Genistein, a specific inhibitor of tyrosine-specific protein kinases.

The biochemistry and medical significance of the flavonoids.

During the process of autophagy, autophagosomes undergo a maturation process consisting of multiple fusions with endosomes and lysosomes, which provide an acidic environment and digestive function to the interior of the autophagosome. Here we found that a fusion protein of monomeric red-fluorescence protein and LC3, the most widely used marker for autophagosomes, exhibits a quite different localization pattern from that of GFP-LC3. GFP-LC3 loses fluorescence due to lysosomal acidic and degradative conditions but mRFP-LC3 does not, indicating that the latter can label the autophagic compartments both before and after fusion with lysosomes. Taking advantage of this property, we devised a novel method for dissecting the maturation process of autophagosomes. mRFP-GFP tandem fluorescent-tagged LC3 (tfLC3) showed a GFP and mRFP signal before the fusion with lysosomes, and exhibited only the mRFP signal subsequently. Using this method, we provided evidence that overexpression of a dominant negative form of Rab7 prevented the fusion of autophagosomes with lysosomes, suggesting that Rab7 is involved in this step. This method will be of general utility for analysis of the autophagosome maturation process.

Dissection of the Autophagosome Maturation Process by a Novel Reporter Protein, Tandem Fluorescent-Tagged LC3

Flavonoids, a class of natural products of high pharmacological potency

Introduction Chapter 1 "Unique Properties of Fluorine and Their Relevance to Medicinal Chemistry and Chemical Biology" by Takashi Yamazaki, Takeo Taguchi and Iwao Ojima Medicinal Chemistry Chapter 2 "Fluorinated Prostanoids: Development of Tafluprost, a New Anti-glaucoma Agent" by Yasushi Matsumura Chapter 3 "Fluorinated conformationally restricted glutamate analogs for CNS drug discovery and development" by Atsuro Nakazato Chapter 4 "Fluorinated Inhibitors of Matrix Metalloproteinases" by Roberta Sinisi, Monika Jagodzinska, Gabriele Candiani, Florent Huguenot, Monica Sani, Alessandro Volonterio, Raffaella Maffezzoni and Matteo Zanda Chapter 5 "Fluoro-Taxoid Anticancer Agents" by Antonella Pepe, Larisa Kuznetsova, Liang Sun and Iwao Ojima Chapter 6 "Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability"by Jean-Pierre Begue, Daniele Bonnet-Delpon Chapter 7 "Synthesis and Biological Activity of Fluorinated Nucleosides" by Tokumi Maruyama, Masahiro Ikejiri, Kunisuke Izawa and Tomoyuki Onishi Synthetic methods for medicinal chemistry and chemical biology Chapter 8 "Synthesis of gem -Difluoromethylenated Nucleosides via gem -Difluoromethylene-Containing Building Blocks" by Wei-Dong Meng and Feng-Ling Qing Chapter 9 "Recent Advances in the Syntheses of Fluorinated Amino Acids" by Kenji Uneyama Chapter 10 "Fluorinated Moieties for Replacement of Amide and Peptide Bonds" by Takeo Taguchi and Hikaru Yanai Chapter 11 "Perfluorinated Heteroaromatic Systems as Scaffolds for Drug Discovery" by David Armstrong, Matthew W. Cartwright, Emma L. Parks, Graham Pattison, Graham Sandford, Rachel Slater, John A. Christopher, David D. Miller, Paul W. Smith and Antonio Vong Chapter 12 " gem -Difluorocyclopropanes as key building blocks for novel biologically active molecules" by Toshiyuki Itoh Chapter 13 "Fluorous Mixture Synthesis (FMS) of Drug-Like Molecules and Enantiomers, Stereoisomers, and Analogs of Natural Products" by Wei Zhang Chapter 14 "Fluorine-18 Radiopharmaceuticals" by Michael R. Kilbourn and Xia Shao Applications of fluorinated amino acids and peptides to chemical biology and pharmacology Chapter 15 "Application of Artificial Model Systems to Study the Interactions of Fluorinated Amino Acids within the Native Environment of Coiled Coil Proteins" by Mario Salwiczek, Toni Vagt and Beate Koksch Chapter 16 "Fluorinated Amino Acids and Biomolecules in Protein Design and Chemical Biology" by He Meng, Ginevra A. Clark , and Krishna Kumar Chapter 17 "Effects of Fluorination on the Bioorganic Properties of Methionine" by John F. Honek Chapter 18 "Structure analysis of membrane-active peptides using 19 F-labeled amino acids and solid state NMR" by Parvesh Wadhwani and Erik Strandberg Chapter 19 "Metabolism of Fluorine-containing Drugs using in vivo Magnetic Resonance Spectroscopy" by Erika Schneider Appendix "FDA-Approved Active Pharmaceutical Ingredients Containing Fluorine" by Elizabeth Pollina-Cormier, Manisha Das, and Iwao Ojima

Fluorine in medicinal chemistry and chemical biology

papain, chymotrypsin, elastase, acid protease and thermolysin have been found in culture filtrates of actinomycetes. Recently we found that exopeptidases have a strong effect on mammalian cell surfaces compared to endopeptidases°). It is possible that the action of hydrolytic enzymes on cell surfaces is involved in various cellular phenomena. We thought that exopeptidase inhibitors would be useful in the analysis of biological functions. So, we started screening of actinomycetes culture filtrates for activity against aminopeptidase B, and found a new compound bestatin, the discovery and isolation of which are reported herein. As described by Hopsu et a1.10', aminopeptidase B (EC 3.4.11.6) is an exopeptidase which can be obtained from rat liver. It hydrolyses an N-terminal peptide bond containing N-terminal arginine or lysine. In order to obtain quantitative values for antiaminopeptidase B activity, we established the following method. The reaction mixture was

Bestatin, an inhibitor of aminopeptidase b, produced by actinomycetes

/pdf/pepstatin-a-new-pepsin-inhibitor-produced-by-agtinomygetes-8a13kfwz8q.pdf

Pepstatin, a new pepsin inhibitor produced by agtinomygetes

https://www.jstage.jst.go.jp/article/antibiotics1968/22/6/22_6_283/_pdf

Leupeptins, new protease inhibitors from Actinomycetes.

Leupeptins, leupeptin Pr and leupeptin Ac, strongly inhibit proteolysis by plasmin, trypsin and papain, but do not inhibit proteolysis by α-chymotrypsin The inhibition is competitive with substrates The inhibitory effect on esterolysis by plasmin and trypsin is weaker than on proteolysis The results with derivatives of leupeptins which contain carboxyl or alcohol instead of aldehyde and of di-n-butyl acetals of leupeptins indicate that the free aldehyde group plays a role in the activities Leupeptins are absorbed orally and at least about 25 % is excreted in urine Oral administration of leupeptins exhibited an anti-inflammatory effect on edema Leupeptins inhibited thrombokinase reaction and coagulation of blood of human and rabbit Type of inhibition was different from heparin Coagulation of blood of rats and dogs are not inhibited The effects of leupeptins on thrombokinase, thrombin, plasmin, trypsin, papain, kallikrein and α-chymotrypsin were compared with those of e-aminocaproic acid, trans-4-aminomethylcyclohexanecarboxylic acid, soybean trypsin inhibitor and trasylol

Takaaki Aoyagi

Papers

Bestatin, an inhibitor of aminopeptidase b, produced by actinomycetes

Pepstatin, a new pepsin inhibitor produced by agtinomygetes

Leupeptins, new protease inhibitors from Actinomycetes.

Biological activities of leupeptins.

Amastatin, an inhibitor of aminopeptidase A, produced by actinomycetes