Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: C44C10 .12
59,182 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between structures of fatty acid derivatives, long-chain fatty alcohols, phospholipids and their calcium-transporting activity was investigated using the two-phase model system in which 45Ca is transported from an aqueous to an immiscible organic phase. Calcium translocation by all saturated and unsaturated fatty acids was significant only at 10 mM concentrations, but minimal or negligible below 1 mM; the corresponding methyl esters and alcohols were inactive at 10 mM. Polyunsaturated fatty acid derivatives, prepared by incubation with lipoxygenase (linoleate: oxygen oxidoreductase; EC 1.13.11.12) or by autoxidation in air, showed a markedly increased potency over the parent compounds. The oxidation products of linoleic and arachidonic acids were most potent. For example, the equieffective concentrations were 10 mM for linoleic acid, 0.4 mM for its lipoxygenase metabolites and 0.094 mM for its autoxidation products. Similarly, for arachidonic acid and its derivatives, equieffective concentrations were 10, 0.104 and 0.112 mM, respectively. The potency of the autoxidized fatty acid derivatives varied with both duration of autoxidation and the specific structure. Methyloleate and oleyl alcohol remained inactive even after a prolonged oxidation, whereas methyllinoleate and linoleyl alcohol were very potent only after 4 weeks but not after 1 week autoxidation. The potency of esters and alcohols with three or more double bonds increased significantly even after a short-term autoxidation, reflecting the differences in both the rate of formation and the contribution to calcium-transporting properties of the primary and secondary oxidation products. All phospholipids tested, with the exception of phosphatidylcholine and lysophosphatidylcholine, showed considerable calcium-transporting activities at 0.01 mM or greater concentrations; some members were of similar or greater potencies than the classical calcium ionophores, X537A and A23187.
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PMID:Calcium translocation by fatty acid derivatives in a two-phase partition model. Structure-activity relationships. 391 77

The reduction of membrane-bound hydroperoxides is a major factor acting against lipid peroxidation in living systems. This paper presents the characterization of the previously described 'peroxidation-inhibiting protein' as a 'phospholipid hydroperoxide glutathione peroxidase'. The enzyme is a monomer of 23 kDa (SDS-polyacrylamide gel electrophoresis). It contains one gatom Se/22 000 g protein. Se is in the selenol form, as indicated by the inactivation experiments in the presence of iodoacetate under reducing conditions. The glutathione peroxidase activity is essentially the same on different phospholipids enzymatically hydroperoxidized by the use of soybean lipoxidase (EC 1.13.11.12) in the presence of deoxycholate. The kinetic data are compatible with a tert-uni ping-pong mechanism, as in the case of the 'classical' glutathione peroxidase (EC 1.11.1.9). The second-order rate constants (K1) for the reaction of the enzyme with the hydroperoxide substrates indicate that, while H2O2 is reduced faster by the glutathione peroxidase, linoleic acid hydroperoxide is reduced faster by the present enzyme. Moreover, the phospholipid hydroperoxides are reduced only by the latter. The dramatic stimulation exerted by Triton X-100 on the reduction of the phospholipid hydroperoxides suggests that this enzyme has an 'interfacial' character. The similarity of amino acid composition, Se content and kinetic mechanism, relative to the difference in substrate specificity, indicates that the two enzymes 'classical' glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase are in some way related. The latter is apparently specialized for lipophylic, interfacial substrates.
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PMID:The selenoenzyme phospholipid hydroperoxide glutathione peroxidase. 397 21

Calcium-translocating activity of linoleic acid and its lipoxygenase (linoleate: oxygen oxidoreductase; EC 1.13.11.12) metabolites or autoxidation products was determined in vitro by estimation of 45Ca transport from a bulk aqueous to a bulk organic phase. Fresh commercial linoleic acid, tested immediately after removal from a sealed vial, stimulated calcium translocation only at concentrations greater than 1 mM. In contrast, 45Ca translocation by linoleic acid exposed to air was detectable at 10 microM. Oxidation products of linoleic acid obtained either by incubation with lipoxygenase or by autoxidation were much less potent than the calcium ionophore A23187. The products obtained by enzymic oxidation of linoleic acid enhanced contractility in the Langendorff-perfused guinea pig heart up to 45% over control (at 3 X 10(-8) M). The inotropic response was transient with rapid onset and not affected by the beta-adrenergic antagonist, propranolol. The autoxidation products of linoleic acid increased cardiac contractility up to 43% at 10(-6) M. In contrast, fresh linoleic acid caused only a negative inotropic effect at 10(-8) to 3 X 10(-7) M, progressing to contracture at 10(-6) M. These findings suggest that conflicting reports on the cardiostimulant effect of linoleic acid may be due to varying levels of the autoxidation products. Linoleic acid metabolites in vivo may have a physiological role in myocardial function related to their Ca2+-ionophoric activity.
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PMID:Calcium-translocating and cardiotonic properties of oxidation products of linoleic acid. 407 58

