A5084988611- Cancer, Hypoxia, and Metabolism
- Microbial Natural Products and Biosynthesis
- Plant biochemistry and biosynthesis
- Eicosanoids and Hypertension Pharmacology
- Metal-Catalyzed Oxygenation Mechanisms
- Pancreatitis Pathology and Treatment
- Glycosylation and Glycoproteins Research
- Proteoglycans and glycosaminoglycans research
- Epigenetics and DNA Methylation
- Synthesis of Indole Derivatives
- Diabetes and associated disorders
- Vitamin K Research Studies
- Alkaloids: synthesis and pharmacology
- Metabolism and Genetic Disorders
- Hormonal Regulation and Hypertension
- Chemical synthesis and alkaloids
- Marine Sponges and Natural Products
- Metabolism, Diabetes, and Cancer
- Signaling Pathways in Disease
- Vitamin C and Antioxidants Research
- Microbial metabolism and enzyme function
- Adrenal and Paraganglionic Tumors
- Piperaceae Chemical and Biological Studies
- Diet and metabolism studies
- Plant Gene Expression Analysis
University of Toyama
2021-2025
Toyohashi Municipal Hospital
2023-2025
Kyushu University
2024
University of Oxford
2020-2024
Oxford Research Group
2021-2024
Mansfield University
2024
The University of Tokyo
2014-2022
Nagoya University
2022
Kyushu Okinawa Agricultural Research Center
2022
Panasonic (Japan)
2022
Paraherquonin (1), a fungal meroterpenoid produced by Penicillium brasilianum NBRC 6234, possesses unique, highly congested hexacyclic molecular architecture. Here we identified the biosynthetic gene cluster of 1 (the prh cluster) and elucidated pathway up to berkeleydione (2), which serves as key intermediate for biosynthesis well many other meroterpenoids. Interestingly, nonheme iron α-ketoglutarate-dependent dioxygenase PrhA constructs cycloheptadiene moiety afford 2 from preaustinoid A1...
Abstract 2-(2-Phenylethyl)chromones (PECs) are the principal constituents contributing to distinctive fragrance of agarwood. How PECs biosynthesized is currently unknown. In this work, we describe a diarylpentanoid-producing polyketide synthase (PECPS) identified from Aquilaria sinensis . Through biotransformation experiments using fluorine-labeled substrate, transient expression PECPS in Nicotiana benthamiana , and knockdown A. calli, demonstrate that C 6 –C 5 scaffold diarylpentanoid...
Non-heme iron and α-ketoglutarate (αKG) oxygenases catalyze remarkably diverse reactions using a single ferrous ion cofactor. A major challenge in studying this versatile family of enzymes is to understand their structure-function relationship. AusE from Aspergillus nidulans PrhA Penicillium brasilianum are two highly homologous Fe(II)/αKG fungal meroterpenoid biosynthetic pathways that use preaustinoid A1 as common substrate divergent rearrangement form the spiro-lactone austinol...
The effects of diltiazem, a calcium antagonist, on the development atherosclerosis were studied in Japanese white rabbits. rabbits examined at end 10 weeks following regimens; diet standard pellets and daily intraperitoneal (ip) injections saline; containing 1% cholesterol ip or diltiazem (50 mg). plasma total LDL levels for third group significantly lower than those group. Macroscopically, atheromatous lesions covered 26.7% +/- 6.7% (mean SE) intimal surface aorta second group, 0.7% 0.3% (p...
Energy metabolism and substrate oxidation during sleep correlate with stage, suggesting that energy affects architecture or vice versa. The aim of the present study was to examine whether changes in sleep, induced by a high-carbohydrate high-fat meal for dinner, affect architecture. Ten healthy males participated this study, sleeping 3 nonconsecutive nights whole-room calorimeter. first night scheduled as an adaptation experimental environment. other 2 were calorimetry balanced cross-over...
AndA, an Fe(II)/α-ketoglutarate (αKG)-dependent enzyme, is the key enzyme that constructs unique and congested bridged-ring system of anditomin (1), by catalyzing consecutive dehydrogenation isomerization reactions. Although we previously characterized AndA to some extent, means which facilitates this drastic structural reconstruction have remained elusive. In study, solved three X-ray crystal structures in its apo form complexes with Fe(II), αKG, two substrates. The mutational experiments...
Amaryllidaceae alkaloids are structurally diverse natural products with a wide range biological properties, and based on the partial identification of biosynthetic enzymes, norbelladine would be common intermediate in pathways. Previous studies suggested that synthase (NBS) catalyzed condensation reaction 3,4-dihydroxybenzaldehyde tyramine to form norcraugsodine, subsequently, noroxomaritidine/norcraugsodine reductase (NR) nicotinamide adenine dinucleotide phosphate (NADPH)-dependent...
Steviol glycosides (SGs) are noncaloric natural sweeteners found in the leaves of stevia (Stevia rebaudiana). These diterpene biosynthesized by attaching varying numbers monosaccharides, primarily glucose, to steviol aglycone. Rebaudioside (Reb) D and Reb M highly glucosylated SGs that valued for their superior sweetness organoleptic properties, yet they present limited quantities leaves. This study aims improve substrate preference catalytic efficiency UDP-sugar-dependent...
Sponge metagenomes are a useful platform to mine cryptic biosynthetic gene clusters responsible for production of natural products involved in the sponge-microbe association. Since numerous sponge-derived bioactive metabolites biosynthesized by symbiotic bacteria, this strategy may concurrently reveal sponge-symbiont produced compounds. Accordingly, metagenomic analysis Japanese marine sponge Discodermia calyx has resulted identification hybrid type I polyketide synthase-nonribosomal peptide...
