Discovery and Theoretical Studies of Nonenzymatic Polyketide Dimerizations of Chaetophenols.

Nonenzymatic reactions sometimes construct complex structures observed in natural products, showing us unique chemical reactions. In our exploration of natural products, we identified a novel type of isochromene-derived polyketide dimer with a 6/6/6/6/6 five-ring system from along with several new related polyketides. We demonstrated that isochromene and its oxidized derivative undergo nonenzymatic dimerization under acidic conditions to give .

Green tea consumption and cerebral white matter lesions in community-dwelling older adults without dementia.

This study investigated the association between green tea or coffee consumption with cerebral white matter lesions and hippocampal and total brain volumes among 8766 community-dwelling participants recruited from the Japan Prospective Studies Collaboration for Aging and Dementia between 2016 and 2018. A Food Frequency Questionnaire was used to assess green tea and coffee consumption, whereas brain magnetic resonance imaging was performed to assess cerebral white matter lesions, hippocampal volume, and total brain volume. Multivariable-adjusted analysis revealed significant correlations between fewer cerebral white matter lesions and higher green tea consumption, whereas no significant differences were found between green tea consumption and hippocampal or total brain volume.

Semi-synthesis of a DNA-Tagged Polyketide-Peptide Hybrid Macrocycle Using a Biosynthetically Prepared Fungal Macrolide as a Synthetic Component.

Presented herein is a synthetic biological method using genome mining and heterologous expression systems that provides access to natural products with desirable structural features as building blocks. In this investigation, we synthesized polyketide-peptide hybrid macrocycles with DNA tags, which have the potential to access a DNA-encoded library containing over one million compounds. This study demonstrates that synthetic biology offers a tool for expanding the diversity of building blocks, facilitating the exploration of unexplored chemical space.

In vivo and in vitro Reconstitution of Biosynthesis of N-Prenylated Phenazines Revealing Diverse Phenazine-Modifying Enzymes.

Phenazine natural products play various roles such as signal molecules, antibiotics, or electron carriers in their producer strains. Among these products, phenazinomycin and lavanducyanin, which are produced by Streptomyces species, are characterized by an N-alkyl modification. Herein, we established the biosynthetic pathways for these two phenazine natural products.

Subcellular compartmentalized localization of transmembrane proteins essential for production of fungal cyclic peptide cyclochlorotine.

Fungal biosynthetic gene clusters often include genes encoding transmembrane proteins, which have been mostly thought to be transporters exporting the products. However, there is little knowledge about subcellular compartmentalization of transmembrane proteins essential for biosynthesis. Fungal mycotoxin cyclochlorotine is synthesized by non-ribosomal peptide synthetase, which is followed by modifications with three transmembrane UstYa-family proteins.

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (-)-sandaracopimaradiene in the fungus .

Labdane-related diterpenoids (LRDs) in fungi are a pharmaceutically important, but underexplored family of natural products. In the biosynthesis of fungal LRDs, bifunctional terpene cyclases (TCs) consisting of αβγ domains are generally used to synthesize the polycyclic skeletones of LRDs. Herein, we conducted genome mining of LRDs in our fungal genome database and identified a unique pair of TCs, AsPS and AsCPS, in the fungus .

Bioinformatics-Guided Reconstitution of Biosynthetic Machineries of Fungal Eremophilane Sesquiterpenes.

Eremophilanes exhibit diverse biological activities and chemical structures. This study reports the bioinformatics-guided reconstitution of the biosynthetic machinery of fungal eremophilanes, eremofortin C and sporogen-AO1, to elucidate their biosynthetic pathways. Their biosyntheses include P450-catalyzed multistep oxidation and enzyme-catalyzed isomerization by the DUF3237 family protein.

Partial replacement of d-glucose with d-allose ameliorates peritoneal injury and hyperglycaemia induced by peritoneal dialysis fluid in rats.

Background: Peritoneal dialysis (PD) is a crucial dialysis method for treating end-stage kidney disease. However, its use is restricted due to high glucose-induced peritoneal injury and hyperglycaemia, particularly in patients with diabetes mellitus. In this study, we investigated whether partially replacing d-glucose with the rare sugar d-allose could ameliorate peritoneal injury and hyperglycaemia induced by peritoneal dialysis fluid (PDF).

Structural diversification of fungal natural products by oxidative enzymes.

Ascomycota and basidiomycota fungi are prolific producers of biologically active natural products. Fungal natural products exhibit remarkable structural diversity and complexity, which are generated by the enzymes involved in their biosynthesis. After the formation of core skeletons, oxidative enzymes play a critical role in converting them into mature natural products.

Identification and Functional Characterization of Fungal Chalcone Synthase and Chalcone Isomerase.

By mining fungal genomic information, a noncanonical iterative type I PKS fused with an N-terminal adenylation-thiolation didomain, which catalyzes the formation of naringenin chalcone, was found. Structural prediction and molecular docking analysis indicated that a C-terminal thioesterase domain was involved in the Claisen-type cyclization. An enzyme responsible for formation of (2)-flavanone in the biosynthesis of fungal flavonoids was also identified.

Recent advances in the biosynthesis of ribosomally synthesized and posttranslationally modified peptides of fungal origin.

Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are growing class of natural products with potent biological activities. Although the core scaffolds of RiPPs are composed of proteinogenic amino acids, remarkable structural diversity is generated through posttranslational modifications (PTMs) of precursor peptides. In addition, ribosomal origin of biosynthetic precursors enables supply of its analogs through genetic approach such as site-directed mutagenesis on corresponding genes.

Elucidation of Late-Stage Biosynthesis of Phomoidride: Proposal of Cyclization Mechanism Affording Characteristic Nine-Membered Ring of Fungal Dimeric Anhydride.

Antihypercholesterolemic agent phomoidride (PMD) B has a highly elaborated bicyclo[4.3.1]deca-1,6-diene core scaffold derived from dimeric anhydride with a nine-membered ring.

Biosynthesis of indole diterpenes: a reconstitution approach in a heterologous host.

Covering: 2013 to 2022In this review, we provide an overview elucidating the biosynthetic pathway and heterologous production of fungal indole diterpenes (IDTs). Based on the studies of six IDT biosynthesis, we extracted nature's strategy: (1) two-stage synthesis for the core scaffold and platform intermediates, and (2) late-stage modifications for installing an additional cyclic system on the indole ring. Herein, we describe reconstitution studies applying this strategy to the synthesis of highly elaborated IDTs.

Discovery of a Cyclic Depsipeptide from by the Genome Mining Approach.

Genome mining and bioinformatics analyses allowed us to rationally find a candidate biosynthetic gene cluster for a new cyclic depsipeptide of . A heterologous reconstitution of the identified biosynthetic pathway predictably afforded a new cyclic depsipeptide composed of l-leucine, l-tryptophan, and a polyketide moiety. Interestingly, the 10-membered macrocycle structure generated equilibrium to an unprecedented cyclol structure.

Biosynthetic machineries of anthraquinones and bisanthraquinones in Talaromyces islandicus.

Talaromyces islandicus is a unique fungus that produces more than 20 numbers of anthraquinones (AQs) and their dimeric natural products, bisanthraquinones (BQs). These compounds share a 9,10-anthracenedione core derived from emodin. The biosynthetic pathway of emodin has been firmly established, while that of other AQs and BQs is still unclear.

Heterologous expression of a polyketide synthase ACRTS2 in Aspergillus oryzae produces host-selective ACR toxins: coproduction of minor metabolites.

Previously, we succeeded to produce the core structure of the host-selective ACR toxin (1) on brown leaf spot on rough lemon when the polyketide synthase ACRTS2 gene was heterologously expressed in Aspergillus oryzae (AO). To confirm the production of 1 in AO, the detection limit and suppressing decarboxylation were improved, and these efforts led us to conclude the direct production of 1 instead of its decarboxylation product. During this examination, minor ACR-toxin-related metabolites were found.

Biosynthetic Studies of Phomopsins Unveil Posttranslational Installation of Dehydroamino Acids by UstYa Family Proteins.

UstYa family proteins (DUF3328) are widely and specifically distributed in fungi. They are known to be involved in the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs) and nonribosomal peptides, and possibly catalyze various reactions, including oxidative cyclization and chlorination. In this study, we focused on phomopsin A, a fungal RiPP consisting of unique nonproteinogenic amino acids.

Biochemistry-Guided Prediction of the Absolute Configuration of Fungal Reduced Polyketides.

Highly reducing polyketide synthases (HR-PKSs) produce structurally diverse polyketides (PKs). The PK diversity is constructed by a variety of factors, including the β-keto processing, chain length, methylation pattern, and relative and absolute configurations of the substituents. We examined the stereochemical course of the PK processing for the synthesis of polyhydroxy PKs such as phialotides, phomenoic acid, and ACR-toxin.

Genome-Based Discovery of Enantiomeric Pentacyclic Sesterterpenes Catalyzed by Fungal Bifunctional Terpene Synthases.

Genome-based discovery of two previously unreported fungal bifunctional terpene synthases (BFTSs) from phytopathogenic fungi are reported: FoFS catalyzing the formation of fusoxypenes A-C (-) and (-)-astellatene () and AtAS capable of synthesizing preaspterpenacid I (). Interestingly, FoFS and AtAS catalyzed the formation of enantiomeric sesterterpenes with a 5-6-7-3-5 ring system. C22-oxidative modification of preaspterpenacid I by AtP450 was characterized as well.

Biosynthesis of Cyclochlorotine: Identification of the Genes Involved in Oxidative Transformations and Intramolecular ,-Transacylation.

Mycotoxin cyclochlorotine () and structurally related astins are cyclic pentapeptides containing unique nonproteinogenic amino acids, such as β-phenylalanine, l--threonine, and 3,4-dichloroproline. Herein, we report the biosynthetic pathway for , which involves intriguing tailoring processes mediated by DUF3328 proteins, including stereo- and regiospecific chlorination and hydroxylation and intramolecular ,-transacylation. Our findings demonstrate that DUF3328 proteins, which are known to be involved in oxidative cyclization of fungal ribosomal peptides, have much higher functional diversity than previously expected.

Time Course Changes in Urinary Angiotensinogen and Circulating N-Terminal Pro-B-Type Natriuretic Peptide in Patients Hospitalized with Acute Heart Failure.

Objective Home care is important in patients with heart failure (HF) in order to maintain their quality of life. A biomarker that can be measured noninvasively is needed to optimize the home care of patients with HF. Urinary angiotensinogen (uAGT) is an indicator of the intrarenal renin-angiotensin system activity, which may be augmented in HF.