| 11983987 |
Pseudophomins A and B, a class of cyclic lipodepsipeptides isolated from a Pseudomonas species |
10.1107/s0108270102004432. |
Acta Crystallogr C |
Pseudophomins A and B, a class of cyclic lipodepsipeptides isolated from a Pseudomonas species
Abstract
- The crystal structures of pseudophomins A and B, with primary structures beta-hydroxydecanoyl-L-Leu-D-Glu-D-allo-Thr-D-Ile-D-Leu-D-Ser-L-Leu-D-Ser-L-Ile monohydrate, C(55)H(97)N(9)O(16).H(2)O, and beta-hydroxydodecanoyl-L-Leu-D-Glu-D-allo-Thr-D-Ile-D-Leu-D-Ser-L-Leu-D-Ser-L-Ile monohydrate, C(57)H(101)N(9)O(16).H(2)O, new cyclic lipodepsipeptides isolated from Pseudomonas fluorescens strain BRG100, have been solved. The absolute configuration of pseudophomin A has been determined from anomalous dispersion and the stereochemistry of the beta-hydroxy acid group is R.
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| 11985602 |
Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge |
10.1046/j.1432-1033.2002.02881.x. |
Eur J Biochem |
Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge
Abstract
- We report the isolation of a novel antimicrobial peptide, bass hepcidin, from the gill of hybrid striped bass, white bass (Morone chrysops) x striped bass (M. saxatilis). After the intraperitoneal injection of Micrococcus luteus and Escherichia coli, the peptide was purified from HPLC fractions with antimicrobial activity against Escherichia coli. Sequencing by Edman degradation revealed a 21-residue peptide (GCRFCCNCCPNMSGCGVCCRF) with eight putative cysteines. Molecular mass measurements of the native peptide and the reduced and alkylated peptide confirmed the sequence with four intramolecular disulfide bridges. Peptide sequence homology to human hepcidin and other predicted hepcidins, indicated that the peptide is a new member of the hepcidin family. Nucleotide sequences for cDNA and genomic DNA were determined for white bass. A predicted prepropeptide (85 amino acids) consists of three domains: a signal peptide (24 amino acids), prodomain (40 amino acids) and a mature peptide (21 amino acids). The gene has two introns and three exons. A TATA box and several consensus-binding motifs for transcription factors including C/EBP, nuclear factor-kappaB, and hepatocyte nuclear factor were found in the region upstream of the transcriptional start site. In white bass liver, hepcidin gene expression was induced 4500-fold following challenge with the fish pathogen, Streptococcus iniae, while expression levels remained low in all other tissues tested. A novel antimicrobial peptide from the gill, bass hepcidin, is predominantly expressed in the liver and highly inducible by bacterial exposure.
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| 11995978 |
Detection and sequencing of new cyclic peptides from linseed by electrospray ionization mass spectrometry |
None |
Acta Biochim Pol |
Detection and sequencing of new cyclic peptides from linseed by electrospray ionization mass spectrometry
Abstract
- Extract of Linum usitatissimum seeds was analyzed by ESI-MS and ESI-MS/MS. The analysis confirms the presence of previously reported cyclolinopeptides: CLA (c(Pro-Pro-Phe-Phe-Leu-Ile-Ile-Leu-Val) and CLB (c(Pro-Pro-Phe-Phe-Val-Ile-Met-Ile-Leu)). Cyclolinopeptides CLD and CLE, which contain methionine oxide, were detected in small quantities only. These peptides likely result from the oxidation of their precursors, not reported previously: CLD' (c(Pro-Phe-Phe-Trp-Ile-Met-Leu-Leu)) and CLE'(c(Pro-Leu-Phe-Ile-Met-Leu-Val-Phe)), present at higher concentrations in unoxidized extract. Two new cyclic octapeptides: CLF (c(Pro-Phe-Phe-Trp-Val-Met-Leu-Met)) and CLG (c(Pro-Phe-Phe-Trp-Ile-Met-Leu-Met)) were detected and their sequences were proposed on the basis of CID experiments and similarity with those of CLD'.
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| 11995983 |
Search for new synthetic immunosuppressants II. Tetrazole analogues of hymenistatin I |
None |
Acta Biochim Pol |
Search for new synthetic immunosuppressants II. Tetrazole analogues of hymenistatin I
Abstract
- Linear and cyclic hymenistatin I (HS I) analogues with dipeptide segments Ile2-Pro3 Pro3-Pro4 and Val6-Pro7 replaced by their tetrazole analogues Ile2-psi[CN4]-Ala3', Pro3-psi[CN4]-Ala4 and Val6-psi[CN4]-Ala7 were synthesized by the solid phase peptide synthesis method and cyclized with the TBTU and/or HATU reagent. The peptides were examined for their immunosuppressive activity in the lymphocyte proliferation test (LPT).