Catechins, phytochemicals contained mainly in green tea, exhibit antiviral activity against various acute infectious diseases experimentally. Clinical evidence supporting these effects, however, is not conclusive. We performed a placebo-controlled, single-blind, randomized control trial to evaluate the clinical effectiveness of consumption catechins-containing beverage for preventing upper respiratory tract infections (URTIs). Two hundred and seventy healthcare workers were randomly...
Abstract Human prolyl‐hydroxylases (PHDs) are hypoxia‐sensing 2‐oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia‐inducible factor target genes. PHD inhibition enables treatment anaemia/ischaemia‐related disease. The inhibitor Molidustat is approved for renal anaemia; it differs from other approved/late‐stage inhibitors in lacking a glycinamide side chain. first reported crystal structures and IOX4 (a brain‐penetrating derivative) complexed with PHD2...
Prenylation is a key post-translational reaction to increase the structural diversity and bioactivity of peptides proteins. Until now, only one modification enzyme, ComQ, has been identified mediate prenylation tryptophan residue in ribosomally synthesized peptides. Here, we report vitro characterization KgpF, novel prenyltransferase which transfers dimethylallyl moieties residues during kawaguchipeptin A biosynthesis. The stereospecific by KgpF was determined combination dimethylallylation...
Abstract 2-Oxoglutarate (2OG) oxygenases are validated agrochemical and human drug targets. The potential for modulating their activity with 2OG derivatives has not been explored, possibly due to concerns regarding selectivity. We report proof-of-principle studies demonstrating selective enhancement or inhibition of oxygenase by 2-oxo acids. studied, factor inhibiting hypoxia-inducible transcription HIF-α (FIH) aspartate/asparagine-β-hydroxylase (AspH), catalyze C3 hydroxylations...
The cyanobacterial prenyltransferase AmbP3 catalyzes the reverse prenylation of tetracyclic indole alkaloid hapalindole U at its C-2 position. Interestingly, also accepts A, a halogenated C-10 epimer U, and normal comparison two ternary crystal structures, AmbP3-DMSPP/hapalindole 1.65-2.00 Å resolution revealed distinct orientations for substrate binding that define or prenylation. tolerance enzyme these altered is attributed to hydrophobicity pocket plasticity amino acids surrounding allyl...
Three neo-clerodane diterpenoids, including two new tinocordifoliols A (1) and B (2) one known tinopanoid R (3), were isolated from the ethyl acetate-soluble fraction of 70% ethanol extract Tinospora cordifolia stems. The structures elucidated by various spectroscopic methods, dimensional (1D) 2D-NMR, high resolution-electrospray ionization (HR-ESI)-MS, electronic circular dichroism (ECD) data. T. all compounds 1–3 possessed arginase I inhibitory activities. Among them, 3 exhibited moderate...
The traditional Japanese beverage amazake was evaluated as a possible treatment for oxidative stress. For this purpose, the radical scavenging activities of four kinds were investigated by determining diphenylpicrylhydrazyl radical, galvinoxyl and superoxide anion quenching using spectrophotometric method an electron spin resonance (ESR) technique. ESR measurements used to assess activity employing dimethylpyrroline N-oxide trapping reagent. ferricyanide-reducing chelating spectroscopically....
Abstract The hypoxia‐inducible factor (HIF) prolyl‐hydroxylases (human PHD1‐3) catalyze prolyl hydroxylation in oxygen‐dependent degradation (ODD) domains of HIFα isoforms, modifications that signal for proteasomal an manner. PHD inhibitors are used treatment anemia kidney disease. Increased erythropoietin (EPO) patients with familial/idiopathic erythrocytosis and pulmonary hypertension is associated mutations EGLN1 (PHD2) EPAS1 (HIF2α); a drug inhibiting HIF2α activity clear cell renal...
The lasso peptide MS-271 is a ribosomally synthesized and post-translationally modified (RiPP) consisting of 21 amino acids with D-tryptophan at the C-terminus, derived from precursor MslA. MslH, encoded in biosynthetic gene cluster (msl), catalyzes epimerization Cα center MslA C-terminal Trp21, leading to epi-MslA. detailed catalytic process, including site cofactors, has remained enigmatic. Herein, based on X-ray crystallographic studies association core analogues, we show that MslH...
The human 2-oxoglutarate (2OG)- and Fe(ii)-dependent oxygenases factor inhibiting hypoxia-inducible factor-α (FIH) HIF-α prolyl residue hydroxylases 1-3 (PHD1-3) regulate the response to hypoxia in humans
Abstract Aspartate/asparagine‐β‐hydroxylase (AspH) is a human 2‐oxoglutarate (2OG) and Fe II oxygenase that catalyses C3 hydroxylations of aspartate/asparagine residues epidermal growth factor‐like domains (EGFDs). Unusually, AspH employs two histidine to chelate rather than the typical triad one glutamate/aspartate residue. We report kinetic, inhibition, crystallographic studies concerning variants in which either its binding are substituted for alanine. Both H725A and, particular, H679A...
Abstract AmbP1 is a cyanobacterial aromatic prenyltransferase and dedicated synthase for ( R )‐3‐geranyl‐3‐isocyanovinyl indolenine 2 ), the biogenetic precursor hapalindole‐type alkaloids. The regioselective geranylation of cis ‐indolyl vinyl isonitrile 1 ) by standalone to give has been shown require magnesium ion (Mg 2+ suppress formation ‐2‐geranylindolyl 3 ). Here, we report high‐resolution crystal structures in complex with geranyl S ‐thiodiphosphate (GSPP) presence absence Mg...