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1.
J Asian Nat Prod Res ; 26(1): 139-145, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38050667

RESUMO

Four new 2-pyrone derivatives, two pairs of enantiomers, (±)-egypyrone A [(±)-1] and (±)-egypyrone B [(±)-2], together with a new benzophenone analogue, orbiophenone B (3), were isolated from the endophytic fungus Penicillium egyptiacum. The enantiomeric mixtures (±)-1 and (±)-2 were separated through chiral HPLC, respectively. Their structures were elucidated by extensive analysis of spectroscopic data and the absolute configuration was determined by comparing the optical rotation of structurally similar molecule. Subsequently, the cytotoxic activities of (±)-1, (±)-2, and 3 against the U87 cell line were tested and no activity was observed at a concentration of 10 µM.


Assuntos
Penicillium , Penicillium/química , Fungos , Pironas/química , Estrutura Molecular
2.
Angew Chem Int Ed Engl ; 62(18): e202217212, 2023 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-36867112

RESUMO

Fungal epidithiodiketopiperazines (ETPs) possess large structural diversity and complexity due to modifications of the cyclodipeptide skeleton. Elucidation of the biosynthetic pathway of pretrichodermamide A (1) in Trichoderma hypoxylon revealed a flexible catalytic machinery of multiple enzymes for generating ETP diversity. Seven tailoring enzymes encoded by the tda cluster are involved in 1 biosynthesis, that is, four P450s TdaB and TdaQ for 1,2-oxazine formation, TdaI for C7'-hydroxylation, and TdaG for C4, C5-epoxidation, two methyltransferases TdaH for C6'- and TdaO for C7'-O-methylation, and a reductase TdaD for furan opening. Gene deletions led to the identification of 25 novel ETPs, including 20 shunt products, indicating the catalytic promiscuity of Tda enzymes. Particularly, TdaG and TdaD accept various substrates and catalyze regiospecific reactions at different stages of 1 biosynthesis. Our study not only uncovers a hidden library of ETP alkaloids, but also helps to understand the hidden chemical diversity of natural products by pathway manipulation.


Assuntos
Metiltransferases , Oxazinas/química , Estrutura Molecular , Metiltransferases/metabolismo , Modelos Moleculares
3.
J Am Chem Soc ; 144(9): 4269-4276, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35192348

RESUMO

The [1,2]-Meisenheimer rearrangement is well known as the [1,2]-migration of an O-substituted hydroxylamine from a tertiary amine N-oxide, and it is frequently employed in organic synthesis to enforce adjacent carbon oxidation or install a 1,2-oxazine core, which is a prevalent structural feature and pharmacophore of many bioactive natural products. Although the [1,2]-Meisenheimer rearrangement was proposed to occur in the biosynthesis of a number of 1,2-oxazine-containing natural products, it has never been proved biosynthetically. Here, we identified the biosynthetic gene cluster of an insecticidal natural product, paeciloxazine (1), from Penicillium janthinellum and characterized a flavin-dependent monooxygenase, PaxA, as the first example that mediates the formation of a 1,2-oxazine moiety via Meisenheimer rearrangement. In vitro biochemical assays, site-directed mutations, docking and molecular dynamics simulations, and density functional theory calculations support the mechanism that PaxA first catalyzes N-oxidation to form an N-oxide intermediate, which undergoes [1,2]-Meisenheimer rearrangement with the assistance of an amino acid with proton transfer property. This study expands the repertoire of rearrangement reactions during the biosynthesis of natural products and provides a new strategy for discovering natural products with N-O tethers by genome mining.


