Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.27 (thermolysin)
 1,894 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Methoxytryptoline (5-MeO-TLN, 6-methoxytetrahydro-beta-carboline) inhibits with high affinity [3H]-imipramine binding to the serotonin transporter in platelets. To evaluate whether 5-MeO-TLN is a substrate for the serotonin transporter, the accumulation of [3H]-5-MeO-TLN into rabbit platelets was studied in vitro. At short incubation times (5 min), [3H]-5-MeO-TLN accumulation was temperature-sensitive, but not saturable over a concentration range from 0.06 mumol/l to 10 mumol/l. Moreover, [3H]-5-MeO-TLN uptake was not affected by 100 mumol/l ouabain, its structural analogs tryptoline and 5-hydroxytryptoline, nor by the serotonin uptake inhibitors imipramine and citalopram. After longer incubation times (60 min), [3H]-5-MeO-TLN accumulation at 0 degree C approached that seen at 37 degrees C and temperature-sensitive [3H]-5-MeO-TLN uptake could no longer be observed. It is concluded that temperature-sensitive accumulation of [3H]-5-MeO-TLN is not mediated by the serotonin transporter and most likely represents a passive, diffusional process, the rate of which is temperature-dependent. The present studies thus confirm the hypothesis that 5-MeO-TLN affects [3H]-imipramine binding in platelets through a competitive mechanism and not via an allosteric interaction mediated through the substrate recognition site of the macromolecular complex of serotonin transporter.
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PMID:[3H]-5-methoxytryptoline is not actively accumulated by rabbit platelets. 362 87

Hypothyroidism (induced by 8 weeks of oral 0.05% propylthiouracil) heightened the phenotype of mdx mouse dystrophin-deficient myopathy to more closely resemble human Duchenne muscular dystrophy. Muscle repair after crush injury to the tibialis anterior muscle (TA) in hypothyroid mdx mice showed decreased myotube formation and delayed debris removal. To investigate whether reduced muscle precursor cell proliferation can account for the effects of hypothyroidism on repair from injury, immunocytochemistry for neural cell adhesion molecule (NCAM) on muscle precursor cells and autoradiography to detect DNA synthesis were performed in control and mdx TA. The proportions of labelled polymorphonuclear leukocyte nuclei (PMN), myotube nuclei (MN), and total mononuclear cell nuclei (TLN, the majority being muscle precursors) were counted in defined areas of regenerating TA after 2 and 4 days recovery. MN and the numbers of activated satellite cell nuclei on intact fibers were counted in surviving areas. In the same muscle, earlier phases of regeneration were observed in areas distal than proximal to the injury. At 2 days of regeneration, labelled PMN were increased in treated compared with untreated mdx TA. In distal areas at 4 days, fewer muscle precursors had recently fused to myotubes in treated than in untreated mdx. In proximal areas 4 days (relatively late in repair), TLN data suggested that muscle precursor proliferation was greater in hypothyroid compared with untreated mdx TA. NCAM immunostaining was consistent with proliferation data and confirmed that there were more muscle precursors in mdx than in control regenerating muscle. These results suggest that hypothyroidism prolongs and increases the phase of replication by mdx muscle precursors and delays precursor fusion into myotubes in regeneration.
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PMID:Hypothyroidism prolongs and increases mdx muscle precursor proliferation and delays myotube formation in normal and dystrophic limb muscle. 757 92

Unreamed nailing with solid tibial nails is an accepted method of treatment for open tibial shaft fractures up to grade III and of closed tibial fractures with severe soft tissue damage. However, fatigue failure of the distal locking bolts is a frequent complication. We report a mechanical study investigating the fatigue limit of six different types of locking bolts used in solid tibila nails (Biorigid Tibial nail/aap, UTN/ace, STN/Howmedica, TLN/Howmedica, delta R & T Tibial nail/Smith & Nephew, AO/ASIF UTN/Synthes). Our results prove a direct correlation between the bolt's diameter and mechanical properties. Further more we found that bolts with a continuing thread were weaker than bolts of the same diameter with only a short thread and an increased diameter at the nail's aperture. Our results suggest that mobilization with half of the average body weight (350N) allows osseous consolidation without fatique failure of any of the tested locking bolts. Some of the tested locking bolts may even withstand full wieght-bearing in a physiological walking cycle, but will not withstand the stress of a running cycle.
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PMID:[Fatigue stability of locking screws for unreamed tibial intramedullary nailing]. 1009 4

