Fungal iterative type I polyketide synthases(iPKSs)are commonly classified into nonreducing(NR-),partially reducing(PR-),and highly reducing(HR-)polyketide synthases based on their assembly mechanisms and domain struc...Fungal iterative type I polyketide synthases(iPKSs)are commonly classified into nonreducing(NR-),partially reducing(PR-),and highly reducing(HR-)polyketide synthases based on their assembly mechanisms and domain structures.These iPKSs have been considered functionally and evolutionarily distinct,characterized by clear boundaries.However,emerging genomic analyses suggest that the diversity of iPKSs in fungi is far from fully understood.Here,we describe the discovery and characterization of PbPKS1 from a marine-derived fungus Penicillium brocae HDN12-143,which exhibits an atypical domain organization arranged as KR-KS-AT-PT-ACP1-ACP2-CMeT-TE.Heterologous expression of PbPKS1 resulted in the production of two monohydroxybenzoic acids and two pyrones.In vivo and in vitro characterizations demonstrated that PbPKS1 has the capability to synthesize Cα-methylated partially reducing polyketides,yet involved a NR-PKS-like assembly mechanism,featuring a product template(PT)domain for aldol cyclization and a C-terminal thioesterase(TE)domain for product release.Phylogenetic analysis suggests that PbPKS1 belongs to a non-canonical PR-PKS(nPR-PKS)family,which is a minor grouping across the fungal kingdom,and possibly evolved from an NR-PKS through gene recombination.The discovery of nPR-PKS not only expands the diversity of iPKSs but also provides new insights into the evolutionary development of fungal iPKSs.展开更多
Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary patter...Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E(Apo E) knockout(Apo E-/-) mice, by enhancing intestinal flora production of indole-3-propionic acid(IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor(PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia/reperfusion injury in Apo E-/-mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathways.展开更多
基金supported by Qingdao Marine Science and Technology Center(2022QNLM030003-1)the Fundamental Research Funds for the Central Universities(202172002,202262015)National Key R&D Program of China(2022YFC2807502).
文摘Fungal iterative type I polyketide synthases(iPKSs)are commonly classified into nonreducing(NR-),partially reducing(PR-),and highly reducing(HR-)polyketide synthases based on their assembly mechanisms and domain structures.These iPKSs have been considered functionally and evolutionarily distinct,characterized by clear boundaries.However,emerging genomic analyses suggest that the diversity of iPKSs in fungi is far from fully understood.Here,we describe the discovery and characterization of PbPKS1 from a marine-derived fungus Penicillium brocae HDN12-143,which exhibits an atypical domain organization arranged as KR-KS-AT-PT-ACP1-ACP2-CMeT-TE.Heterologous expression of PbPKS1 resulted in the production of two monohydroxybenzoic acids and two pyrones.In vivo and in vitro characterizations demonstrated that PbPKS1 has the capability to synthesize Cα-methylated partially reducing polyketides,yet involved a NR-PKS-like assembly mechanism,featuring a product template(PT)domain for aldol cyclization and a C-terminal thioesterase(TE)domain for product release.Phylogenetic analysis suggests that PbPKS1 belongs to a non-canonical PR-PKS(nPR-PKS)family,which is a minor grouping across the fungal kingdom,and possibly evolved from an NR-PKS through gene recombination.The discovery of nPR-PKS not only expands the diversity of iPKSs but also provides new insights into the evolutionary development of fungal iPKSs.
基金supported by the grants to J.G. from the National Basic Research Center of China (T2288101)the Shanghai Clinical Research Center for Interventional Medicine (19MC1910300)+7 种基金the Shanghai Municipal Key Clinical Specialty (shslczdzk01701)the State Key Clinical Specialty Construction Project (YW2021-002)the National Natural Science Foundation of China (81970298)the Clinical Research Special Fund of Zhongshan Hospital Fudan University (2020ZSLC57)2021 Clinical Research Navigation Project of Shanghai Medical College of Fudan Universitythe National Natural Science Foundation of China (82100355)the Shanghai Sailing Program (21YF1406000)the Shanghai Science and Technology Innovation Fund (22S31904900)
文摘Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E(Apo E) knockout(Apo E-/-) mice, by enhancing intestinal flora production of indole-3-propionic acid(IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor(PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia/reperfusion injury in Apo E-/-mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathways.