Eighteen known nonsteroidal antiinflammatory drugs (NSAID) were tested for their action against soybean lipoxygenase (E.C.1.13.11.12) using linoleic acid as substrate. It was found that the best inhibitors of lipoxygenase were naproxen, BW 755C, indomethacin and isoxicam. Drugs with intermediate potency were meclofenamic acid, phenylbutazone and benoxaprofen. Other drugs such as ibuprofen and zomepirac were only weakly active in the test.
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PMID:Soybean lipoxygenase inhibition by nonsteroidal antiinflammatory drugs. 640 11

Selenium-containing glutathione peroxidase (EC 1.11.1.9) was purified 6000-fold from bovine red blood cells to apparent homogeneity. Lipoxygenase (EC 1.13.11.12) was enriched 20-fold from soybean acetone powder. Linoleic acid was peroxidized with lipoxygenase and then used as a substrate in the glutathione peroxidase reaction. Analogous experiments were conducted with synthetic 1,2-dilinoleoyl-L-alpha-glycerophosphocholine and with natural bovine heart cardiolipin. The peroxidized phospholipids were reactive with glutathione peroxidase only after enzymatic attack by phospholipase A2 (EC 3.1.1.4). This result implies that the membrane-protective function of glutathione peroxidase includes preceeding phospholipase action and excludes a direct interaction of this enzyme with membrane-bound lipid hydroperoxides.
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PMID:Non-reactivity of the selenoenzyme glutathione peroxidase with enzymatically hydroperoxidized phospholipids. 641 5

Arachidonate (0.12-1.5 mM) initiated a concentration-dependent, saturable shape change of rat platelets suspended in citrated plasma. Interaction of arachidonate with platelets led to the formation of active metabolites that appeared to be the actual inducers of shape change. Among these, prostaglandin endoperoxides rather than thromboxane A2 seemed necessary for shape change. No role of the products of the lipoxygenase pathway could be shown. In the presence of cyclooxygenase and lipoxygenase inhibitors, arachidonate (0.25-0.5 mM) prevented platelet shape change induced by the endoperoxide analog U-46619 but not by other agonists such as ADP or serotonin. Arachidonate acts therefore as both an agonist and an antagonist of platelet shape change. The agonistic effect requires arachidonate metabolism while the antagonistic activity seems to be linked to the fatty acid molecule itself.
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PMID:Effects of metabolized and unmetabolized arachidonate on rat platelet shape change. 643 24

The oxygenation of [1-14C]-arachidonic acid by a soluble soybean lipoxygenase (E.C.1.13.11.12) preparation was determined in the presence of various cyclo-oxygenase and lipoxygenase inhibitors. The results showed that several non-inhibitory compounds drastically blunted the inhibitory potency of potent lipoxygenase inhibitors. Studies on the combined effects of a variety of structurally unrelated inhibitors of lipoxygenase, cyclo-oxygenase or both oxygenation pathways provided strong evidence for the existence of a supplementary binding site on soybean lipoxygenase which reduces the effective interactions of inhibitors with the catalytic site. Thus several cyclo-oxygenase inhibitors (which do not inhibit at the lipoxygenase catalytic site), as well as low concentrations of lipoxygenase inhibitors, interact with this putative supplementary site and blunt the inhibitory efficacy of potent lipoxygenase inhibitors. Although the degree of interaction with the catalytic site determines the absolute potency of inhibitors, the additional interaction at the putative supplementary binding site is also obligatory for inhibitory potency. In this new multiple-site model the potent lipoxygenase inhibitors (e.g. acetone phenylhydrazone, phenidone) possess high affinities for both sites, whereas weak inhibitors and certain cyclo-oxygenase inhibitors (e.g. benoxaprofen, phenylbutazone, indomethacin) interact predominantly with the supplementary site on the lipoxygenase but lack affinity for the catalytic site.
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PMID:Interactions of inhibitors of the lipoxygenase and cyclooxygenase pathways with a supplementary binding site on soybean lipoxygenase. 644 Jun 14