Simian immunodeficiency virus (SIV)-specific B cell responses and the Th1- or Th2-type profiles of cytokine expression were determined for rhesus macaques immunized with SIV antigens via the iliac lymph nodes (by use of a targeted lymph node [TLN] procedure) or orally with SIV p55gag plus cholera toxin (CT) as a mucosal adjuvant. Analysis of CD4+ T cells purified from SIV-stimulated peripheral blood mononuclear cells of immunized macaques revealed that Th2 cytokine production gradually increased after the second and third TLN immunization. Analysis of SIV-specific B cell responses revealed that peak SIV-specific IgA B cell responses followed the third TLN immunization and occurred during peak Th2-type T cell responses. Oral immunization of macaques with p55gag plus CT induced interferon-gamma-secreting Th1-type and select Th2-type cytokine-producing CD4+ T helper cells, which most likely accounted for the induction of p55-specific systemic IgG and mucosal IgA responses.
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PMID:Mucosal Th1- versus Th2-type responses for antibody- or cell-mediated immunity to simian immunodeficiency virus in rhesus macaques. 1009 24

Talin is a high-molecular-weight cytoskeletal protein, localized at cell-extracellular matrix associations known as focal contacts. In these regions, talin is thought to link integrin receptors to the actin cytoskeleton. Talin plays a key role in the assembly of actin filaments and in spreading and migration of various cell types. Talin proteins are found in a wide variety of organisms, from slime molds to humans. The human Talin (HGMW-approved symbol TLN) gene was previously mapped to chromosome 9p, but little was known of its sequence and genomic structure. To characterize human TLN further, we have isolated a single bacterial artificial chromosome clone, harboring the entire gene. The gene extends over more than 23 kb and consists of 57 exons. We have localized TLN to human chromosome band 9p13 by both fluorescence in situ hybridization and radiation hybrid mapping. Northern blot analysis detected TLN expression in various human tissues, including leukocytes, lung, placenta, liver, kidney, spleen, thymus, colon, skeletal muscle, and heart. Based on its chromosomal location, expression pattern, and protein function, we considered TLN as a candidate gene for cartilage-hair hypoplasia (CHH), an autosomal recessive metaphyseal chondrodysplasia, previously mapped to 9p13. We sequenced the entire TLN coding sequence in several CHH patients, but no functional mutations were detected.
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PMID:Characterization of the human talin (TLN) gene: genomic structure, chromosomal localization, and expression pattern. 1061 Jul 30

A new crystallization protocol for thermolysin (EC 3.4.24.27) from Bacillus thermoproteolyticus is presented. After dissolving the protein in the presence of KSCN, which avoids the use of DMSO and CsCl, crystals were obtained following the salting-in method. Crystal cell parameters are isomorphous with those previously reported from DMSO/CsCl mixtures. The new SCN(-) crystal structure has been analyzed. It shows the presence of one thiocyanate ion in the catalytic site and several rearrangements in the S(1) and S(2) subsites. These results are in agreement with the measurements of Inouye et al. [(1998), J. Biochem. (Tokyo), 123, 847-852], who observed in solution that the solubility of TLN, which is particularly poor in low ionic strength solutions, increases dramatically in the presence of several neutral salts. The results reported here suggest possible explanations for the solubility increase and for the inhibitory effects of high SCN(-) concentrations on thermolysin activity.
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PMID:The 2.2 A resolution structure of thermolysin (TLN) crystallized in the presence of potassium thiocyanate. 1245

A new alpha-aminophosphinic compound able to inhibit both zinc-containing exopeptidases and endopeptidases has been crystallized with TLN as a model in order to investigate the mode of zinc recognition by the phosphinic moiety and to evaluate the potential role of the free alpha-amino group in the formation of enzyme-inhibitor complexes. In addition to the main interactions between the backbone of the inhibitor and the enzyme active site, it is observed that the phosphinic group acts as a distorted bidentate ligand for the zinc ion, while the free alpha-amino function does not directly participate in interactions within the active site. Association of the present data and the K(i) values of various analogues of the inhibitor towards TLN and neprilysin suggests differences in the hydrophobicity of the S(1)-S(2) domains of the enzymes. This could be taken into account in the design of selective inhibitors.
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PMID:Interactions of a new alpha-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition. 1283 63

