Alexander V Zhdanov, Ruslan I Dmitriev, Dmitri B Papkovsky
Mitochondrial uncoupling is implicated in many patho(physiological) states. Using confocal live cell imaging and an optical O2 sensing technique, we show that moderate uncoupling of the mitochondria with plecomacrolide Baf (bafilomycin A1) causes partial depolarization of the mitochondria and deep sustained deoxygenation of human colon cancer HCT116 cells subjected to 6% atmospheric O2. A decrease in iO2 (intracellular O2) to 0-10 μM, induced by Baf, is sufficient for stabilization of HIFs (hypoxia inducible factors) HIF-1α and HIF-2α, coupled with an increased expression of target genes including GLUT1 (glucose transporter 1), HIF PHD2 (prolyl hydroxylase domain 2) and CAIX (carbonic anhydrase IX)...
December 2012: Bioscience Reports
Nicholas E Shepherd, Rosemary S Harrison, David P Fairlie
Bacterial resistance to antibiotics is now a serious problem, with traditional classes of antibiotics having gradually become ineffective. New drugs are therefore needed to target and inhibit novel pathways that affect the growth of bacteria. An important feature in the survival of bacteria is that they coordinate their efforts together as a colony via secreted auto-inducing molecules. Competence stimulating peptides (CSPs) are among the quorum sensing pheromones involved in this coordination. These peptides activate a two-component system in gram-negative bacteria, binding to and activating a histidine kinase receptor called ComD, which phosphorylates a response regulator called ComE, leading to gene expression and induction of competence...
October 2012: Current Drug Targets
Chung S Lim, Serafim Kiriakidis, Ewa M Paleolog, Alun H Davies
BACKGROUND: Venous hypoxia has been postulated to contribute to varicose vein (VV) formation. Direct measurements of vein wall oxygen tension have previously demonstrated that the average minimum oxygen tensions were significantly lower in VVs compared with non-varicose veins (NVVs). Hypoxia-inducible factors (HIFs) are nuclear transcriptional factors that regulate the expression of several genes of oxygen homeostasis. This study aimed to investigate if hypoxia was associated with VVs by assessing the expression of HIF-1α, HIF-2α, HIF target genes, and upstream HIF regulatory enzymes in VVs and NVVs, and their regulation by hypoxia...
May 2012: Journal of Vascular Surgery
Khangembam Victoria Chanu, Ashok Kumar, Satish Kumar
Hepcidin is an anti-microbial peptide expressed predominantly in the liver of many species. Based on the amino acid sequence deduced from buffalo (Bubalus bubalis) hepcidin cDNA (Accession no. EU399814), six peptides Hepc(1-25), Hepc(6-25), Hepc(7-25), Hepc(9-25), Hepc(11-25) and Hepc(15-25) were synthesized using solid-phase fluorenylmethoxycarbonyl (Fmoc) chemistry. CD spectroscopy revealed different spectra of the peptides in different solvents and in all the cases beta-structure was found to be dominant with less alpha-helix as predicted...
October 2011: Indian Journal of Biochemistry & Biophysics
Todd V Cartee, Kellie J White, Marvin Newton-West, Robert A Swerlick
BACKGROUND: We previously reported that iron chelators inhibit TNFα-mediated induction of VCAM-1 in human dermal microvascular endothelial cells. We hypothesized that iron chelators mediate inhibition of VCAM-1 via inhibition of iron-dependent enzymes such as those involved with oxygen sensing and that similar inhibition may be observed with agents which simulate hypoxia. OBJECTIVE: We proposed to examine whether non-metal binding hypoxia mimetics inhibit TNFα-mediated VCAM-1 induction and define the mechanisms by which they mediate their effects on VCAM-1 expression...
February 2012: Journal of Dermatological Science
María Flor García-Mayoral, Mohammed Moussaoui, Beatriz G de la Torre, David Andreu, Ester Boix, M Victòria Nogués, Manuel Rico, Douglas V Laurents, Marta Bruix
Eosinophil cationic protein (ECP) is a highly stable, cytotoxic ribonuclease with the ability to enter and disrupt membranes that participates in innate immune defense against parasites but also kills human cells. We have used NMR spectroscopy to characterize the binding of ECP to membrane and heparin mimetics at a residue level. We believe we have identified three Arg-rich surface loops and Trp(35) as crucial for membrane binding. Importantly, we have provided evidence that the interaction surface of ECP with heparin mimetics is extended with respect to that previously described (fragment 34-38)...