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| 11996584 |
Solution-phase parallel synthesis of a pharmacophore library of HUN-7293 analogues: a general chemical mutagenesis approach to defining structure-function properties of naturally occurring cyclic (depsi)peptides |
10.1021/ja020166v. |
J Am Chem Soc |
Solution-phase parallel synthesis of a pharmacophore library of HUN-7293 analogues: a general chemical mutagenesis approach to defining structure-function properties of naturally occurring cyclic (depsi)peptides
Abstract
- HUN-7293 (1), a naturally occurring cyclic heptadepsipeptide, is a potent inhibitor of cell adhesion molecule expression (VCAM-1, ICAM-1, E-selectin), the overexpression of which is characteristic of chronic inflammatory diseases. Representative of a general approach to defining structure-function relationships of such cyclic (depsi)peptides, the parallel synthesis and evaluation of a complete library of key HUN-7293 analogues are detailed enlisting solution-phase techniques and simple acid-base liquid-liquid extractions for isolation and purification of intermediates and final products. Significant to the design of the studies and unique to solution-phase techniques, the library was assembled superimposing a divergent synthetic strategy onto a convergent total synthesis. An alanine scan and N-methyl deletion of each residue of the cyclic heptadepsipeptide identified key sites responsible for or contributing to the biological properties. The simultaneous preparation of a complete set of individual residue analogues further simplifying the structure allowed an assessment of each structural feature of 1, providing a detailed account of the structure-function relationships in a single study. Within this pharmacophore library prepared by systematic chemical mutagenesis of the natural product structure, simplified analogues possessing comparable potency and, in some instances, improved selectivity were identified. One potent member of this library proved to be an additional natural product in its own right, which we have come to refer to as HUN-7293B (8), being isolated from the microbial strain F/94-499709.
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| 12003784 |
Eosinophil adhesion to cholinergic nerves via ICAM-1 and VCAM-1 and associated eosinophil degranulation |
10.1152/ajplung.00279.2001. |
Am J Physiol Lung Cell Mol Physiol |
Eosinophil adhesion to cholinergic nerves via ICAM-1 and VCAM-1 and associated eosinophil degranulation
Abstract
- In vivo, eosinophils localize to airway cholinergic nerves in antigen-challenged animals, and inhibition of this localization prevents antigen-induced hyperreactivity. In this study, the mechanism of eosinophil localization to nerves was investigated by examining adhesion molecule expression by cholinergic nerves. Immunohistochemical and functional studies demonstrated that primary cultures of parasympathetic nerves express vascular cell adhesion molecule-1 (VCAM-1) and after cytokine pretreatment with tumor necrosis factor-alpha and interferon-gamma intercellular adhesion molecule-1 (ICAM-1). Eosinophils adhere to these parasympathetic neurones after cytokine pretreatment via a CD11/18-dependent pathway. Immunohistochemistry and Western blotting showed that a human cholinergic nerve cell line (IMR-32) expressed VCAM-1 and ICAM-1. Inhibitory experiments using monoclonal blocking antibodies to ICAM-1, VCAM-1, or CD11/18 and with the very late antigen-4 peptide inhibitor ZD-7349 showed that eosinophils adhered to IMR-32 cells via these adhesion molecules. The protein kinase C signaling pathway is involved in this process as a specific inhibitor-attenuated adhesion. Eosinophil adhesion to IMR-32 cells was associated with the release of eosinophil peroxidase and leukotriene C(4). Thus eosinophils adhere to cholinergic nerves via specific adhesion molecules, and this leads to eosinophil activation and degranulation; this may be part of the mechanism of eosinophil-induced vagal hyperreactivity.
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| 12019176 |
Expression of the type 1 insulin-like growth factor receptor is up- regulated in primary prostate cancer and commonly persists in metastatic disease. |
10.1074/jbc.m000089200 |
Cancer Res. |
Expression of the type 1 insulin-like growth factor receptor is up- regulated in primary prostate cancer and commonly persists in metastatic disease.