Developmental dynamics can be influenced by external and endogenous factors in a more or less analogous manner. To compare the phenotypic effects of (i) environmental [i.e. standard (stPhP) and extended (exPhP) photoperiods] changes in Arabidopsis wild types and (ii) endogenous genetic variation in eav1-eav61 early flowering mutants, two temporal indicators were analysed, the time to bolting (DtB) and the number of leaves (TLN). It was found that DtB and TLN are differentially affected in different environmental and genetic contexts, and some factors of dynamic convergence were identified. The quantitative response to photoperiod is markedly contingent on the phototrophic input for DtB, but less so for TLN. To discriminate the light quantity and period components in DtB, two novel temporal indicators were determined, LtB (photosynthetic time to bolting) and PChron (DtB h(-1) of photoperiod), respectively. The use of PChron results in a coincidence of the variation profiles across stPhP and exPhP, interpreted as a buffering of the trophic response. Unlike natural accessions and later flowering mutants, the variation profiles across stPhP and eav mutants are significantly divergent, pointing to differences in environmental and genetic variation in flowering time. Yet, phenocopy effects and dynamic convergence between wild-type and mutant profiles are detected by using exPhP and the LtB indicator. Additional analyses of the cauline leaf number (CLN) show that the apical and basal boundaries of the primary inflorescence vary co-ordinately. The finding that the correlativity between CLN and TLN changes across photoperiods suggests that different states of intra-connectedness are involved in ontogenetic specification of flowering time and embodied in the primary inflorescence.
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PMID:Comparison of environmental and mutational variation in flowering time in Arabidopsis. 1711 May 84

The deposited strain of the hazimicin producer, Micromonospora echinospora ssp. challisensis NRRL 12255 has considerable biosynthetic capabilities as revealed by genome scanning. Among these is a locus containing both type I and type II PKS genes. The presumed products of this locus, TLN-05220 (1) and TLN-05223 (2), bear a core backbone composed of six fused rings starting with a 2-pyridone moiety. The structures were confirmed by conventional spectral analyses including MS, and 1D and 2D NMR experiments. Comparison of both the 1H and 13C NMR data of the newly isolated compound with those of echinosporamicin and bravomicin A led us to propose a revision of the structure of the latter to include a 2-pyridone instead of the pyran originally postulated. Both compounds (1 and 2) possessed strong antibacterial activity against a series of gram-positive pathogens including several strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci (VRE), and cytotoxic activities against several human tumor cell lines. The TLN compounds are the first of this group with reported anticancer activity.
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PMID:TLN-05220, TLN-05223, new Echinosporamicin-type antibiotics, and proposed revision of the structure of bravomicins(*). 1968 Feb 83

TLN-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER, Thallion's proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity (low micromol/l) when tested in the NCI 60 tumor cell line panel and has shown in-vivo antitumor activity in several xenograft models. Related to its farnesylated moiety, the effect of TLN-4601 on Ras mitogen-activated protein kinase signaling was assessed. Downstream Ras signaling events, Raf-1, MEK, and ERK1/2 phosphorylation in MCF7 cells were evaluated by western blot analysis. TLN-4601 prevented epidermal growth factor-induced phosphorylation of Raf-1, MEK, and ERK1/2. This effect was time-dependent and dose-dependent with complete inhibition of protein phosphorylation within 4-6 h at 10 micromol/l. The inhibition of Ras signaling was not mediated by the inhibition of protein prenylation, documented by the lack of effect TLN-4601 on the prenylation of HDJ2 (specific substrate of farnesyltransferase), RAP1A (specific substrate of geranylgeranyl transferase-1), or Ras. As TLN-4601 did not inhibit EGFR, Raf-1, MEK or ERK1/2 kinase activities, the inhibitory effect of TLN-4601 on Ras signaling is not mediated by direct kinase inhibition. Using an Elk-1 trans-activation reporter assay, we found that TLN-4601 inhibits the MEK/ERK pathway at the level of Raf-1. Interestingly, TLN-4601 induces Raf-1 proteasomal-dependent degradation. These data indicate that TLN-4601 may inhibit the Ras-mitogen-activated protein kinase-signaling pathway by depleting the Raf-1 protein.
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PMID:TLN-4601, a novel anticancer agent, inhibits Ras signaling post Ras prenylation and before MEK activation. 2022 May 16


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