Assuntos
Produtos Biológicos , Oxigenases de Função Mista , Dinitrocresóis , Flavinas/metabolismo , Oxigenases de Função Mista/química , Compostos Orgânicos , Oxazinas , Óxidos
4.
Fungal Genet Biol ; 160: 103687, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35315337

RESUMO

The filamentous fungi Monascus spp. have been widely used in the production of food colorants. However, the presence of mycotoxin citrinin and the antihypercholestrolemia agent monacolin K in Monascus-fermented products (MFPs) has raised food safety concerns. Here we de novo-sequenced the genomes of 26 Monascus species and proposed an unprecedented classification system, consist of sections A, B and C, according to the biosynthetic gene clusters (BGCs) distribution and phylogeny results. Based on the absence of citrinin gene cluster, section B species were genetically incapable of synthesizing citrinin. A distinguished section A strain named Monascus sanguineus was believed to be a promising food-pigment-producer particularly owing to the simultaneous inactivation of citrinin and monacolin K clusters. Interestingly, gene losses within Monascus secondary metabolism gene clusters were broadly discovered, which may convey a selective advantage in nutrients and energy competition to support the strong pigment-producing ability. Overall, our sectional delimitation system will reshape the industrial strategies for this economically important fungus.


Assuntos
Citrinina , Monascus , Citrinina/metabolismo , Lovastatina , Monascus/genética , Família Multigênica , Pigmentos Biológicos , Metabolismo Secundário
5.
Org Biomol Chem ; 20(11): 2205-2208, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35229094

RESUMO

A concise synthesis of (±)-herbertenolide has been accomplished herein. The strategy relies on a H2O2-mediated oxidative ring contraction of all-substituted cyclic α-formyl ketones for the stereospecific construction of contiguous quaternary carbon centers (CQCCs). Furthermore, a Sc(OTf)3/chiral N,N'-dioxide catalyzed asymmetric Michael addition of benzofuranone to MVK has been optimized for forging a chiral aromatic quaternary carbon center, which enables the formal synthesis of (+)-ent-herbertenolide.

6.
Nat Prod Rep ; 38(8): 1469-1505, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33404031

RESUMO

Covering: up to August 2020The dramatic increase in the identification of dimeric natural products generated by microorganisms and plants has played a significant role in drug discovery. The biosynthetic pathways of these products feature inherent dimerization reactions, which are valuable for biosynthetic applications and chemical transformations. The extraordinary mechanisms of the dimerization of secondary metabolites should advance our understanding of the uncommon chemical rules for natural product biosynthesis, which will, in turn, accelerate the discovery of dimeric reactions and molecules in nature and provide promising strategies for the total synthesis of natural products through dimerization. This review focuses on the enzymes involved in the dimerization in the biosynthetic pathway of microbial natural products, with an emphasis on cytochrome P450s, laccases, and intermolecular [4 + 2] cyclases, along with other atypical enzymes. The identification, characterization, and catalytic landscapes of these enzymes are also introduced.


Assuntos
Produtos Biológicos/metabolismo , Vias Biossintéticas , Dimerização , Bactérias/enzimologia , Bactérias/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Lacase/metabolismo
7.
Angew Chem Int Ed Engl ; 60(12): 6639-6645, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33314510

RESUMO

Self-resistance genes are employed by many microbial producers of bioactive natural products to avoid self-harm. Herein, we describe a unique strategy for self-resistance toward a macrolide antibiotic, A26771B (1), identified by elucidating its biosynthetic pathway in the fungus Penicillium egyptiacum. A highly reducing polyketide synthase and a trans-acting thioesterase generate the macrolide backbone, and a cytochrome P450 and an acyltransferase, respectively catalyze hydroxylation and succinylation to form the prodrug berkeleylactone E (2). Then, extracellular oxidative activation by a secreted flavin-dependent oxidase forms 1, while intracellular reductive inactivation by a short-chain reductase reforms 2, forming a redox cycle. Our work illustrates a unique redox-mediated resistance mechanism for fungal antibiotics and contributes to the understanding of antibiotic biosynthesis and resistance.


