Chemoenzymatic Total Synthesis and Structural Diversification of Tylactone-Based Macrolide Antibiotics through Late-Stage Polyketide Assembly, Tailoring, and C-H Functionalization.

Polyketide synthases (PKSs) represent a powerful catalytic platform capable of effecting multiple carbon-carbon bond forming reactions and oxidation state adjustments. We explored the functionality of two terminal PKS modules that produce the 16-membered tylosin macrocycle, using them as biocatalysts in the chemoenzymatic synthesis of tylactone and its subsequent elaboration to complete the first total synthesis of the juvenimicin, M-4365, and rosamicin classes of macrolide antibiotics via late-stage diversification. Synthetic chemistry was employed to generate the tylactone hexaketide chain elongation intermediate that was accepted by the juvenimicin (Juv) ketosynthase of the penultimate JuvEIV PKS module. The hexaketide is processed through two complete modules (JuvEIV and JuvEV) in vitro, which catalyze elongation and functionalization of two ketide units followed by cyclization of the resulting octaketide into tylactone. After macrolactonization, a combination of in vivo glycosylation, selective in vitro cytochrome P450-mediated oxidation, and chemical oxidation was used to complete the scalable construction of a series of macrolide natural products in as few as 15 linear steps (21 total) with an overall yield of 4.6%.

Phytochemicals in Morinda citrifolia fruit selectively modulate age-associated immunity and antioxidant enzyme activities through ERK pathway in splenic lymphocytes of male F344 rats.

CONTEXT/OBJECTIVE: The mechanisms of immunomodulatory effects of Morinda citrifolia (Noni) were examined through intracellular signaling pathways in the splenocytes and their modulation by phytochemicals using bioinformatics tools. MATERIALS AND METHODS: Noni fruit juices without seeds (NSL) and with seeds (NWS) were co-incubated in vitro with splenocytes from young, middle-aged and old F344 male rats and proliferation of lymphocytes, cytokine production, antioxidant enzyme activities and intracellular signaling markers were measured. RESULTS: NSL decreased lymphoproliferation in early middle-aged rats, and IL-2 and IFN-γ production in old rats. In contrast, NWS enhanced lymphoproliferation in young and old rats, IL-2 and IFN-γ production in middle-aged and old rats. The activities of antioxidant enzymes were augmented by NWS and NSL in old rats. NWS reversed age-related increase in lipid peroxidation in all age-groups, while NSL increased lipid peroxidation in old rats. NSL increased p-ERK in old rats and decreased p-CREB in young and middle-aged rats. In contrast, NWS decreased p-ERK in all age groups and increased p-CREB in old rats. Both NSL and NWS increased p-Akt expression in middle-aged and old rats. Both NSL and NWS suppressed p-NF-κB expression in middle-aged and old rats. Docking studies demonstrated that Noni phytochemicals, damnacanthal, myricetin and ursolic acid, are potent inhibitors of ERK with binding sites in the catalytic and phosphorylation sites of the molecule. CONCLUSIONS: These results suggest that Noni fruit juices with or without seeds modulate cell-mediated immunity and antioxidant enzyme activities based on the phytochemicals that may differentially influence cell signaling and therefore, age-associated immunity.

Strategies for enhancing the efficacy of anaerobic digestion of food industry wastewater: An insight into bioreactor types, challenges, and future scope.

Food waste have become a growing concern worldwide with raising population and economic growth. Wastewater discharged from food industries contains many valuable and toxic components that have a negative impact on the ecological system. Large amounts of wastewater are discharged from the food industry, which necessitates the creation of effective technologies. Wastewater from the food industry can be seen as a rich source of energy and a primary source for generating valuable products. Waste disposal and resource recovery are sustainably valued by anaerobic digestion of wastewater from the food sector. The characteristics, composition, and nature of wastewater produced from various food sectors are elaborated upon in this review. An overview of the anaerobic digestion process for wastewater treatment in the food industry is included. Enhancement strategies for the anaerobic digestion process have been discussed in detail. In addition, various types of reactors utilized for performing anaerobic digestion is illustrated. Though anaerobic digestion process possesses advantages, the challenges and future scope are examined for improving the outcome.

Comparative analysis of the biosynthetic systems for fungal bicyclo[2.2.2]diazaoctane indole alkaloids: the (+)/(-)-notoamide, paraherquamide and malbrancheamide pathways.

The biosynthesis of fungal bicyclo[2.2.2]diazaoctane indole alkaloids with a wide spectrum of biological activities have attracted increasing interest. Their intriguing mode of assembly has long been proposed to feature a non-ribosomal peptide synthetase, a presumed intramolecular Diels-Alderase, a variant number of prenyltransferases, and a series of oxidases responsible for the diverse tailoring modifications of their cyclodipeptide-based structural core. Until recently, the details of these biosynthetic pathways have remained largely unknown due to lack of information on the fungal derived biosynthetic gene clusters. Herein, we report a comparative analysis of four natural product metabolic systems of a select group of bicyclo[2.2.2]diazaoctane indole alkaloids including (+)/(-)-notoamide, paraherquamide and malbrancheamide, in which we propose an enzyme for each step in the biosynthetic pathway based on deep annotation and on-going biochemical studies.