Direct Utilization of Peroxisomal Acetyl-CoA for the Synthesis of Polyketide Compounds in Saccharomyces cerevisiae.

Polyketides are a class of natural products with many applications but are mainly appealing as pharmaceuticals. Heterologous production of polyketides in the yeast Saccharomyces cerevisiae has been widely explored because of the many merits of this model eukaryotic microorganism. Although acetyl-CoA and malonyl-CoA, the precursors for polyketide synthesis, are distributed in several yeast subcellular organelles, only cytosolic synthesis of polyketides has been pursued in previous studies. In this study, we investigate polyketide synthesis by directly using acetyl-CoA in the peroxisomes of yeast strain CEN.PK2-1D. We first demonstrate that the polyketide flaviolin can be synthesized in this organelle upon peroxisomal colocalization of native acetyl-CoA carboxylase and 1,3,6,8-tetrahydroxynaphthalene synthase (a type III polyketide synthase). Next, using the synthesis of the polyketide triacetic acid lactone as an example, we show that (1) a new peroxisome targeting sequence, pPTS1, is more effective than the previously reported ePTS1 for peroxisomal polyketide synthesis; (2) engineering peroxisome proliferation is effective to boost polyketide production; and (3) peroxisomes provide an additional acetyl-CoA reservoir and extra space to accommodate enzymes so that utilizing the peroxisomal pathway plus the cytosolic pathway produces more polyketide than the cytosolic pathway alone. This research lays the groundwork for more efficient heterologous polyketide biosynthesis using acetyl-CoA pools in subcellular organelles.

Inhibition of human glioblastoma multiforme cells by 10,11-dehydrocurvularin through the MMP-2 and PI3K/AKT signaling pathways.

Glioblastoma, formerly known as glioblastoma multiforme (GBM), is a malignant nervous system tumor with high morbidity, recurrence rate, and mortality. Treating glioblastoma is difficult due to complicating factors, and novel therapeutic strategies are required to overcome resistance. In this study, we investigate the glioblastoma inhibitory activity of 10,11-dehydrocurvularin (DCV), a polyketide compound with broad biological activities, despite the fact that its anti-glioma properties and related mechanisms have yet to be studied. We look at how DCV affects glioblastoma cell lines U251 and U87 versus HEB cells. We discover that DCV inhibits glioblastoma cell proliferation, colony formation, migration, and invasion, as well as causing cell apoptosis. DCV treatment inhibits AKT phosphorylation and decreases the level of the PI3K/AKT pathway downstream protein MMP2. Our findings suggest that DCV could be a candidate for developing more potent glioblastoma chemotherapeutic drugs.

Northward migration of the East Asian summer monsoon northern boundary during the twenty-first century.

The northern fringe area of the East Asian summer monsoon (EASM) between arid and semiarid regions is a fragile eco-environment zone and ecological transition zone, and it is highly sensitive to climate change. Predicting the future migration of the northern boundary of the EASM is important for understanding future East Asian climate change and formulating of decisions on ecological protection and economic development in arid and semiarid regions. The reanalysis dataset and simulations of 23 models from the Coupled Models Intercomparison Project Phase 6 (CMIP6) were used to investigate the response of the boundary of the ESAM to the global warming. The multi-model ensemble showed a northwestward migration of the EASM northern boundary during the near-term (2020-2060) and late-term (2061-2099) of the twenty-first century under various Shared Socioeconomic Pathways (SSPs). The northern boundary migrated northwestward by 23-28 and 74-76 km in the near-term and late-term respectively, under SSP1-2.6, 2-4.5 and 3-7.0 and by ~ 44 km and ~ 107 km respectively during the near-term and late-term under SSP5-8.5. During the twenty-first century, under various SSPs, the surface of the East Asian subcontinent warmed more than the ocean, thereby increasing the contrast of near-surface temperature and sea level pressure in summer between the East Asian subcontinent and the surrounding oceans. In turn, the intensified land-sea thermal contrast reinforced the EASM meridional circulation and thus transported more moisture from the Indian Ocean into northern China. Additionally, a poleward migration and weakening of the East Asian subtropical westerly jet would also favor an increase in precipitation, eventually caused a northwestward migration of the EASM northern boundary. The results suggest that the arid and semiarid ecotone will become wetter, which could dramatically improve the eco-environment in the future.