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1.
Am J Physiol Endocrinol Metab ; 317(4): E597-E604, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31386565

RESUMO

It has been suggested that interleukin-6 (IL-6) produced by adipocytes in obesity leads to liver insulin resistance, although this hypothesis has never been definitively tested. Accordingly, we did so by generating adipocyte-specific IL-6-deficient (AdipoIL-6-/-) mice and studying them in the context of diet-induced and genetic obesity. Mice carrying two floxed alleles of IL-6 (C57Bl/6J) were crossed with Cre recombinase-overexpressing mice driven by the adiponectin promoter to generate AdipoIL-6-/- mice. AdipoIL-6-/- and floxed littermate controls were fed a standard chow or high-fat diet (HFD) for 16 wk and comprehensively metabolically phenotyped. In addition to a diet-induced obesity model, we also examined the role of adipocyte-derived IL-6 in a genetic model of obesity and insulin resistance by crossing the AdipoIL-6-/- mice with leptin-deficient (ob/ob) mice. As expected, mice on HFD and ob/ob mice displayed marked weight gain and increased fat mass compared with chow-fed and ob/+ (littermate control) animals, respectively. However, deletion of IL-6 from adipocytes in either model had no effect on glucose tolerance or fasting hyperinsulinemia. We concluded that adipocyte-specific IL-6 does not contribute to whole body glucose intolerance in obese mice.


Assuntos
Adipócitos/metabolismo , Intolerância à Glucose/genética , Interleucina-6/genética , Obesidade/genética , Aumento de Peso/genética , Adiponectina/biossíntese , Adiponectina/genética , Adiposidade/genética , Animais , Composição Corporal/genética , Dieta Hiperlipídica , Intolerância à Glucose/etiologia , Resistência à Insulina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/metabolismo
2.
Diabetes Obes Metab ; 20(8): 1928-1936, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29652108

RESUMO

AIMS: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance. MATERIALS AND METHODS: An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters. Two studies were conducted, the first with direct intramuscular (IM) injection of the AAV:Hsp72 into the tibialis anterior hind-limb muscle and the second with a systemic injection to enable body-wide skeletal muscle transduction. RESULTS: IM injection of the AAV:Hsp72 significantly improved skeletal muscle insulin-stimulated glucose clearance in treated hind-limb muscles, as compared with untreated muscles of the contralateral leg when mice were fed an HFD. Despite this finding, systemic administration of AAV:Hsp72 did not improve body composition parameters such as body weight, fat mass or percentage body fat, nor did it lead to an improvement in fasting glucose levels or glucose tolerance. Furthermore, no differences were observed for other metabolic parameters such as whole-body oxygen consumption, energy expenditure or physical activity levels. CONCLUSIONS: At the levels of Hsp72 over-expression reported herein, skeletal muscle-specific Hsp72 overexpression via IM injection has the capacity to increase insulin-stimulated glucose clearance in this muscle. However, upon systemic injection, which results in lower muscle Hsp72 overexpression, no beneficial effects on whole-body metabolism are observed.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Intolerância à Glucose/prevenção & controle , Proteínas de Choque Térmico HSP72/metabolismo , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Insulina/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Absorção Fisiológica/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Técnicas de Transferência de Genes , Glucose/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Proteínas de Choque Térmico HSP72/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Especificidade de Órgãos , Projetos Piloto , Ratos
3.
Mol Metab ; 5(11): 1083-1091, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27818934

RESUMO

OBJECTIVE: The development of skeletal muscle insulin resistance is an early physiological defect, yet the intracellular mechanisms accounting for this metabolic defect remained unresolved. Here, we have examined the role of glucose-6-phosphate dehydrogenase (G6PDH) activity in the pathogenesis of insulin resistance in skeletal muscle. METHODS: Multiple mouse disease states exhibiting insulin resistance and glucose intolerance, as well as obese humans defined as insulin-sensitive, insulin-resistant, or pre-diabetic, were examined. RESULTS: We identified increased glucose-6-phosphate dehydrogenase (G6PDH) activity as a common intracellular adaptation that occurs in parallel with the induction of insulin resistance in skeletal muscle and is present across animal and human disease states with an underlying pathology of insulin resistance and glucose intolerance. We observed an inverse association between G6PDH activity and nitric oxide synthase (NOS) activity and show that increasing NOS activity via the skeletal muscle specific neuronal (n)NOSµ partially suppresses G6PDH activity in skeletal muscle cells. Furthermore, attenuation of G6PDH activity in skeletal muscle cells via (a) increased nNOSµ/NOS activity, (b) pharmacological G6PDH inhibition, or (c) genetic G6PDH inhibition increases insulin-independent glucose uptake. CONCLUSIONS: We have identified a novel, previously unrecognized role for G6PDH in the regulation of skeletal muscle glucose metabolism.


