DNA intercalation and cleavage of an antitumor antibiotic dynemicin that contains anthracycline and enediyne cores

Dynemicin is a hybrid containing anthraquinone and enediyne cores, which contribute to binding and cleavage of DNA, respectively. DNA strand scission by the antitumor antibiotic is significantly enhanced by the addition of NADPH or thiol compounds. The preferential cutting site of dynemicin is on the 3' side of purine bases (i.e., 5'-GC, -GT, and -AG) and is clearly different from the cutting sites of esperamicin and calicheamicin. The double-stranded and the stem regions of single-stranded DNAs are preferentially cleaved by dynemicin. Therefore, dynemicin may be a useful reagent for probing secondary structures of DNA. Pretreatment of DNA with Adriamycin and actinomycin D alters the cutting mode of dynemicin. Dynemicin-mediated DNA breakage is strongly inhibited by pretreatment of the DNA with distamycin A and anthramycin, suggesting that dynemicin interacts with the minor groove of the DNA helix. Intercalation of the anthraquinone core into the DNA followed by the attack of the phenyl diradical formed from the enediyne core is considered as a possible mechanism of action of dynemicin

Structural Basis for Reaction Mechanism and Drug Delivery System of Chromoprotein Antitumor Antibiotic C-1027 (BIOORGANIC CHEMISTRY-Bioactive Chemistry)

Antitumor antibiotic C-1027 that is regarded as a natural model of drug delivery system, consists of a carrier apoprotein (Apo) and an enediyne chromophore (Chr). We have compared three solution structures of the DNA-Chr complex, Apo-Chr complex, and free Chr determined by high-resolution NMR experiments. The guest molecule, C-1027 chromophore, showed two distinct binding modes fitted to binding sites of the hosts (target DNA and carrier Apo). The novel Chr interacts with DNA through its benzoxazolinate and aminosugar moieties, and also with Apo through the benzoxazolinate and macrocyclic moieties. The superposition of Chrs in these three states clearly revealed conformational deviation of the 16-membered macrocyclic moiety containing intra-chlorophenol ring. Ab initio calculations supported good correlation between the reactivity and the conformational alteration of Chr induced in hosts. The present results provide molecular basis and implication for the host-recognition mode, the reaction mechanism, and drug delivery system of chromoprotein C-1027

Daily intake of β-cryptoxanthin prevents bone loss by preferential disturbance of osteoclastic activation in ovariectomized mice

AbstractAlthough β-cryptoxanthin, a xanthophyll carotenoid, has been shown to exert an anabolic effect on bone calcification, little attention has been paid thus far to the precise mechanism of bone remodeling. Daily oral administration of β-cryptoxanthin significantly inhibited osteoclastic activation as well as reduction of bone volume in ovariectomized mice. In vitro studies revealed that β-cryptoxanthin inhibited differentiation and maturation of osteoclasts by repression of the nuclear factor-κB-dependent transcriptional pathway. Our results suggest that supplementation with β-cryptoxanthin would be beneficial for prophylaxis and for therapy of metabolic bone diseases associated with abnormal osteoclast activation

Whole-Genome Sequence of the Microcystin-Degrading Bacterium Sphingopyxis sp. Strain C-1

This report describes the whole-genome sequence of an alkalitolerant microcystin-degrading bacterium, Sphingopyxis sp. strain C-1, isolated from a lake in China

Characteristics of a Microcystin-Degrading Bacterium under Alkaline Environmental Conditions

The pH of the water associated with toxic blooms of cyanobacteria is typically in the alkaline range; however, previously only microcystin-degrading bacteria growing in neutral pH conditions have been isolated. Therefore, we sought to isolate and characterize an alkali-tolerant microcystin-degrading bacterium from a water bloom using microcystin-LR. Analysis of the 16S rRNA gene sequence revealed that the isolated bacterium belonged to the genus Sphingopyxis, and the strain was named C-1. Sphingopyxis sp. C-1 can grow; at pH 11.0; however, the optimum pH for growth was pH 7.0. The microcystin degradation activity of the bacterium was the greatest between pH 6.52 and pH 8.45 but was also detected at pH 10.0. The mlrA homolog encoding the microcystin-degrading enzyme in the C-1 strain was conserved. We concluded that alkali-tolerant microcystin-degrading bacterium played a key role in triggering the rapid degradation of microcystin, leading to the disappearance of toxic water blooms in aquatic environments

Pdz adaptors: Their regulation of epithelial transporters and involvement in human diseases

金沢大学医薬保健研究域薬学系Homeostasis in the body is at least partially maintained by mechanisms that control membrane permeability, and thereby serve to control the uptake of essential substances (e.g., nutrients) and the efflux of unwanted substances (e.g., xenobiotics and metabolites) in epithelial cells. Various transporters play fundamental roles in such bidirectional transport, but little is known about how they are organized on plasma membranes. Protein-protein interactions may play a key role: several transporters in epithelial cells interact with the so-called adaptor proteins, which are membrane anchored and interact with both transporters and other membranous proteins. Although most of the evidences for transporter-adaptor interaction has been obtained in vitro, recent studies suggest that adaptor-mediated transporter regulation does occur in vivo and could be relevant to human diseases. Thus, protein-protein interaction is not only associated with the formation of macromolecular complexes but is also involved in various cellular events, and may provide transporters with additional functionality by forming transporter networks on plasma membranes. Interactions between xenobiotic transporters and PSD95/Dlg/ZO1 (PDZ) adaptors were previously reviewed by Kato and Tsuji (2006. Eur J Pharm Sci 27:487-500); the present review focuses on the latest findings about PDZ adaptors as regulators of transporter networks and their potential role in human diseases. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci © 2011 Wiley-Liss, Inc

Rational design of DNA sequence-specific zinc fingers

AbstractWe developed a rational scheme for designing DNA binding proteins. The scheme was applied for a zinc finger protein and the designed sequences were experimentally characterized with high DNA sequence specificity. Starting with the backbone of a known finger structure, we initially calculated amino acid sequences compatible with the expected structure and the secondary structures of the designed fingers were then experimentally confirmed. The DNA-binding function was added to the designed finger by reconsidering a section of the amino acid sequence and computationally selecting amino acids to have the lowest protein–DNA interaction energy for the target DNA sequences. Among the designed proteins, one had a gap between the lowest and second lowest protein–DNA interaction energies that was sufficient to give DNA sequence-specificity