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PubMed1990

Growth and siderophore production by Bordetella pertussis under iron-restricted conditions.

It has been demonstrated that under iron-restricted conditions Bordetella pertussis can obtain iron from iron-saturated human transferrin. Direct contact between B. pertussis and transferrin was not required as B. pertussis was able to acquire iron from transferrin when they were separated by a dialysis membrane. Siderophore activity was detected in supernatants from iron-restricted cultures of B. pertussis, B. bronchiseptica and B. parapertussis. Siderophores were identified as hydroxamates and were produced by both virulent and avirulent strains of B. pertussis.

Bordetella pertussis↗
PubMed1996

The structure of the Aeromonas proteolytica aminopeptidase complexed with a hydroxamate inhibitor. Involvement in catalysis of Glu151 and two zinc ions of the co-catalytic unit.

The structure of the complex of Aeromonas proteolytica aminopeptidase, a two-zinc exopeptidase, with the inhibitor p-iodo-D-phenylalanine hydroxamate has been determined by X-ray crystallography. Refinement of the structure, which includes 220 water molecules, using data at 0.80-0.23-nm resolution resulted in a crystallographic residual R value of 16%. The hydroxamate group adopts a planar conformation whereby the two oxygen atoms interact with the zinc ions. The N-hydroxyl group of the inhibitor is located between the two zinc ions, a position which is close to that occupied by a water molecule in the native structure. The carbonyl oxygen of the inhibitor binds to Zn1, which becomes pentacoordinated while Zn2 remains tetracoordinated, in contrast to the native protein where both zinc ions were shown to be tetracoordinated and structurally equivalent. Interactions of the carboxylate oxygens of Glu151 with the hydroxamate group play an important role in the stabilization of the complex.

Aeromonas↗
PubMed2006

The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance.

Multiple myeloma represents an incurable disease, for which development of new therapies is required. Here, we report the effect on myeloma cells of LBH589, a new hydroxamic acid-derived histone deacetylase inhibitor. LBH589 was a potent antimyeloma agent (IC(50) < 40 nmol/L) on both cell lines and fresh cells from multiple myeloma patients, including cells resistant to conventional chemotherapeutic agents. In addition, LBH589 potentiated the action of drugs, such as bortezomib, dexamethasone, or melphalan. Using gene array, quantitative PCR, and Western analyses, we observed that LBH589 affected a large number of genes involved in cell cycle and cell death pathways. LBH589 blocked cell cycle progression, and this was accompanied by p21, p53, and p57 up-regulation. LBH589 induced cell death through an increase in the mitochondrial outer membrane permeability. LBH589 favored apoptosome formation by inducing cytochrome c release, Apaf-1 up-regulation, and caspase-9 cleavage. In addition, LBH589 stimulated a caspase-independent pathway through the release of AIF from the mitochondria. LBH589 down-regulated Bcl-2 and particularly Bcl-X. Moreover, overexpression of Bcl-X in multiple myeloma cells prevented LBH589-induced cell death. All these data indicate that LBH589 could be a useful drug for the treatment of multiple myeloma patients.

Acetylation↗
PubMed1995

Inactivation of gamma-aminobutyric acid aminotransferase by L-3-chloroalanine hydroxamate.

The mechanism of inactivation of gamma-aminobutyric acid aminotransferase (GABA-AT) by L-3-chloroalanine hydroxamate (1) was investigated. Inactivation of [3H]PLP-reconstituted GABA-AT with 1 followed by denaturation gave no PMP or enamine adduct to the PLP; however, a new unknown metabolite was observed which was identical to the metabolite formed upon inactivation of GABA-AT by L-cycloserine. Time-dependent inactivation occurs, but the kinetics are second order; the rate of inactivation increases with time. After inactivation occurs the addition of fresh enzyme results in a faster rate of inactivation than prior to the initial inactivation. This indicates that the actual inactivator is generated from L-3-chloroalanine hydroxamate, and is not L-3-chloroalanine hydroxamate itself. Added gabaculine-inactivated enzyme to fresh enzyme does not increase the rate of inactivation, suggesting that the conversion of L-3-chloroalanine hydroxamate to the active form is not catalyzed by peripheral amino acid residues. L-3-Chloroalanine hydroxamate was shown to undergo buffer-catalyzed cyclization to L-cycloserine, which is the actual inactivator of GABA-AT.

4-Aminobutyrate Transaminase↗
PubMed2003

Characterization of the ectodomain shedding of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1).