Abstract
- The type 1 insulin-like growth factor receptor (IGF1R) mediates tumor cell growth, adhesion, and protection from apoptosis. High plasma IGF-I levels predispose to prostate cancer, but there is no consensus regarding IGF1R expression in primary and metastatic prostate cancer. Recent studies in a human cell line and a mouse model suggest that metastatic prostate cancer cell detachment may be favored by impairing cadherin function via loss of expression of insulin receptor substrate-1 (IRS-1), the principal IGF1R docking molecule. This may be accompanied by PTEN mutation, reactivating a key antiapoptotic pathway, and by IGF1R down-regulation to prevent Shc-mediated differentiation. We studied IGF1R expression in 54 samples of primary prostate tissue including 44 archival and 10 prospectively collected biopsies. We performed semiquantitative immunostaining for the IGF1R, IRS-1, and PTEN, and in situ hybridization for IGF1R. The IGF1R was significantly up-regulated at the protein and mRNA level in primary prostate cancer compared with benign prostatic epithelium. There was a trend toward increased expression of IRS-1 in the malignant biopsies. We also measured IGF1R, IRS-1, and PTEN expression in 12 paired biopsies of primary prostate cancer and subsequent bone metastases. In four cases, IGF1R and IRS-1 levels were lower in the metastases than in the primary tumors. Three of these metastases also lacked significant PTEN staining, compatible with findings in the model systems described above. However, this pattern was relatively uncommon, and 8 of 12 cases expressed detectable IGF1R and IRS-1 in both primary and metastatic biopsies. These findings challenge earlier reports of IGF1R down-regulation in metastatic disease and reinforce the importance of the IGF1R in prostate cancer biology.
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| 12021776 |
Paneth cell trypsin is the processing enzyme for human defensin-5 |
10.1038/ni797. |
Nat Immunol |
Paneth cell trypsin is the processing enzyme for human defensin-5
Abstract
- The antimicrobial peptide human alpha-defensin 5 (HD5) is expressed in Paneth cells, secretory epithelial cells in the small intestine. Unlike other characterized defensins, HD5 is stored in secretory vesicles as a propeptide. The storage quantities of HD5 are approximately 90 450 microg per cm2 of mucosal surface area, which is sufficient to generate microbicidal concentrations in the intestinal lumen. HD5 peptides isolated from the intestinal lumen are proteolytically processed forms--HD5(56-94) and HD5(63-94)--that are cleaved at the Arg55-Ala56 and Arg62-Thr63 sites, respectively. We show here that a specific pattern of trypsin isozymes is expressed in Paneth cells, that trypsin colocalizes with HD5 and that this protease can efficiently cleave HD5 propeptide to forms identical to those isolated in vivo. By acting as a prodefensin convertase in human Paneth cells, trypsin is involved in the regulation of innate immunity in the small intestine.
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| 12023989 |
Genotype-phenotype correlation in inherited severe insulin resistance |
10.1093/hmg/11.12.1465. |
Hum Mol Genet |
Genotype-phenotype correlation in inherited severe insulin resistance
Abstract
- The insulin receptor is a ligand-activated tyrosine kinase. Mutations in the corresponding gene cause the rare inherited insulin-resistant disorders leprechaunism and Rabson-Mendenhall syndrome. Patients with the most severe syndrome, leprechaunism, have growth restriction, altered glucose homeostasis and early death (usually before 1 year of age). Rabson-Mendenhall syndrome is less severe, with survival up to 5-15 years of age. These disorders are transmitted as autosomal recessive traits. Here we report six new patients and correlate mutations in the insulin receptor gene with survival. Patients with leprechaunism were homozygous or compound heterozygous for mutations in the extracellular domain of the insulin receptor and their cells had markedly impaired insulin binding (<10% of controls). Mutations in their insulin receptor gene inserted premature stop codons (E124X, R372X, G650X, E665X and C682X), resulting in decreased levels of mature mRNA, or affected the extracellular domain of the receptor (R86P, A92V, DeltaN281, I898T and R899W). Three patients with Rabson-Mendenhall syndrome had at least one missense mutation in the intracellular domain of the insulin receptor (P970T, I1116T, R1131W and R1174W). Expression studies in CHO cells indicated that the R86P, A92V, DeltaN281, I898T, R899W and R1131W mutations markedly impaired insulin binding (<5% of control), while the P970T, I1116T and R1174W mutant receptors retained significant insulin-binding activity. These results indicate that mutations in the insulin receptor retaining residual insulin-binding correlate with prolonged survival in our series of patients with extreme insulin resistance.
|
| 12024216 |
HDAC6 is a microtubule-associated deacetylase. |
10.1038/417455a |
Nature |
HDAC6 is a microtubule-associated deacetylase.
Abstract
- Reversible acetylation of alpha-tubulin has been implicated in regulating microtubule stability and function. The distribution of acetylated alpha-tubulin is tightly controlled and stereotypic. Acetylated alpha-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts. However, the enzymes responsible for regulating tubulin acetylation and deacetylation are not known. Here we report that a member of the histone deacetylase family, HDAC6, functions as a tubulin deacetylase. HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules and localizes with the microtubule motor complex containing p150(glued) (ref. 3). In vivo, the overexpression of HDAC6 leads to a global deacetylation of alpha-tubulin, whereas a decrease in HDAC6 increases alpha-tubulin acetylation. In vitro, purified HDAC6 potently deacetylates alpha-tubulin in assembled microtubules. Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility. Our
Results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription.