Assuntos
Glucose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Músculo Esquelético/metabolismo , Animais , Glucose-6-Fosfato , Humanos , Insulina , Resistência à Insulina , Camundongos , Fibras Musculares Esqueléticas , Óxido Nítrico
4.
FASEB J ; 25(3): 1040-7, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21148417

RESUMO

Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell models. Our previous studies have shown that responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cß1b (PLCß1b), because only this PLCß subtype localizes at the cardiac sarcolemma. In the current study, we investigated the proteins involved in targeting PLCß1b to the sarcolemma in neonatal rat cardiomyocytes. PLCß1b, but not PLCß1a, coimmunoprecipitated with the high-MW scaffolding protein SH3 and ankyrin repeat protein 3 (Shank3), as well as the known Shank3-interacting protein α-fodrin. The 32-aa splice-variant-specific C-terminal tail of PLCß1b also associated with Shank3 and α-fodrin, indicating that PLCß1b binds via the C-terminal sequence. Shank3 colocalized with PLCß1b at the sarcolemma, and both proteins were enriched in the light membrane fractions. Knockdown of Shank3 using siRNA reduced PLC activation and downstream hypertrophic responses, demonstrating the importance of sarcolemmal localization for PLC signaling. These data indicate that PLCß1b associates with a Shank3 complex at the cardiac sarcolemma via its splice-variant-specific C-terminal tail. Sarcolemmmal localization is central to PLC activation and subsequent downstream signaling following Gq-coupled receptor activation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Processamento Alternativo/fisiologia , Miocárdio/enzimologia , Miócitos Cardíacos/enzimologia , Fosfolipase C beta/metabolismo , Sarcolema/enzimologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Cardiomegalia/metabolismo , Cardiotônicos/farmacologia , Proteínas de Transporte/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Microdomínios da Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Tecido Nervoso , Fenilefrina/farmacologia , Fosfolipase C beta/química , Fosfolipase C beta/genética , Estrutura Terciária de Proteína , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Domínios de Homologia de src/fisiologia
5.
Anal Biochem ; 360(2): 227-34, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17134675

RESUMO

The enzymes 6-hydroxymethylpterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) catalyze sequential steps in folate biosynthesis. They are present in microorganisms but absent in mammals and therefore are especially suitable targets for antimicrobials. Sulfa drugs (sulfonamides and sulfones) currently are used as antimicrobials targeting DHPS, although resistance to these drugs is increasing. The most widely used assay that measures activity of these enzymes, to assess new inhibitors in vitro, is not amenable to automation. This article describes a simple, coupled, enzymatic spectrophotometric assay where the product of the DHPS reaction, dihydropteroate, is reduced to tetrahydropteroate by excess dihydrofolate reductase (DHFR) using the cofactor NADPH. The oxidation of NADPH is monitored at 340 nm. The activity of both HPPK and DHPS can be measured in this assay, and it has been used to measure kinetic parameters of wild-type and sulfa drug-resistant DHPS enzymes to demonstrate the utility of the assay. It is a sensitive and reproducible assay that can be readily automated and used in multiwell plates. This NADPH-coupled microplate photometric assay could be used for rapid screening of chemical libraries for novel inhibitors of folate biosynthesis as the first step in developing new antimicrobial drugs targeting the folate biosynthetic pathway.


Assuntos
Di-Hidropteroato Sintase/antagonistas & inibidores , Di-Hidropteroato Sintase/metabolismo , Inibidores Enzimáticos/farmacologia , Dapsona/farmacologia , Ativação Enzimática/efeitos dos fármacos , Modelos Biológicos , NADP/metabolismo , Pterinas/metabolismo , Reprodutibilidade dos Testes , Espectrofotometria/métodos , Sulfacloropiridazina/farmacologia , Sulfametoxazol/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo
6.
J Mol Biol ; 348(3): 655-70, 2005 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-15826662

