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At least 1,315 records · Page 73Linked to original sources
PubMed2000

Protein processing mechanisms: from angiotensin-converting enzyme to Alzheimer's disease.

Angiotensin-converting enzyme (ACE) and the Alzheimer's disease amyloid precursor protein are two examples of membrane-bound proteins that are released in a soluble form by a post-translational proteolytic cleavage event involving a secretase. Site-specific antibodies and matrix-assisted laser desorption ionization-time-of-flight ('MALDI-TOF') MS have been used to map the secretase cleavage site in somatic ACE to Arg-1203/Ser-1204, 24 residues proximal to the membrane-anchoring domain. Trypsin, which can solubilize ACE from the membrane, cleaves the protein at the same site. The use of structurally related hydroxamic acid-based zinc metalloproteinase inhibitors indicate that tumour necrosis factor-alpha convertase, a member of the ADAMs ('a disintegrin and metalloproteinase') family of proteins, is not involved in the proteolytic release of ACE, or in the constitutive or regulated alpha-secretase release of the amyloid precursor protein from a human neuronal cell line.

ADAM Proteins↗
PubMed1982

Isolation and characterization of Chinese hamster ovary cell mutants resistant to the amino acid analog beta-aspartyl hydroxamate.

Chinese hamster ovary cell lines which are resistant to an amino acid analog, beta-aspartyl hydroxamate, have been isolated and characterized. Mutants resistant to 100-150 microM beta-aspartyl hydroxamate arose from ethyl methane sulfonate-treated parental lines at frequencies of 3.4 x 10(-6) to 1.3 x 10(-7). The mutants fell into at least two genetic classes: 18% of the mutants behaved codominantly in hybrids, the others recessively. Complementation studies indicated that all the recessive mutants belonged to the same class. Mutants selected after one step of mutagenesis overproduce the enzyme asparagine synthetase constitutively with four- to sixfold increases in specific activities over the basal levels of the parental lines. beta-Aspartyl hydroxamate-resistant cell lines with up to 20-fold elevations in asparagine synthetase activity have been isolated after two steps of mutageneis. In addition, highly resistant lines have been selected by long-term growth of a dominant mutant in increasing concentrations of the drug. Resistance in the latter appears to be due not only to overproduction of asparagine synthetase but also to an alteration in the affinity of the enzyme for beta-aspartyl hydroxamate.

Animals↗
PubMed1998

Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors.

The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNF alpha-converting enzyme and FasL-converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI-treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNF alpha and fasL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF alpha shedding and cytotoxicity of myelin-autoreactive human cytotoxic CD4+ T-cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNF alpha shedding by human myelin-autoreactive T cells.

Animals↗
PubMed1990

In vitro and in vivo anti-tumor activity of L-glutamic acid gamma-monohydroxamate against L1210 leukemia and B16 melanoma.

A glutamine analogue, L-glutamic acid gamma-monohydroxamate (GAH) demonstrated complete cytotoxicity against L1210 cells in culture and marked anti-tumoral activity in vivo against L1210 leukemia and B16 melanoma. In vitro, GAH caused concentration-dependent inhibition of L1210 cell growth, with complete cell death being reached at 72 hr and at a 500 microM concentration. A minimal incubation time of 38 hr with 500 microM GAH was necessary to obtain complete cell death at 72 hr. During incubation, GAH is metabolized to hydroxylamine. Hydroxylamine acts as the active form of GAH, since the concentration-dependent inhibition of cell growth caused by hydroxylamine is the same as that observed with GAH. The cytotoxic effects of GAH and hydroxylamine on L1210 cells were not reversed or prevented by L-glutamine or L-glutamic acid and purine nucleosides but were prevented or reversed by pyruvate, 2-oxaloacetate and 2-oxoglutarate. In vivo, GAH considerably increased survival of mice bearing L1210 leukemia or a solid tumor, the B16 melanoma. Antitumor activity of GAH against L1210 leukemia and B16 melanoma was schedule-dependent. The administration of GAH 3 times daily was more effective than a twice daily treatment and the maximum ILS was observed using split-dose schedules on days 1 through 3 and 7 through 9 without noticeable toxicity. Under these conditions hydroxylamine is highly toxic, suggesting that in vivo GAH might act as an hydroxylamine releaser in the tumor cells and is not significantly metabolized in the body.

Animals↗
PubMed1977

Stability of (pyrrolidone-5-hydroxamato)iron (III) chelates.

Overall stability constants of mono-, bis-, and tris(pyrrolidone-k-hydroxamato)iron(III) chelates were determined in aqueous solutions at 25 degrees as log beta1=1.49, log beta11=1.55, and log betaIII=0.21, respectively, where beta1=[Fe(C5H7O3N2)2+][H+]/[F=E3+][HC5H7O3N2], betaII=[Fe(C5H7O3N2)2+][H+]2/[Fe3+][hc5h7o3n2]2, and betaIII=[Fe(C5H7O3N2)3][H+]3/[Fe3+][HC5H7O3N2]3. Stability constants of all three chelates were determined potentiometrically in the 3.00-3.23 pH region. The stability constant of the mono chelate also was determined spectrophotometrically at 25 degrees as log beta1-1.52 by measuring absorbance at 500 nm (absorbance maximum), where the molar absorptivity was epsilon=1124 liters/(mole cm). Biological implications of hydroxamic acid-containing compounds are discussed.