Assuntos
Antibacterianos/biossíntese , Penicillium/química , Antibacterianos/química , Lactonas/química , Lactonas/metabolismo , Conformação Molecular , Oxirredução , Penicillium/metabolismo
8.
J Nat Prod ; 83(11): 3262-3269, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33064488

RESUMO

Seven new ß-caryophyllene derivatives, pestalotiphains A-G (1-7), along with six known analogues (8-13), were isolated from the plant-associated Pestalotiopsis hainanensis. Compound 1 represents the first example of a caryophyllene-adenine hybrid, and 2 contains a novel oxatricyclo[4.3.1.0] system. Their structures and absolute configurations were assigned by interpretation of a combination of spectroscopic data and electronic circular dichroism calculations. Compound 8 exhibited moderate inhibition of HL-60 and THP-1 cell lines (IC50, 6.2 and 2.0 µM, respectively). A candidate biosynthetic gene cluster responsible for these compounds was uncovered by bioinformatics analyses and confirmed by a biochemical approach.


Assuntos
Genes Fúngicos , Família Multigênica , Oxigênio/metabolismo , Pestalotiopsis/metabolismo , Sesquiterpenos Policíclicos/metabolismo , Vias Biossintéticas/genética , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pestalotiopsis/genética , Filogenia , Sesquiterpenos Policíclicos/farmacologia , Análise Espectral/métodos
9.
J Nat Prod ; 83(1): 169-173, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31920082

RESUMO

The reported fumiquinazoline-related alkaloids cottoquinazolines E-G (1-3) were reisolated from solid cultures of the fungus Neosartorya fischeri, which was isolated from the medicinal arthropod Cryptotympana atrata. The unresolved issues regarding the absolute configurations (for cottoquinazolines E and F) prompted a reinvestigation of the configurations for all three compounds, as enabled by extensive spectroscopic methods, comparisons of experimental electronic circular dichroism data, and X-ray crystallography. In addition, cottoquinazoline F (2) showed significant antibacterial activity against ESBL-producing Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecalis with MIC values of 8, 32, 32, and 16 µg/mL, respectively.


Assuntos
Alcaloides/farmacologia , Antibacterianos/farmacologia , Artrópodes/química , Aspergillus/química , Enterococcus faecalis/química , Fungos/química , Pseudomonas aeruginosa/química , Quinazolinas/farmacologia , Alcaloides/química , Animais , Antibacterianos/química , Dicroísmo Circular , Cristalografia por Raios X , Estrutura Molecular , Quinazolinas/química
10.
J Am Chem Soc ; 141(36): 14052-14056, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31461283

RESUMO

Diels-Alder reactions are among the most powerful synthetic transformations to construct complex natural products. Despite that increasing of enzymatic intramolecular Diels-Alder reactions have been discovered, natural intermolecular Diels-Alderases are rarely described. Here, we report an intermolecular hetero-Diels-Alder reaction in the biosynthesis of tropolonic sesquiterpenes and functionally characterize EupfF as the first fungal intermolecular hetero-Diels-Alderase. We demonstrate that EupfF catalyzed the dehydration of a hydroxymethyl-containing tropolone (5) to generate a reactive tropolone o-quinone methide (6) and might further stereoselectively control the subsequent intermolecular hetero-Diels-Alder reaction with (1E,4E,8Z)-humulenol (8) to produce enantiomerically pure neosetophomone B (1). Our results reveal the biosynthetic pathway of 1 and expand the repertoire of activities of Diels-Alder cyclases.


Assuntos
Proteínas Fúngicas/metabolismo , Metiltransferases/metabolismo , Sesquiterpenos/metabolismo , Reação de Cicloadição , Proteínas Fúngicas/química , Metiltransferases/química , Conformação Molecular , Sesquiterpenos/química
11.
Angew Chem Int Ed Engl ; 58(20): 6569-6573, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-30908782

RESUMO

Fenestranes, a specific class of natural products, contain four fused rings that share a central quaternary carbon atom. The fungal natural product penifulvin A (1) is a potent insecticidal sesquiterpene that features the [5.5.5.6]dioxafenestrane ring. Although the chemical synthesis of 1 has been achieved recently, the enzymes catalysing the cyclization and oxidation of FPP to 1 remain unknown. In this work, we identified a concise pathway that uses only three enzymes to produce 1. A new sesquiterpene cyclase (PeniA) generates the angular triquinane scaffold silphinene (6). A cytochrome P450 (PeniB) and a flavin-dependent monooxygenase (PeniC) catalyse a series of oxidation reactions to transform 6 into 1, including oxidation of the C15 methyl group to a carboxylate moiety, oxidative coupling of the C15 carboxylate and the C1-C2 olefin to form a γ-lactone, and Baeyer-Villiger oxidation to form a δ-lactone. Our results demonstrate the highly concise and efficient ways in which fungal biosynthetic pathways can generate complex sesquiterpene scaffolds.


