Predicting substrates for orphan Solute Carrier Proteins using multi-omics datasets

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 24, 2024

Abstract Solute carriers (SLC) are integral membrane proteins responsible for transporting a wide variety of metabolites, signaling molecules and drugs across cellular membranes. Despite key roles in metabolism, pharmacology, around one third SLC ‘orphans’ whose substrates unknown. Experimental determination is technically challenging given the range possible physiological candidates. Here, we develop predictive algorithm to identify correlations between expression levels intracellular metabolite concentrations by leveraging existing cancer multi-omics datasets. Our predictions recovered known SLC-substrate pairs with high sensitivity specificity compared simulated random pairs. CRISPR loss-of-function screen data metabolic pathway adjacency further improved performance our algorithm. In parallel, combined drug profiles predict new SLC-drug interactions. Together, provide novel bioinformatic pipeline substrate SLCs, offering opportunities de-orphanise SLCs important implications understanding their health disease.

Язык: Английский

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Evidence for the Role of the Mitochondrial ABC Transporter MDL1 in the Uptake of Clozapine and Related Molecules into the Yeast Saccharomyces cerevisiae

Pharmaceuticals, Год журнала: 2024, Номер 17(7), С. 938 - 938

Опубликована: Июль 13, 2024

Clozapine is an antipsychotic drug whose accumulation in white cells can sometimes prove toxic; understanding the transporters and alleles responsible thus highly desirable. We used a strategy which yeast (Saccharomyces cerevisiae) CRISPR-Cas9 knock-out library was exposed to cytotoxic concentrations of clozapine determine those absence made it more resistant; we also recognised structural similarity fluorescent dye safranin O (also known as T) clozapine, allowing be surrogate marker. Strains lacking mitochondrial ABC transporter MDL1 (encoded by YLR188W) showed substantial resistance clozapine. overexpression conferred extra sensitivity admitted massive increase cellular uptake O, determined using flow cytometry microscopically. Yeast mitochondria no such unusual accumulation. Mitochondrial main means S. cerevisiae. The closest human homologue cerevisiae ABCB10.

Язык: Английский

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Stichoposide C and Rhizochalin as Potential Aquaglyceroporin Modulators

Marine Drugs, Год журнала: 2024, Номер 22(8), С. 335 - 335

Опубликована: Июль 25, 2024

Aquaporins (AQPs) are a family of integral membrane proteins that selectively transport water and glycerol across the cell membrane. Because AQPs involved in wide range physiological functions pathophysiological conditions, AQP-based therapeutics may have broad potential for clinical utility, including disorders energy balance. However, AQP modulators not yet been developed as suitable candidates applications. In this study, to identify AQPs, we screened 31 natural products by measuring permeability mouse erythrocyte membranes using stopped-flow light scattering method. None tested compounds substantially affected osmotic permeability. several considerably Stichoposide C increased membranes, whereas rhizochalin decreased it at nanomolar concentrations. Immunohistochemistry revealed AQP7 was main aquaglyceroporin membranes. We further verified effects stichoposide on aquaglyceroporins human AQP3-expressing keratinocyte cells. C, but D, AQP3-mediated transepithelial transport, peracetyl aglycon most potent inhibitor among derivatives. Collectively, might function AQP3 AQP7, suggests possibility these drug modulators.

Язык: Английский

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Predicting substrates for orphan Solute Carrier Proteins using multi- omics datasets

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 5, 2024

Solute carriers (SLC) are integral membrane proteins responsible for transporting a wide variety of metabolites, signaling molecules and drugs across cellular membranes. Despite key roles in metabolism, pharmacology, around one third SLC ‘orphans’ whose substrates unknown. Experimental determination is technically challenging given the range possible physiological candidates. Here, we develop predictive algorithm to identify correlations between expression levels intracellular metabolite concentrations by leveraging existing cancer multi-omics datasets. Our predictions recovered known SLC-substrate pairs with high sensitivity specificity compared simulated random pairs. CRISPR loss-of-function screen data metabolic pathway adjacency further improved performance our algorithm. In parallel, combined drug profiles predict new SLC-drug interactions. Together, provide novel bioinformatic pipeline substrate SLCs, offering opportunities de-orphanise SLCs important implications understanding their health disease.

Язык: Английский

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Reduce drug uptake in the development of resistance

Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 53 - 75

Опубликована: Ноя. 1, 2024

Язык: Английский

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