June 2, 2010: Biophysical Journal
Hyun Ho Jung, Sung-Tae Yang, Ji-Yeong Sim, Seungkyu Lee, Ju Yeon Lee, Ha Hyung Kim, Song Yub Shin, Jae Il Kim
Dermcidin is a human antibiotic peptide that is secreted by the sweat glands and has no homology to other known antimicrobial peptides. As an initial step toward understanding dermcidin's mode of action at bacterial membranes, we used homonuclear and heteronuclear NMR to determine the conformation of the peptide in 50% trifluoroethanol solution. We found that dermcidin adopts a flexible amphipathic alpha-helical structure with a helix-hinge-helix motif, which is a common molecular fold among antimicrobial peptides...
May 2010: BMB Reports
Kasuen Mauldin, Brian L Lee, Marta Oleszczuk, Brian D Sykes, Robert O Ryan
Apolipoprotein (apo) A-V is a 343-residue, multidomain protein that plays an important role in regulation of plasma triglyceride homeostasis. Primary sequence analysis revealed a unique tetraproline sequence (Pro293-Pro296) near the carboxyl terminus of the protein. A peptide corresponding to the 48-residue segment beyond the tetraproline motif was generated from a recombinant apoA-V precursor wherein Pro295 was replaced by Met. Cyanogen bromide cleavage of the precursor protein, followed by negative affinity chromatography, yielded a purified peptide...
June 15, 2010: Biochemistry
Derek P Ng, Charles M Deber
In studies of the structural biology of membrane proteins, the success of strategies based on the "divide and conquer" approach, where peptides are used to model the individual transmembrane (TM) alpha-helices of membrane proteins, depends on the correct identification of the membrane-embedded TM alpha-helix amino acid sequence within the full-length protein. In the present work, we examine the effects of excluding or including TM boundary residues on the intrinsic properties of a Lys-tagged TM2 alpha-helix of myelin proteolipid protein (PLP), of parent sequence KKKK-66AFQYVIYGTASFFFLYGALLLAEG89-KKKK along with analogs containing an additional wild type Phe-90, Phe-90 and Tyr-91, and of a hydrophobic mutant Leu-90...
April 2010: Biochemistry and Cell Biology
Christopher G Cummings, Andrew D Hamilton
Many biological processes are regulated by protein-protein interactions (PPIs) and as such their misregulation can cause a multitude of diseases. Often the interactions between large proteins are mediated by small protein secondary structural domains, which project a minimum number of specifically arranged residues into the complementary surface of an interacting protein. Nature has the advantage of time, and over time has optimized those secondary structures, such as alpha-helices, beta-sheets and beta-strands, found at the interfaces of PPIs...
June 2010: Current Opinion in Chemical Biology
Petra Tosovská, Paramjit S Arora
A new class of nonpeptidic alpha-helix mimetics derived from alpha-amino acids and featuring chiral backbones is described. NMR and circular dichroism spectroscopies, in combination with molecular modeling studies, provide compelling evidence that oligooxopiperazine dimers adopt stable conformations that reproduce the arrangement of i, i+4, and i+7 residues on an alpha-helix.
April 2, 2010: Organic Letters
Jinxia Deng, Raveendra Dayam, Nouri Neamati
The interaction between p53 and murine double minute 2 (MDM2) provides an attractive drug target in oncology. Small molecule inhibitors of this interaction have not only provided strong evidence for blocking the protein-protein interaction, but are also extremely useful as biological probes and ultimately as novel therapeutics. Here, a comprehensive review of the patented small molecule inhibitors of the p53-MDM2 interaction are provided. These inhibitors are divided into eight classes of compounds that include cis-imidazolines, benzodiazepines, fused indoles, substituted piperazines, substituted piperidines, aryl boronic acids, spiro-indoles, and alpha-helix mimetic compounds...
February 2006: Expert Opinion on Therapeutic Patents
Qin Li, Thomas Kluz, Hong Sun, Max Costa
Nickel (Ni) compounds have been found to cause cancer in humans and animal models and to transform cells in culture. At least part of this effect is mediated by stabilization of hypoxia inducible factor (HIF1a) and activating its downstream signaling. Recent studies reported that hypoxia signaling might either antagonize or enhance c-myc activity depending on cell context. We investigated the effect of nickel on c-myc levels, and demonstrated that nickel, hypoxia, and other hypoxia mimetics degraded c-myc protein in a number of cancer cells (A549, MCF-7, MDA-453, and BT-474)...