Assuntos
Fungos/química , Sesquiterpenos/síntese química , Vias Biossintéticas
12.
J Am Chem Soc ; 140(22): 6991-6997, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29741874

RESUMO

Duclauxins are dimeric and heptacyclic fungal polyketides with notable bioactivities. We characterized the cascade of redox transformations in the biosynthetic pathway of duclauxin from Talaromyces stipitatus. The redox reaction sequence is initiated by a cupin family dioxygenase DuxM that performs an oxidative cleavage of the peri-fused tricyclic phenalenone and affords a transient hemiketal-oxaphenalenone intermediate. Additional redox enzymes then morph the oxaphenoalenone into either an anhydride or a dihydrocoumarin-containing monomeric building block that is found in dimeric duxlauxins. Oxidative coupling between the monomers to form the initial C-C bond was shown to be catalyzed by a P450 monooxygenase, although the enzyme responsible for the second C-C bond formation was not found in the pathway. Collectively, the number and variety of redox enzymes used in the duclauxin pathway showcase Nature's strategy to generate structural complexity during natural product biosynthesis.


Assuntos
Dioxigenases/metabolismo , Fenalenos/metabolismo , Policetídeos/metabolismo , Talaromyces/química , Cromonas/química , Cromonas/metabolismo , Estrutura Molecular , Oxirredução , Fenalenos/química , Policetídeos/química , Talaromyces/metabolismo
13.
Appl Environ Microbiol ; 84(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30217843

RESUMO

Purine nucleoside antibiotic pairs, concomitantly produced by a single strain, are an important group of microbial natural products. Here, we report a target-directed genome mining approach to elucidate the biosynthesis of the purine nucleoside antibiotic pair aristeromycin (ARM) and coformycin (COF) in Micromonospora haikouensis DSM 45626 (a new producer for ARM and COF) and Streptomyces citricolor NBRC 13005 (a new COF producer). We also provide biochemical data that MacI and MacT function as unusual phosphorylases, catalyzing an irreversible reaction for the tailoring assembly of neplanocin A (NEP-A) and ARM. Moreover, we demonstrate that MacQ is shown to be an adenosine-specific deaminase, likely relieving the potential "excess adenosine" for producing cells. Finally, we report that MacR, an annotated IMP dehydrogenase, is actually an NADPH-dependent GMP reductase, which potentially plays a salvage role for the efficient supply of the precursor pool. Hence, these findings illustrate a fine-tuned pathway for the biosynthesis of ARM and also open the way for the rational search for purine antibiotic pairs.IMPORTANCE ARM and COF are well known for their prominent biological activities and unusual chemical structures; however, the logic of their biosynthesis has long been poorly understood. Actually, the new insights into the ARM and COF pathway will not only enrich the biochemical repertoire for interesting enzymatic reactions but may also lay a solid foundation for the combinatorial biosynthesis of this group of antibiotics via a target-directed genome mining strategy.