RESUMO

In Saccharomyces cerevisiae and other fungi, the enzymes dihydroneopterin aldolase, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) are encoded by a polycistronic gene that is translated into a single polypeptide having all three functions. These enzymatic functions are essential to both prokaryotes and lower eukaryotes, and catalyse sequential reactions in folate biosynthesis. Deletion or disruption of either function leads to cell death. These enzymes are absent from mammals and thus make ideal antimicrobial targets. DHPS is currently the target of antifolate therapy for a number of infectious diseases, and its activity is inhibited by sulfonamides and sulfones. These drugs are typically used as part of a synergistic cocktail with the 2,4-diaminopyrimidines that inhibit dihydrofolate reductase. A gene encoding the S.cerevisiae HPPK and DHPS enzymes has been cloned and expressed in Escherichia coli. A complex of the purified bifunctional polypeptide with a pterin monophosphate substrate analogue has been crystallized, and its structure solved by molecular replacement and refined to 2.3A resolution. The polypeptide consists of two structural domains, each of which closely resembles its respective monofunctional bacterial HPPK and DHPS counterpart. The mode of ligand binding is similar to that observed in the bacterial enzymes. The association between the domains within the polypeptide as well as the quaternary association of the polypeptide via its constituent DHPS domains provide insight into the assembly of the trifunctional enzyme in S.cerevisiae and probably other fungal species.


Assuntos
Di-Hidropteroato Sintase/química , Difosfotransferases/química , Estrutura Terciária de Proteína , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/enzimologia , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Di-Hidropteroato Sintase/genética , Difosfotransferases/genética , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Quaternária de Proteína , Proteínas de Saccharomyces cerevisiae/genética , Alinhamento de Sequência
7.
Microb Drug Resist ; 11(1): 1-8, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15770087

RESUMO

Pneumocystis jirovecii is a major opportunistic pathogen that causes Pneumocystis pneumonia (PCP). Drug treatment failure has been associated epidemiologically with point mutations in the gene for dihydropteroate synthase which is part of a gene that encodes three covalently linked enzymes involved in folic acid synthesis (FAS). The evaluation of whether mutations found in P. jirovecii FAS lead to sulfa drug resistance is hampered by the lack of a culture system for P. jirovecii as well as the failure of P. jirovecii FAS to complement in a heterologous system. Therefore, we chose to model the P. jirovecii mutations in the Saccharomyces cerevisiae FAS protein (encoded by FOL1) via its expression in Escherichia coli. An optimized drug diffusion assay was used to evaluate the FAS mutants against 15 sulfa drugs. It was established that the single amino acid substitution, P599S, in the (DHPS) domain of FAS led to sulfa drug resistance, whereas the T597A substitution led to increased sensitivity. The presence of both mutations (T597A and P599S) was cooperative and led to increased sulfa drug resistance. Analysis of a novel double mutant, (T597V P599S) was found to have significantly higher sulfa drug resistance than the T597A P599S mutant. These data suggest that further amino acid substitutions may lead to the evolution of higher sulfa drug resistance. Two sulfa drugs (sulfachloropyridazine and sulfathiazole) were identified that had higher inhibitory potential than sulfamethoxazole, which is currently the preferred treatment for PCP.


Assuntos
Di-Hidropteroato Sintase/genética , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Pneumocystis/genética , Sulfametoxazol/farmacologia , Substituição de Aminoácidos , Escherichia coli/genética , Vetores Genéticos , Testes de Sensibilidade Microbiana , Mutação , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Transformação Genética
8.
Antimicrob Agents Chemother ; 49(2): 741-8, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15673759

RESUMO

Pneumocystis jirovecii is a major opportunistic pathogen that causes Pneumocystis pneumonia (PCP) and results in a high degree of mortality in immunocompromised individuals. The drug of choice for PCP is typically sulfamethoxazole (SMX) or dapsone in conjunction with trimethoprim. Drug treatment failure and sulfa drug resistance have been implicated epidemiologically with point mutations in dihydropteroate synthase (DHPS) of P. jirovecii. P. jirovecii cannot be cultured in vitro; however, heterologous complementation of the P. jirovecii trifunctional folic acid synthesis (PjFAS) genes with an E. coli DHPS-disrupted strain was recently achieved. This enabled the evaluation of SMX resistance conferred by DHPS mutations. In this study, we sought to determine whether DHPS mutations conferred sulfa drug cross-resistance to 15 commonly available sulfa drugs. It was established that the presence of amino acid substitutions (T(517)A or P(519)S) in the DHPS domain of PjFAS led to cross-resistance against most sulfa drugs evaluated. The presence of both mutations led to increased sulfa drug resistance, suggesting cooperativity and the incremental evolution of sulfa drug resistance. Two sulfa drugs (sulfachloropyridazine [SCP] and sulfamethoxypyridazine [SMP]) that had a higher inhibitory potential than SMX were identified. In addition, SCP, SMP, and sulfadiazine (SDZ) were found to be capable of inhibiting the clinically observed drug-resistant mutants. We propose that SCP, SMP, and SDZ should be considered for clinical evaluation against PCP or for future development of novel sulfa drug compounds.


