Screening of Protein Tyrosine Phosphatase 1B Inhibitors from Actinomycete Extracts Using Recombinant Saccharomyces cerevisiae

TL;DR

Researchers used genetically modified yeast to find new inhibitors for PTP1B, a protein linked to diabetes and obesity, from actinomycete extracts.

Contribution

A novel screening method using recombinant yeast to identify PTP1B inhibitors from natural sources.

Findings

Eight actinomycete extracts inhibited PTP1B and suppressed recombinant yeast growth.

Extract 4585DW showed PTP1B inhibitory activity comparable to known inhibitors like suramin and vanadate.

4585DW was non-toxic and had specific kinetic parameters for PTP1B inhibition.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) removes phosphate groups from phosphorylated tyrosine proteins in human cells, particularly in the insulin and leptin signaling pathways. It is a key drug target for ailments such as type 2 diabetes and obesity. However, there is a lack of highly specific PTP1B inhibitor drugs. This study employed recombinant Saccharomyces cerevisiae that co-expressed PTP1B and v-Src (viral sarcoma protein tyrosine kinase) to screen for novel PTP1B inhibitors derived from actinomycete extracts. Eight extracts significantly suppressed the growth of the recombinant S. cerevisiae by inhibiting PTP1B expression, indicating their potential as PTP1B inhibitors. In a protein-chip assay, actinomycete extract 4585DW showed PTP1B inhibitory activity comparable to the positive controls, suramin and vanadate. The extract was non-cytotoxic in mammalian and yeast cells and inhibited PTP1B with Km and Vmax values of 10.91 ± 0.50 mM and 0.02 ± 0.00 μmol/min, respectively. In conclusion, 4585DW is a promising candidate for further investigation as a PTP1B inhibitor.

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