Assuntos
Actinobacteria/metabolismo , Adenosina/análogos & derivados , Antibacterianos/metabolismo , Coformicina/biossíntese , Nucleosídeos de Purina/biossíntese , Actinobacteria/genética , Adenosina/biossíntese , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Vias Biossintéticas , GMP Redutase/genética , GMP Redutase/metabolismo
14.
Appl Microbiol Biotechnol ; 102(1): 297-304, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29098413

RESUMO

Aurovertins are the structurally diverse polyketides that distribute widely in different fungal species. They feature a 2,6-dioxabicyclo[3.2.1]-octane ring in structure and exhibit the potential antitumor activity against breast cancer as F1-ATPase ß subunit inhibitor. In this study, we constructed the biosynthetic pathway of aurovertin in an Aspergillus nidulans host and obtained seven aurovertin-type compounds. Surprisingly, three new aurovertin geometric isomers were characterized. By introducing an inducible promoter xylP(p) in the pathway gene acyltransferase aurG, we can control the product ratios among different aurovertin compounds by adding glucose and/or inducer xylose. The yields of aurovertins could be increased up to about 20 times by adding a constitutive promoter gpdA(p) to transcription factor AurF, which indicates AurF's positive role in the biosynthesis of aurovertin. Taken together, our results provided not only an efficient way to generate bioactive fungal natural products but also realized the rational controlling their yields with designed promoters.


Assuntos
Aspergillus nidulans/metabolismo , Aurovertinas/metabolismo , Vias Biossintéticas/genética , Aciltransferases/genética , Aspergillus nidulans/efeitos dos fármacos , Aspergillus nidulans/enzimologia , Aspergillus nidulans/genética , Aurovertinas/análise , Aurovertinas/química , Aurovertinas/isolamento & purificação , Sítios de Ligação , Produtos Biológicos/metabolismo , Vias Biossintéticas/fisiologia , Glucose/farmacologia , Cinética , Regiões Promotoras Genéticas , Xilose/farmacologia
15.
Mar Drugs ; 16(11)2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30453472

RESUMO

Six new diphenyl ethers (1⁻6) along with eleven known analogs were isolated from the ethyl acetate extract of a marine-derived Aspergillus sydowii guided by LC-UV-MS. Their structures were unambiguously characterized by HRESIMS, NMR, as well as chemical derivatization. Compounds 1 and 2 are rare diphenyl ether glycosides containing d-ribose. The absolute configuration of the sugar moieties in compounds 1⁻3 was determined by a LC-MS method. All the compounds were evaluated for their cytotoxicities against eight cancer cell lines, including 4T1, U937, PC3, HL-60, HT-29, A549, NCI-H460, and K562, and compounds 1, 5, 6, and 8⁻11 were found to exhibit selective cytotoxicity against different cancer cell lines.


Assuntos
Antineoplásicos/farmacologia , Organismos Aquáticos/química , Aspergillus/química , Éteres Fenílicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Éteres Fenílicos/química , Éteres Fenílicos/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray
16.
Zhongguo Zhong Yao Za Zhi ; 43(4): 755-759, 2018 Feb.
Artigo em Zh | MEDLINE | ID: mdl-29600651

RESUMO

Trace chemical constituents from the ethyl acetate extract of Red Yeast Rice were investigated. Four phenolic compounds were isolated by various column chromatographies, and their structures were identified on the basis of spectroscopic analysis including UV, MS, IR and NMR. The four compounds were identified as 2-methyl-5-(2'R-methyl-4'-hydroxy-butyl)-cinnamic acid(1), 5-(2'-hydroxy-6'-methyl phenyl)-3-methylfuran-2-carboxylic acid(2), daidzein(3), and genistein(4). Compound 1 was new and 2 was firstly discovered from the genus Monascus, while 3-4 were obtained from Red Yeast Rice for the first time.


Assuntos
Produtos Biológicos/química , Monascus , Fenóis/química , Espectroscopia de Ressonância Magnética
17.
Molecules ; 22(6)2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28545244

RESUMO

Two new phloroglucinols, lysidisides X and Y (1 and 2), and two known compounds, 2-(2-methylbutyryl)phloroglucinol 1-O-ß-d-glucopyranoside (3) and (E)-resveratrol 3-(6″-galloyl)-O-ß-d-glucopyranoside (4), have been isolated from the roots of Lysidice rhodostegia. The structures of 1 and 2 were elucidated primarily by NMR experiments. Their absolute configurations were deduced via circular dichroism (CD) data and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 exhibited significant antioxidative activities with IC50 values of 12.0 and 11.8 µM, respectively.