Assuntos
Antibacterianos/farmacologia , Di-Hidropteroato Sintase/genética , Mutação/genética , Pneumocystis/genética , Sulfonamidas/farmacologia , Substituição de Aminoácidos , Meios de Cultura , Di-Hidropteroato Sintase/antagonistas & inibidores , Farmacorresistência Bacteriana , Inibidores Enzimáticos/farmacologia , Escherichia coli/genética , Vetores Genéticos , Testes de Sensibilidade Microbiana , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Transformação Bacteriana
9.
Fungal Genet Biol ; 41(12): 1053-62, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15531210

RESUMO

Pneumocystis pneumonia or PCP is caused by Pneumocystis jirovecii, an obligate parasite of the human lung. In this study P. jirovecii genomic sequence encoding FAS, a trifunctional protein including dihydroneopterin aldolase (DHNA), hydroxymethyldihydropterin pyrophosphokinase (PPPK) and dihydropteroate synthase (DHPS) were identified by PCR amplification from fixed broncheolar lavage samples from patients having Pneumocystis pneumonia. The P. jirovecii trifunctional DHNA-PPPK-DHPS genes (PjFAS) showed a high degree of conservation with the rat Pneumocystis carinii and P. carinii f. sp. macaca sequences. To test the functionality of the PjFAS sequences introns were removed followed by cloning and expression of PjFAS sequences in a DHPS-disrupted Escherichia coli strain. Complementation depended on the presence of N-terminal FAS sequences in addition to a glutathione S- transferase tag to the N-terminus of PjFAS. Functional complementation allowed evaluation of DHPS mutations implicated with sulfa drug resistance.


Assuntos
Proteínas Fúngicas/genética , Pneumocystis carinii/enzimologia , Pneumocystis carinii/genética , Aldeído Liases/genética , Sequência de Aminoácidos , Anti-Infecciosos/farmacologia , Líquido da Lavagem Broncoalveolar/microbiologia , Sequência Conservada/genética , DNA Fúngico/química , DNA Fúngico/isolamento & purificação , Di-Hidropteroato Sintase/genética , Difosfotransferases/genética , Farmacorresistência Fúngica/genética , Escherichia coli/genética , Escherichia coli/fisiologia , Proteínas Fúngicas/metabolismo , Genes Fúngicos , Teste de Complementação Genética , Humanos , Íntrons/genética , Dados de Sequência Molecular , Pneumocystis carinii/isolamento & purificação , Pneumonia por Pneumocystis/microbiologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Sulfanilamidas/farmacologia
10.
Antimicrob Agents Chemother ; 48(7): 2617-23, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15215118

RESUMO

Dihydropteroate synthase (DHPS) mutations in Pneumocystis jiroveci have been associated epidemiologically with resistance to sulfamethoxazole (SMX). Since P. jiroveci cannot be cultured, inherent drug resistance cannot be measured. This study explores the effects of these mutations in a tractable model organism, Saccharomyces cerevisiae. Based on the sequence conservation between the DHPS enzymes of P. jiroveci and S. cerevisiae, together with the structural conservation of the three known DHPS structures, DHPS substitutions commonly observed in P. jiroveci were reverse engineered into the S. cerevisiae DHPS. Those mutations, T(597)A and P(599)S, can occur singly but are most commonly found together and are associated with SMX treatment failure. Mutations encoding the corresponding changes in the S. cerevisiae dhps were made in a yeast centromere vector, p414FYC, which encodes the native yeast DHPS as part of a trifunctional protein that also includes the two enzymes upstream of DHPS in the folic acid synthesis pathway, dihydroneopterin aldolase and 2-amino-4-hydroxymethyl dihydropteridine pyrophosphokinase. A yeast strain with dhps deleted was employed as the host strain, and transformants having DHPS activity were recovered. Mutants having both T(597) and P(599) substitutions had a requirement for p-aminobenzoic acid (PABA), consistent with resistance being associated with altered substrate binding. These mutants could be adapted for growth in the absence of PABA, which coincided with increased sulfa drug resistance. Upregulated PABA synthesis was thus implicated as a mechanism for sulfa drug resistance for mutants having two DHPS substitutions.