Chlorpromazine was found to inhibit oxygen consumption by lipoxidase from soybean and from blood platelets. The inhibition of 15-lipoxidase (linoleate:oxygen oxidoreductase, EC 1.13.11.12) (from soybean) depends on substrate concentration. IC50 values for this inhibition were 50-150 muM chlorpromazine at an arachidonic acid concentration of 20-300 muM. Inhibition of crude 12-lipoxidase preparation (100 000 X g supernatant from horse platelet homogenate) was weaker than 15-lipoxidase. IC50 at the arachidonic acid concentration of 100 muM was about 1000 muM chlorpromazine.
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PMID:The influence of chlorpromazine on lipoxidases. 677 56

Deuterium NMR spectra for a series of selectively deuterated substrates and inhibitors in the presence of lipoxygenase-1 (EC 1.13.11.12) are presented. Extrapolation of the 2H NMR line widths yielded transverse relaxation rates for the bound inhibitors [2H21]dodecanoic acid (protonated at the 2,2-position), [2,2-2H]dodecanoic acid, and [12,12,12-2H]dodecanoic acid which are 1/T2,bd = 5.0 X 10(3), 1.12 X 10(4), and 1.16 X 10(3) s-1, respectively. The substrates [9,10,12,13-2H]linoleic acid and [11,11-2H]linoleic acid had 1/T2,bd = 8.2 X 10(3) and 7.95 X 10(3) s-1, respectively. Kinetic measurements established Ki = 1.5 X 10(-3) M for dodecanoic acid (lauric acid) inhibition of lipoxygenase when the substrate is linoleic acid (Km = 2.6 X 10(-5) M). Lipoxygenase, with Mr 102,000, is predicted to have a rotational correlation time tau c - 1.2 X 10(-7) s, yielding a 1/T2,bd = 1.56 X 10(4) s-1 for tightly bound ligand. Hence, the correlation times of the selectively deuterated inhibitors indicate internal motions are present in the bound species.
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PMID:Deuterium nuclear magnetic resonance study of the interaction of substrates and inhibitors with soybean lipoxygenase. 678 61

Application of 12-O-tetradecanoylphorbol-13-acetate (TPA; 20 nmol/mouse), a tumor-promoting agent, to mouse skin results in an induction of epidermal ornithine decarboxylase (ODC; EC 4.1.1.17). Induction of ODC by TPA was inhibited by treatment of skin with indomethacin (1.12 mumol/mouse), a cyclooxygenase inhibitor, and the ODC activity suppressed by indomethacin was completely restored by concurrent application of prostaglandin E2 (PGE2) (140 nmol/mouse) as described first by Verma et al. (Cancer Res., 40: 308-315, 1980). Treatment of mice with tetracaine (20 and 100 mumol/mouse), a nonspecific phospholipase A2 inhibitor, inhibited the induction of ODC by TPA. More specific phospholipase A2 inhibitors, mepacrine (20 mumol/mouse) and p-bromophenacyl bromide (10 mumol/mouse), also inhibited the ODC induction. The TPA-induced ODC inhibited by mepacrine was not restored by the treatment of mice with PGE2. TPA-induced ODC inhibited by either mepacrine or p-bromophenacyl bromide was partially but significantly restored by treatment with arachidonic acid (1 to 40 mumol/mouse). Neither PGE2 nor arachidonic acid alone could induce the epidermal ODC. Treatment of mice with nordihydroguaiaretic acid (10 to 90 mumol/mouse), a lipoxygenase inhibitor, also inhibited the induction of ODC by TPA. These results strongly indicate that the stimulation of phospholipase A2 activity is a crucial process in inducing mouse epidermal ODC by TPA and not only cyclooxygenase product (i.e., PGE2) but also lipoxygenase product(s) are involved in the mechanism of ODC induction. Our present data also suggest that the above arachidonate metabolites are essential but not sufficient factors for the TPA-stimulated induction of ODC.
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PMID:Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by phospholipase A2 inhibitors and lipoxygenase inhibitor. 680 48


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