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1.
Biomolecules ; 14(1)2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38254717

RESUMO

With the rise in antimicrobial resistance, there is an urgent need for new classes of antibiotic with which to treat infectious disease. Marinomycin, a polyene antibiotic from a marine microbe, has been shown capable of killing methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF), as well as having promising activity against melanoma. An attractive solution to the photoprotection of this antibiotic has been demonstrated. Here, we report the identification and analysis of the marinomycin biosynthetic gene cluster (BGC), and the biosynthetic assembly of the macrolide. The marinomycin BGC presents a challenge in heterologous expression due to its large size and high GC content, rendering the cluster prone to rearrangement. We demonstrate the transformation of Streptomyces lividans using a construct containing the cluster, and the heterologous expression of the encoded biosynthetic machinery and production of marinomycin B.


Assuntos
Antineoplásicos , Melanoma , Staphylococcus aureus Resistente à Meticilina , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Antibacterianos/farmacologia , Família Multigênica
2.
Mol Cell ; 82(23): 4537-4547.e7, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36327975

RESUMO

Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.


Assuntos
Malato Desidrogenase , NAD , NAD/metabolismo , Malato Desidrogenase/genética , Malato Desidrogenase/metabolismo , Oxirredução , Ciclo do Ácido Cítrico/fisiologia , Respiração
3.
Nat Commun ; 13(1): 4674, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945217

RESUMO

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.


Assuntos
Apoptose , Glutamina , Apoptose/genética , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico , Fibroblastos/metabolismo , Glutamina/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
4.
Chem Sci ; 10(32): 7549-7553, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31588306

RESUMO

The photoprotection and isolation of marinomycin A using sporopollenin exine capsules (SpECs) derived from the spores of the plant Lycopodium clavatum is described. The marinomycins have a particularly short half-life in natural light, which severely impacts their potential biological utility given that they display potent antibiotic and anticancer activity. The SpEC encapsulation of the marinomycin A dramatically increases the half-life of the polyene macrodiolide to the direct exposure to UV radiation by several orders of magnitude, thereby making this a potentially useful strategy for other light sensitive bioactive agents. In addition, we report that the SpECs can also be used to selectively extract culture broths that contain the marinomycins, which provides a significantly higher recovery than with conventional XAD resins and provides concomitant photoprotection.

5.
Prog Mol Subcell Biol ; 55: 159-186, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28238038

RESUMO

Nature provides a valuable resource of medicinally relevant compounds, with many antimicrobial and antitumor agents entering clinical trials being derived from natural products. The generation of analogues of these bioactive natural products is important in order to gain a greater understanding of structure activity relationships; probing the mechanism of action, as well as to optimise the natural product's bioactivity and bioavailability. This chapter critically examines different approaches to generating natural products and their analogues, exploring the way in which synthetic and biosynthetic approaches may be blended together to enable expeditious access to new designer natural products.


Assuntos
Organismos Aquáticos/química , Produtos Biológicos/química , Técnicas de Química Sintética/tendências , Química Farmacêutica/tendências , Desenho de Fármacos , Preparações Farmacêuticas/síntese química , Animais , Técnicas de Química Combinatória/tendências , Avaliação Pré-Clínica de Medicamentos/tendências , Ensaios de Triagem em Larga Escala/tendências , Tecnologia Farmacêutica/tendências
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