as a novel drug target for CBSDH. We determined the effect of SAM and its close structural analogs on CBS activity, their binding to and stabilization of the regulatory domain in the absence and presence of competing SAM. Binding of S-adenosylhomocysteine and sinefungin lead to stabilization of the regulatory domains without activation of CBS. Direct titrations and competition experiments support specific binding of these two SAM analogs to the stabilizing sites. Binding of these two ligands also affects the enzyme proteolysis rate supporting the role of the stabilizing sites in CBS dynamics. Our results indicate that binding of SAM to regulatory and stabilizing sites in CBS may have evolved to display an exquisite thermodynamic and structural specificity towards SAM as well as the ability to transduce the allosteric signal responsible for CBS activation. Thus, ligands may be developed to function as kinetic stabilizers or pharmacological chaperones without interfering with the physiological activation of CBS by SAM.


Assuntos
Cistationina beta-Sintase/metabolismo , Homocistinúria/tratamento farmacológico , Homocistinúria/enzimologia , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/farmacologia , Estabilidade Enzimática/efeitos dos fármacos , Humanos , Cinética , S-Adenosilmetionina/química
19.
CNS Neurol Disord Drug Targets ; 15(1): 35-44, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26295824

RESUMO

OBJECTIVE: To review the antidepressant efficacy of S-Adenosyl-L-Methionine (SAMe) both in monotherapy and/or in augmentation with antidepressants to better understand its potential role in the treatment of patients with Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD). DATA SOURCES: A MEDLINE/PubMed search was carried out by using the following set of keywords: ((SAMe OR SAdenosyl- L-Methionine) AND (major depressive disorder OR depression)). Data Selection and Data Extraction: No language or time restrictions were placed on the electronic searches. Randomized controlled trials and open trials involving humans were here included and analyzed. The references of published articles identified in the initial search process were also examined for any additional studies appropriate for the review. DATA SYNTHESIS: SAMe is an important physiologic compound, playing a central role as precursor molecule in several biochemical reactions. Numerous studies have shown that SAMe may affect the regulation of various critical components of monoaminergic neurotransmission involved in the pathophysiology of MDD. Some findings have suggested its antidepressant efficacy in treating MDD. Several randomized controlled trials have supported that the antidepressant efficacy of SAMe in monotherapy is superior to placebo and tricyclic antidepressants. Recent findings have also demonstrated its efficacy in patients nonresponsive to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. CONCLUSION: Overall, SAMe is a well-tolerated medication, which may offer considerable advantages as an alternative to antidepressant drugs or as an add-on therapy in the treatment of MDD and TRD. More large-scale controlled trials are needed to gain a better understanding of the relative efficacy of this drug.


Assuntos
Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , S-Adenosilmetionina/análogos & derivados , Transtorno Depressivo Maior/diagnóstico , Quimioterapia Combinada , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , S-Adenosilmetionina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Resultado do Tratamento
20.
ACS Chem Biol ; 11(3): 583-97, 2016 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-26540123

RESUMO

S-Adenosyl-L-methionine (SAM) is a sulfonium molecule with a structural hybrid of methionine and adenosine. As the second largest cofactor in the human body, its major function is to serve as methyl donor for SAM-dependent methyltransferases (MTases). The resultant transmethylation of biomolecules constitutes a significant biochemical mechanism in epigenetic regulation, cellular signaling, and metabolite degradation. Recently, numerous SAM analogs have been developed as synthetic cofactors to transfer the activated groups on MTase substrates for downstream ligation and identification. Meanwhile, new compounds built upon or derived from the SAM scaffold have been designed and tested as selective inhibitors for important MTase targets. Here, we summarized the recent development and application of SAM analogs as chemical biology tools for MTases.


Assuntos
Metiltransferases/antagonistas & inibidores , S-Adenosil-Homocisteína/análogos & derivados , S-Adenosilmetionina/análogos & derivados , Epigênese Genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Humanos , Metiltransferases/genética , Metiltransferases/metabolismo
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