Assuntos
Anti-Infecciosos/farmacologia , Di-Hidropteroato Sintase/genética , Mutação/genética , Pneumocystis carinii/enzimologia , Pneumocystis carinii/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Sulfametoxazol/farmacologia , Ácido 4-Aminobenzoico/farmacologia , Alelos , Sequência de Aminoácidos , Meios de Cultura , Difusão , Farmacorresistência Fúngica , Escherichia coli/enzimologia , Escherichia coli/genética , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Mutação/fisiologia , Fenótipo , Transformação Genética
11.
Int J Parasitol ; 34(1): 95-100, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14711594

RESUMO

Mutations in Plasmodium falciparum dihydropteroate synthase have been linked to resistance to the antimalarial drug, sulfadoxine, which competes with the dihydropteroate synthase substrate, p-aminobenzoate. In an effort to evaluate the role of these mutations in a simple model system, we have expressed six relevant alleles of the P. falciparum dihydropteroate synthase gene in Escherichia coli. When each construct was produced in a dihydropteroate synthase disrupted E. coli strain that required thymidine, the thymidine requirement was lost, indicating heterologous complementation had occurred. In the presence of sulfadoxine, the growth of the strain with the wild-type dihydropteroate synthase allele was inhibited while those containing each of the five mutant alleles grew, indicating that these mutations can confer sulfadoxine resistance in E. coli. When tested against twelve additional 'sulfa' drugs a variety of responses were obtained. All strains were resistant to sulfadiazine, but the wild-type allele conferred sensitivity to all other sulfa drugs. Three alleles conferred resistance to dapsone, a drug that is to be targetted for a new regime of malaria treatment in Africa. All mutant alleles remained sensitive to sulfachloropyridazine and sulfacetamide. These results suggest new drugs that could be tried for effective malaria treatment.


Assuntos
Di-Hidropteroato Sintase/metabolismo , Resistência Microbiana a Medicamentos , Malária/tratamento farmacológico , Plasmodium falciparum/enzimologia , Sulfadoxina , Alelos , Animais , Di-Hidropteroato Sintase/genética , Escherichia coli/enzimologia , Expressão Gênica , Humanos , Concentração Inibidora 50 , Mutação
12.
Microb Drug Resist ; 9(3): 249-55, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12959403

RESUMO

The enzyme dihydropteroate synthase (DHPS) is an important target for sulfa drugs in both prokaryotic and eukaryotic microbes. However, the understanding of DHPS function and the action of antifolates in eukaryotes has been limited due to technical difficulties and the complexity of DHPS being a part of a bifunctional or trifunctional protein that comprises the upstream enzymes involved in folic acid synthesis (FAS). Here, yeast strains have been constructed to study the effects of FOL1 expression on growth and sulfa drug resistance. A DHPS knockout yeast strain was complemented by yeast vectors expressing the FOL1 gene under the control of promoters of different strengths. An inverse relationship was observed between the growth rate of the strains and FOL1 expression levels. The use of stronger promoters to drive FOL1 expression led to increased sulfamethoxazole resistance when para-aminobenzoic acid (pABA) levels were elevated. However, high FOL1 expression levels resulted in increased susceptibility to sulfamethoxazole in pABA free media. These data suggest that up-regulation of FOL1 expression can lead to sulfa drug resistance in Saccharomyces cerevisiae.


Assuntos
Anti-Infecciosos/farmacologia , Ácido Fólico/biossíntese , Ácido Fólico/genética , Regiões Promotoras Genéticas/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Sulfonamidas/farmacologia , Ácido 4-Aminobenzoico/farmacologia , Antibacterianos , Meios de Cultura , Difusão , Di-Hidropteroato Sintase/antagonistas & inibidores , Farmacorresistência Fúngica , Escherichia coli/genética , Vetores Genéticos , Testes de Sensibilidade Microbiana , Oligonucleotídeos/química , Sulfametoxazol/farmacologia , Transformação Bacteriana , beta-Galactosidase/genética
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