Chemical Phenomena↗
PubMed1996

Active site properties of monomeric triosephosphate isomerase (monoTIM) as deduced from mutational and structural studies.

MonoTIM is a stable monomeric variant of the dimeric trypanosomal enzyme triose phosphate isomerase (TIM) with less, but significant, catalytic activity. It is known that in TIM, three residues, Lys 13 (loop 1), His 95 (loop 4), and Glu 167 (loop 6) are the crucial catalytic residues. In the wild-type TIM dimer, loop 1 and loop 4 are very rigid because of tight interactions with residues of the other subunit. Previous structural studies indicate that Lys 13 and His 95 have much increased conformational flexibility in monoTIM. Using site-directed mutagenesis, it is shown here that Lys 13 and His 95 are nevertheless essential for optimal catalysis by monoTIM: monoTIM-K13A is completely inactive, although it can still bind substrate analogues, and monoTIM-H95A is 50 times less active. The best inhibitors of wild-type TIM are phosphoglycolohydroxamate (PGH) and 2-phosphoglycolate (2PG), with KI values of 8 microM and 26 microM, respectively. The affinity of the monoTIM active site for PGH has been reduced approximately 60-fold, whereas for 2PG, only a twofold weakening of affinity is observed. The mode of binding, as determined by protein crystallographic analysis of these substrate analogues, shows that, in particular, 2PG interacts with Lys 13 and His 95 in a way similar but not identical to that observed for the wild-type enzyme. This crystallographic analysis also shows that Glu 167 has the same interactions with the substrate analogues as in the wild type. The data presented suggest that, despite the absence of the second subunit, monoTIM catalyzes the interconversion of D-glyceraldehyde-3-phosphate and dihydroxyacetone phosphate via the same mechanism as in the wild type.

Amino Acid Sequence↗
PubMed1976

An alternate respiratory pathway in Candida albicans.

Usual concentrations of antimycin A, rotenone and EDTA, individually or in combination, reduced aerobic growth rate and cell yield of Candida albicans to about half its normal level and to about the levels of previously-described acetate-negative, cytochrome-complete and aa3-deficient variants which were little affected by the inhibitors. Anaerobic conditions (not affected by antimycin A) reduced growth rate and cell yield of all cultures-including that of a nonrespiring aa3, b-deficient mutant-to low, equal levels. Antimycin A but not rotenone prevented growth of the normal strain on ethanol medium. Cyanide and antimycin A blocked most of the respiration of the normal strain and cytochrome-complete variant, but did not affect that of the cytochrome aa3-deficient mutant. Rotenone and EDTA did not affect respiration of any of the cultures. SHAM blocked cyanide-and antimycin A-insensitive respiration and prolonged the lag phases of the three respiring cultures, especially in the presence of antimycin A, but alone increased oxygen-uptake rate of the cytochrome-complete cultures while curtailing that of the cytochrome aa3-deficient mutant. Resting cells, especially wild-type, grown in medium containing antimycin A exhibited lowered oxygen-uptake rate, which was increased upon the addition of cyanide or antimycin A. Antimycin A stimulated, but cyanide inhibited, respiration of cytochrome-complete cultures grown in the presence of rotenone but did not affect that of the cytochrome aa3-deficient mutant. SHAM inhibited respiration of all antimycin A- or rotenone-grown cultures. The high rate of respiration of C. albicans in the presence of inhibitors for three sites of electron transport in the conventional oxidative pathway, the inhibition of this respiration by SHAM and its loss by the absence of cytochrome b, indicate an alternate oxidative pathway in this organism which crosses the conventional one at cytochrome b.

Aerobiosis↗
PubMed1996

Stopped-flow kinetic investigation of the oxidation of ascorbic acid by iron (III) benzohydroxamic acid.

The fast oxidation of ascorbic acid by Fe(III)benzohydroxamic acid complex [Fe(BHA)3] has been investigated by the stopped-flow technique in aqueous ethanol medium at three pH values (4.6, 7.0, and 9.0). The reaction exhibits a first-order dependence of rate each on [ascorbic acid] and [Fe(BHA)3], obeying Michaelis-Menton kinetics. The rate of the reaction was found to be pH-dependent.

Ascorbic Acid↗
PubMed2001

A differential scanning calorimetric study of the effects of metal ions, substrate/product, substrate analogues and chaotropic anions on the thermal denaturation of yeast enolase 1.

The thermal denaturation of yeast enolase 1 was studied by differential scanning calorimetry (DSC) under conditions of subunit association/dissociation, enzymatic activity or substrate binding without turnover and substrate analogue binding. Subunit association stabilizes the enzyme, that is, the enzyme dissociates before denaturing. The conformational change produced by conformational metal ion binding increases thermal stability by reducing subunit dissociation. 'Substrate' or analogue binding additionally stabilizes the enzyme, irrespective of whether turnover is occurring, perhaps in part by the same mechanism. More strongly bound metal ions also stabilize the enzyme more, which we interpret as consistent with metal ion loss before denaturation, though possibly the denaturation pathway is different in the absence of metal ion. We suggest that some of the stabilization by 'substrate' and analogue binding is owing to the closure of moveable polypeptide loops about the active site, producing a more 'closed' and hence thermostable conformation.

Anions↗