Generation of the amyloid peptide through proteolytic processing of the amyloid precursor protein by beta- and gamma-secretases is central to the etiology of Alzheimer's disease. beta-secretase, known more widely as the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), has been identified as a transmembrane aspartic proteinase, and its ectodomain has been reported to be cleaved and secreted from cells in a soluble form. The extracellular domains of many diverse proteins are known to be cleaved and secreted from cells by a process known as ectodomain shedding. Here we confirm that the ectodomain of BACE1 is secreted from cells and that this processing is up-regulated by agents that activate protein kinase C. A metalloproteinase is involved in the cleavage of BACE1 as hydroxamic acid-based metalloproteinase inhibitors abolish the release of shed BACE1. Using potent and selective inhibitors, we demonstrate that ADAM10 is a strong candidate for the BACE1 sheddase. In addition, we show that the BACE1 sheddase is distinct from alpha-secretase and, importantly, that inhibition of BACE1 shedding does not influence amyloid precursor protein processing at the beta-site.

Amyloid Precursor Protein Secretases↗
PubMed1963

HYDROXYUREA: MECHANISM OF ACTION.

Acetohydroxamic acid has been identified, by paper chromatography, in the blood of three patients with chronic myelogenous leukemia on hydroxyurea therapy. This suggests that the drug is hydrolyzed yielding hyroxylamine, which then cleaves thioesters, in particular acetyl-coenzyme A.

Blood Chemical Analysis↗
PubMed1980

Genetic control of hydroxamate-mediated iron uptake in Escherichia coli.

Cells of Escherichia coli can derive iron from a variety of chelators (siderophores) in addition to enterochelin, the catechol derivative excreted by many enteric bacteria. The genetic control of hydroxamate siderophore utilization was investigated in mutants of E. coli K-12 selected for resistance to lethal agents which adsorb to the tonA protein of the outer membrane (albomycin, colicin M, and phages T5 and phi80). Many of the mutants were unable to utilize hydroxamate siderophores as an iron source. This phenotype was termed Fhu, for ferric hydroxamate uptake. Mutants carrying lesions in the tonA region of the chromosome were studied and fell into several types. Members of one class had lost some or all of the tonA receptor protein's functions in that they were resistant to the lethal agents and unable to utilize ferrichrome and its analogs, although able to respond to the hydroxamate rhodotorulic acid (FhuA phenotype). Other mutants were unable to utilize any of the hydroxamate siderophores tested and were resistant to albomycin, althogh many were sensitive to the other lethal agents (FhuB phenotype). Members of these classes lacked ferrichrome-mediated iron uptake. Strains carrying transposon Tn10 insertions in fhuA (previously termed tonA) lacked the 78,000-molecular-weight outer membrane protein previously described; insertions in fhuB retained this protein and had no detectable change in outer membrane composition. Three-point transduction crosses revealed the gene order to be pan-fhuA-fhuB-metD in the min 3.5 region of the chromosome map. Complementation analyses with F' merodiploid strains showed that fhuA and fhuB comprise separate transcription units which are both required for utilization of ferrichrome. Response of diploid strains to rhodotorulic acid suggested the existence of a third gene, fhuC, required for utilization of this siderophore, but not ferrichrome. It is suggested that fhuB encodes a transport component in the cytoplasmic membrane that is necessary for the uptake of all hydroxamate siderophores following their receptor-mediated passage across the outer membrane.

Bacterial Proteins↗
PubMed2002

Histone deacetylase inhibitors: from target to clinical trials.

Transformed cells, characterised by inappropriate cell proliferation, do not necessarily lose the capacity to undergo growth arrest under certain stimuli. DNA, genetic information, is packaged in chromatin proteins, for example, histones. The structure of chromatin may be altered by post-translational modifications (e.g., acetylation, phosphorylation, methylation and ubiquitylation) which play a role in regulating gene expression. Two groups of enzymes, histone deacetylases (HDACs) and acetyl transferases, determine the acetylation status of histones. This review focuses on compounds that inhibit HDAC activity. These agents have been shown to be active in vitro and in vivo in causing cancer cell growth arrest, differentiation and/or apoptosis. Several HDAC inhibitors are currently in clinical trials as anticancer agents and, in particular, hydroxamic acid-based HDAC inhibitors have shown activity against cancers at well-tolerated doses.

Antineoplastic Agents↗
PubMed1991

Different systems for iron supply of Salmonella typhimurium and Escherichia coli wild strains as tool for typing.

Hitherto the siderophore-pattern analysis included bioassays to detect enterobactin,aerobactin and other siderophores of Enterobacteriaceae. In addition, 2,3-dihydroxybenzoic acid, the precursor of enterobactin, and new hydroxamate siderophores could be examined by means of two new Salmonella mutants as indicator strains. In this manner the siderophore pattern analysis extends its discriminating ability. Among 167 Salmonella typhimurium strains tested, we detected 5 siderophore patterns. 6 siderophore patterns could be detected among a total of 204 E. coli strains. Using siderophore pattern analysis for clinical-epidemiological and ecological purposes appropriate technical methods can be recommended.

Biological Assay↗