ABSTRACT
Indolizidine alkaloids such as anticancer drugs vinblastine and vincristine are exceptionally attractive due to their widespread occurrence, prominent bioactivity, complex structure, and sophisticated involvement in the chemical defense for the producing organisms. However, the versatility of the indolizidine alkaloid biosynthesis remains incompletely addressed since the knowledge about such biosynthetic machineries is only limited to several representatives. Herein, we describe the biosynthetic gene cluster (BGC) for the biosynthesis of curvulamine, a skeletally unprecedented antibacterial indolizidine alkaloid from Curvularia sp. IFB-Z10. The molecular architecture of curvulamine results from the functional collaboration of a highly reducing polyketide synthase (CuaA), a pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (CuaB), an NADPH-dependent dehydrogenase (CuaC), and a FAD-dependent monooxygenase (CuaD), with its transportation and abundance regulated by a major facilitator superfamily permease (CuaE) and a Zn(II)Cys6 transcription factor (CuaF), respectively. In contrast to expectations, CuaB is bifunctional and capable of catalyzing the Claisen condensation to form a new C-C bond and the α-hydroxylation of the alanine moiety in exposure to dioxygen. Inspired and guided by the distinct function of CuaB, our genome mining effort discovers bipolamines A-I (bipolamine G is more antibacterial than curvulamine), which represent a collection of previously undescribed polyketide alkaloids from a silent BGC in Bipolaris maydis ATCC48331. The work provides insight into nature's arsenal for the indolizidine-coined skeletal formation and adds evidence in support of the functional versatility of PLP-dependent enzymes in fungi.
Subject(s)
Alkaloids/biosynthesis , Ascomycota/enzymology , Ascomycota/metabolism , Indolizidines/metabolism , Polyketide Synthases/metabolism , Pyridoxal Phosphate/metabolism , Alkaloids/genetics , Alkaloids/isolation & purification , Anti-Bacterial Agents/metabolism , Ascomycota/genetics , Aspergillus oryzae/genetics , Aspergillus oryzae/metabolism , Catalysis , Fungal Proteins/genetics , Fungal Proteins/metabolism , Genes, Fungal/genetics , Hydroxylation , Indole Alkaloids , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Multigene Family , Phylogeny , Polyketide Synthases/classification , Polyketide Synthases/genetics , Polyketides , Pyridoxal Phosphate/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Transaminases/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
BACKGROUND: Improving patients' perception of social support is significant not only for their re-adaptation to life but also for alleviating caregivers' burden. AIM: This study aims to examine an integrated model regarding social support, psychotic symptoms and caregiver burden. METHODS: Persons with schizophrenia (N1 = 300) and their family caregivers (N2 = 300) in Xinjin County, Chengdu, China, completed the survey to report their demographics, patients' perception of social support (Duke Social Support Index), psychotic symptoms (Positive and Negative Syndrome Scale) and caregiver burden (Burden Scale for Family Caregivers, Short Version). Structural equation modelling was utilised to test the proposed model. RESULTS: The degree of caregiver burden differed significantly within subgroups of patients' gender and education, as well as caregivers' gender, education and employment. Caregiver burden was negatively related to patients' age and household income. Social interaction partially mediated the relationship between instrumental and subjective social support (total effect = 0.451, p < .01). Subjective social support fully mediated the impact of social interaction on psychotic symptoms (total effect = -0.099, p < .05). In the final model, instrumental social support was positively associated with social interaction (p < .001) and increased subjective social support (p < .05). Increased subjective social support showed correlation with a lower degree of psychotic symptoms (p < .01), which was related to a lower level of caregiver burden (p < .001). CONCLUSION: This study shows the associations of patients' social support with psychotic symptoms and caregiver burden. Culture-specific psychosocial interventions should be provided for both patients and caregivers to enrich external support and reduce psychotic symptoms and caregivers' burden within the health care environment.
