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1.
J Am Chem Soc ; 146(20): 14235-14245, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38719200

RESUMO

Pyrroloiminoquinone-containing natural products have long been known for their biological activities. They are derived from tryptophan, but their biosynthetic pathways have remained elusive. Studies on the biosynthetic gene cluster (BGC) that produces the ammosamides revealed that the first step is attachment of Trp to the C-terminus of a scaffold peptide in an ATP- and tRNA-dependent manner catalyzed by a PEptide Aminoacyl-tRNA Ligase (PEARL). The indole of Trp is then oxidized to a hydroxyquinone. We previously proposed a chemically plausible and streamlined pathway for converting this intermediate to the ammosamides using additional enzymes encoded in the BGC. In this study, we report the activity of four additional enzymes from two gene clusters, which show that the previously proposed pathway is incorrect and that Nature's route toward pyrroloiminoquinones is much more complicated. We demonstrate that, surprisingly, amino groups in pyrroloiminoquinones are derived from (at least) three different sources, glycine, asparagine, and leucine, all introduced in a tRNA-dependent manner. We also show that an FAD-dependent putative glycine oxidase (Amm14) is required for the process that incorporates the nitrogens from glycine and leucine and that a quinone reductase is required for the incorporation of asparagine. Additionally, we provide the first insights into the evolutionary origin of the PEARLs as well as related enzymes, such as the glutamyl-tRNA-dependent dehydratases involved in the biosynthesis of lanthipeptides and thiopeptides. These enzymes appear to all have descended from the ATP-GRASP protein family.


Assuntos
Pirroliminoquinonas , Pirroliminoquinonas/metabolismo , Pirroliminoquinonas/química , Família Multigênica , Vias Biossintéticas
2.
Bioorg Med Chem Lett ; 40: 127910, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33711443

RESUMO

Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two heme-containing enzymes which catalyze the conversion of tryptophan to N-formylkynurenine. Both enzymes are well establish therapeutic targets as important factors in the tumor immune evasion mechanism. A number of analogues of the marine pyrroloquinoline alkaloids tsitsikammamines or wakayin have been synthesized, two of them were synthesized using an original method to build the bispyrroloquinone framework. All the derivatives were evaluated in a cellular assay for their capacity to inhibit the enzymes. Six compounds have shown a significant potency on HEK 293-EBNA cell lines expressing hIDO1 or hTDO.


Assuntos
Alcaloides/síntese química , Inibidores Enzimáticos/síntese química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Pirroliminoquinonas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Triptofano Oxigenase/antagonistas & inibidores , Alcaloides/metabolismo , Organismos Aquáticos/química , Inibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Alcaloides Indólicos/química , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Pirróis/química , Pirroliminoquinonas/metabolismo , Quinolinas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-Atividade
3.
Mar Drugs ; 17(1)2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30654589

RESUMO

The temperate marine sponge, Tsitsikamma favus, produces pyrroloiminoquinone alkaloids with potential as anticancer drug leads. We profiled the secondary metabolite reservoir of T. favus sponges using HR-ESI-LC-MS/MS-based molecular networking analysis followed by preparative purification efforts to map the diversity of new and known pyrroloiminoquinones and related compounds in extracts of seven specimens. Molecular taxonomic identification confirmed all sponges as T. favus and five specimens (chemotype I) were found to produce mainly discorhabdins and tsitsikammamines. Remarkably, however, two specimens (chemotype II) exhibited distinct morphological and chemical characteristics: the absence of discorhabdins, only trace levels of tsitsikammamines and, instead, an abundance of unbranched and halogenated makaluvamines. Targeted chromatographic isolation provided the new makaluvamine Q, the known makaluvamines A and I, tsitsikammamine B, 14-bromo-7,8-dehydro-3-dihydro-discorhabdin C, and the related pyrrolo-ortho-quinones makaluvamine O and makaluvone. Purified compounds displayed different activity profiles in assays for topoisomerase I inhibition, DNA intercalation and antimetabolic activity against human cell lines. This is the first report of makaluvamines from a Tsitsikamma sponge species, and the first description of distinct chemotypes within a species of the Latrunculiidae family. This study sheds new light on the putative pyrroloiminoquinone biosynthetic pathway of latrunculid sponges.


Assuntos
Poríferos/metabolismo , Pirroliminoquinonas/química , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/isolamento & purificação , Antimetabólitos Antineoplásicos/farmacologia , Vias Biossintéticas , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , DNA/química , DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Ensaios Enzimáticos , Células HEK293 , Células HeLa , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/isolamento & purificação , Substâncias Intercalantes/farmacologia , Estrutura Molecular , Pirroliminoquinonas/isolamento & purificação , Pirroliminoquinonas/metabolismo , Pirroliminoquinonas/farmacologia , Espectrometria de Massas em Tandem/métodos , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia
4.
J Med Chem ; 55(12): 5851-8, 2012 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-22686608

RESUMO

A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 µM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).


Assuntos
Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Poríferos/química , Pirroliminoquinonas/isolamento & purificação , Pirroliminoquinonas/farmacologia , Animais , Antimaláricos/metabolismo , Antimaláricos/toxicidade , Linhagem Celular , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Pirroliminoquinonas/metabolismo , Pirroliminoquinonas/toxicidade
5.
Mar Biotechnol (NY) ; 14(6): 681-91, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22310802

RESUMO

Tsitsikamma favus is a latrunculid sponge endemic to the coast of South Africa that produces unique pyrroloiminoquinones known as tsitsikammamines. Wakayin and makaluvamine A are structurally similar to the tsitsikammamines and are the only pyrroloiminoquinones isolated from a source other than Porifera (namely a Fijian ascidian Clavelina sp. and a laboratory culture of the myxomycete Didymium bahiense, respectively). The source of the tsitsikammamines is hypothesised to be microbial, which could provide a means of overcoming the current supply problem. This study focuses on characterising the microbial diversity associated with T. favus. We have used denaturing gradient gel electrophoresis together with clonal and deep sequencing of microbial 16S rRNA gene amplicons to show that specimens of this sponge species contain a distinct and conserved microbial population, which is stable over time and is dominated by a unique Betaproteobacterium species.


Assuntos
Betaproteobacteria/isolamento & purificação , Betaproteobacteria/metabolismo , Biodiversidade , Poríferos/microbiologia , Pirróis/metabolismo , Pirroliminoquinonas/metabolismo , Quinolinas/metabolismo , Animais , Betaproteobacteria/classificação , Oceano Índico , Consórcios Microbianos/fisiologia , Especificidade da Espécie
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