December 31, 2009: PloS One
Simone Kosol, Klaus Zangger
In order to investigate the functional and structural properties of cationic alpha-helical peptides in two different membranes, we studied the 20-residue peptide maximin H6 in two membrane-mimetic systems by NMR spectroscopy using partially (15)N-labeled peptide and paramagnetic relaxation enhancements. Maximin H6, which is found in skin secretions of frogs of the Bombinae family, attacks gram-negative bacteria and acts haemolytically. While the peptide spontaneously folds into similar structures in both neutral dodecylphosphocholine (DPC) and negatively charged sodium dodecyl sulphate (SDS) micelles, its structure is more flexible in SDS as shown by (15)N relaxation measurements...
April 2010: Journal of Structural Biology
Ishu Saraogi, James A Hebda, Jorge Becerril, Lara A Estroff, Andrew D Miranker, Andrew D Hamilton
No abstract text is available yet for this article.
2010: Angewandte Chemie
Wei Zhong, Mariusz Skwarczynski, Istvan Toth
One of the factors responsible for the poor immunogenicity of synthetic peptide antigens is the lack of conformational integrity. Embedding the minimal epitopes in helix-promoting peptide sequences has successfully enhanced the immunogenicity of the epitopes derived from the alpha-helical regions of the M protein of group A streptococci (Streptococcus pyogenes, GAS). However, the introduction of "foreign" peptide sequences is believed to have an unfavourable impact on the antigen specificity. In the current study, we employed a non-peptide approach, using topological carbohydrate templates, to induce helical conformation of the peptide antigens...
October 2009: Current Drug Delivery
James A Hebda, Ishu Saraogi, Mazin Magzoub, Andrew D Hamilton, Andrew D Miranker
Protein fiber formation is associated with diseases ranging from Alzheimer's to type II diabetes. For many systems, including islet amyloid polypeptide (IAPP) from type II diabetes, fibrillogenesis can be catalyzed by lipid bilayers. Paradoxically, amyloid fibers are beta sheet rich while membrane-stabilized states are alpha-helical. Here, a small molecule alpha helix mimetic, IS5, is shown to inhibit bilayer catalysis of fibrillogenesis and to rescue IAPP-induced toxicity in cell culture. Importantly, IAPP:IS5 interactions localize to the putative alpha-helical region of IAPP, revealing that alpha-helical states are on pathway to fiber formation...
September 25, 2009: Chemistry & Biology
Srinivasa Marimganti, Murthy N Cheemala, Jung-Mo Ahn
To mimic amphiphilic alpha-helices, a new scaffold was designed based on a bis-benzamide that places four side-chain functional groups found at the i, i+2, i+5, and i+7 positions of a helix. Its two hydrogen bonds fix the conformation and provide accurate bifacial arrangement of the four substituents, simultaneously representing two opposing helical sides. An efficient synthetic route was achieved for the construction of bis-benzamides, and their superior alpha-helix mimicry was confirmed by X-ray crystallography...
October 1, 2009: Organic Letters
Tetsuhiro Tanaka, Michael Wiesener, Wanja Bernhardt, Kai-Uwe Eckardt, Christina Warnecke
HIF (hypoxia-inducible factor)-3alpha is the third member of the HIF transcription factor family. Whereas HIF-1alpha and -2alpha play critical roles in the cellular and systemic adaptation to hypoxia, little is known about the regulation and function of HIF-3alpha. At least five different splice variants may be expressed from the human HIF-3alpha locus that are suggested to exert primarily negative regulatory effects on hypoxic gene induction. In the present paper, we report that hypoxia induces the human HIF-3alpha gene at the transcriptional level in a HIF-1-dependent manner...
November 15, 2009: Biochemical Journal
A L Farrall, M L Whitelaw
The short isoform of single-minded 2 (SIM2s), a basic helix-loop-helix/PAS (bHLH/PAS) transcription factor, is upregulated in pancreatic and prostate tumours; however, a mechanistic role for SIM2s in these cancers is unknown. Microarray studies in prostate DU145 cells identified the pro-cell death gene, BNIP3 (Bcl-2/adenovirus E1B 19 kDa interacting protein 3), as a novel putative target of SIM2s repression. Further validation showed BNIP3 repression in several prostate and pancreatic carcinoma-derived cell lines with ectopic expression of human SIM2s...
October 15, 2009: Oncogene
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