Assuntos
Antioxidantes/química , Fabaceae/química , Floroglucinol/química , Raízes de Plantas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular
18.
Angew Chem Int Ed Engl ; 56(17): 4782-4786, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28370936

RESUMO

Redox modifications are key complexity-generating steps in the biosynthesis of natural products. The unique structure of rubratoxin A (1), many of which arise through redox modifications, make it a nanomolar inhibitor of protein phosphatase 2A (PP2A). We identified the biosynthetic pathway of 1 and completely mapped the enzymatic sequence of redox reactions starting from the nonadride 5. Six redox enzymes are involved, including four α-ketoglutarate- and iron(II)-dependent dioxygenases that hydroxylate four sp3 carbons; one flavin-dependent dehydrogenase that is involved in formation of the unsaturated lactone; and the ferric-reductase-like enzyme RbtH, which regioselectively reduces one of the maleic anhydride moieties in rubratoxin B to the γ-hydroxybutenolide that is critical for PP2A inhibition. RbtH is proposed to perform sequential single-electron reductions of the maleic anhydride using electrons derived from NADH and transferred through a ferredoxin and ferredoxin reductase pair.


Assuntos
Vias Biossintéticas , Inibidores Enzimáticos/metabolismo , Micotoxinas/metabolismo , Penicillium/enzimologia , Proteína Fosfatase 2/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Família Multigênica , Micotoxinas/química , Micotoxinas/farmacologia , Penicillium/genética , Penicillium/metabolismo
19.
Nat Chem Biol ; 10(7): 552-4, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24838010

RESUMO

Despite the remarkable versatility displayed by flavin-dependent monooxygenases (FMOs) in natural product biosynthesis, one notably missing activity is the oxidative generation of carbonate functional groups. We describe a multifunctional Baeyer-Villiger monooxygenase, CcsB, which catalyzes the formation of an in-line carbonate in the macrocyclic portion of cytochalasin E. This study expands the repertoire of activities of FMOs and provides a possible synthetic strategy for transformation of ketones into carbonates.


Assuntos
Aspergillus/química , Carbonatos/química , Citocalasinas/química , Proteínas Fúngicas/química , Regulação Fúngica da Expressão Gênica , Cetonas/química , Oxigenases de Função Mista/química , Sequência de Aminoácidos , Aspergillus/enzimologia , Aspergillus/genética , Catálise , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Técnicas de Inativação de Genes , Teste de Complementação Genética , Oxigenases de Função Mista/deficiência , Oxigenases de Função Mista/genética , Oxirredução
20.
Proc Natl Acad Sci U S A ; 110(4): 1303-8, 2013 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-23297231

RESUMO

The polyketide natural product Leptomycin B inhibits nuclear export mediated by the karyopherin protein chromosomal region maintenance 1 (CRM1). Here, we present 1.8- to 2.0-Å-resolution crystal structures of CRM1 bound to Leptomycin B and related inhibitors Anguinomycin A and Ratjadone A. Structural and complementary chemical analyses reveal an unexpected mechanism of inhibition involving covalent conjugation and CRM1-mediated hydrolysis of the natural products' lactone rings. Furthermore, mutagenesis reveals the mechanism of hydrolysis by CRM1. The nuclear export signal (NES)-binding groove of CRM1 is able to drive a chemical reaction in addition to binding protein cargoes for transport through the nuclear pore complex.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Acrilatos/química , Acrilatos/farmacologia , Substituição de Aminoácidos , Cristalografia por Raios X , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/metabolismo , Ácidos Graxos Insaturados/farmacologia , Humanos , Hidrólise , Carioferinas/antagonistas & inibidores , Carioferinas/química , Carioferinas/genética , Modelos Anatômicos , Mutagênese Sítio-Dirigida , Sinais de Exportação Nuclear/genética , Conformação Proteica , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Eletricidade Estática , Triazóis/química , Triazóis/farmacologia , Proteína Exportina 1
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