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| 12027653 |
Progress toward the Synthesis of garsubellin A and related phloroglucins: the direct diastereoselective synthesis of the bicyclo[3.3.1]nonane core |
10.1021/ol025968+. |
Org Lett |
Progress toward the Synthesis of garsubellin A and related phloroglucins: the direct diastereoselective synthesis of the bicyclo[3.3.1]nonane core
Abstract
- [reaction: see text] A highly diastereoselective single-step cyclization reaction provides access to the bicyclo[3.3.1]nonane core of the polyprenylated phloroglucin natural product garsubellin A. Further elaboration to a more functionalized analogue involves a sequential Claisen rearrangement/Grubbs olefin cross-metathesis strategy. Additionally, this strategy was extended to the preparation of the bis-quaternary carbon array found at the bridgehead positions of the phloroglucin natural products.
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| 12030609 |
Cortistatin-14 inhibits cell proliferation of human thyroid carcinoma cell lines of both follicular and parafollicular origin |
10.1007/BF03344019. |
J Endocrinol Invest |
Cortistatin-14 inhibits cell proliferation of human thyroid carcinoma cell lines of both follicular and parafollicular origin
Abstract
- Cortistatin (CST-14, Pro-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Ser-Ser-Cys]-Lys-NH2), a neuropeptide member of the SRIH family, binds to all 5 SRIH receptor (sst) subtypes, but also possesses a significant binding affinity to GH secretagogue receptors (GHS-R), which have been reported to mediate the antiproliferative activity of GHS on thyroid cancer cells. The effect of CST-14 on cell proliferation was studied in 3 different human thyroid carcinoma cell lines of follicular origin (N-PAP, WRO, ARO) and in one thyroid medullary carcinoma cell line (TT). CST-14 1 pM determined a significant inhibition of cell proliferation in TT, N-PAP and WRO cells and this effect was dose-dependent and more pronounced than that displayed by SRIH-14 (Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH) treatment. To a minor extent, CST-14, but not SRIH-14, also temporary inhibited ARO cell proliferation. By immunofluorescence, sst2, sst3 and sst5 have been demonstrated in TT cells, whereas types 3 and 5 only were expressed in N-PAP and WRO cells, and no sst subtype was found in ARO cells. The presence of both GHS-Rla and lb mRNA has been studied and demonstrated in the TT medullary carcinoma cell line, whereas follicular derived cell lines were already known to express GHS binding sites. Addition of EP-80874 (D-Mrp-c[D-Cyspyridilalanyl3-D-Trp-Lys-Val-Cys]-Mrp-NH2), a synthetic peptide that binds to SRIH and GHS-R, completely abolished the antiproliferative effects of CST-14 or SRIH-14 on sst/GHS-R positive thyroid carcinoma cell lines (WRO, N-PAP and TT). EP-80874 was also able to antagonize the inhibitory activity of CST-14 on the growth of cells (ARO) expressing GHS-R but not sst. Taken together, these data firstly demonstrate that EP-80874 has a mixed SRIH/CST antagonist activity and suggest that the oncostatic effect of CST-14 on thyroid cancer cells could be mediated by both sst and/or GHS-R.
|
| 12032081 |
The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. |
10.1093/emboj/21.11.2682 |
EMBO J. |
The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase.
Abstract
- Transcriptional repression mediated through histone deacetylation is a critical component of eukaryotic gene regulation. Here we demonstrate that the class II histone deacetylase HDAC4 is covalently modified by the ubiquitin-related SUMO-1 modifier. A sumoylation-deficient point mutant (HDAC4-K559R) shows a slightly impaired ability to repress transcription as well as reduced histone deacetylase activity. The ability of HDAC4 to self-aggregate is a prerequisite for proper sumoylation in vivo. Calcium/calmodulin-dependent protein kinase (CaMK) signalling, which induces nuclear export, abrogates SUMO-1 modification of HDAC4. Moreover, the modification depends on the presence of an intact nuclear localization signal and is catalysed by the nuclear pore complex (NPC) RanBP2 protein, a factor newly identified as a SUMO E3 ligase. These findings suggest that sumoylation of HDAC4 takes place at the NPC and is coupled to its nuclear import. Finally, modification experiments indicate that the MEF2-interacting transcription repressor (MITR) as well as HDAC1 and -6 are similarly SUMO modified, indicating that sumoylation may be an important regulatory mechanism for the control of transcriptional repression mediated by both class I and II HDACs.
|
| 12036875 |
A new platelet polymorphism Duv(a+), localized within the RGD binding domain of glycoprotein IIIa, is associated with neonatal thrombocytopenia |
10.1182/blood.v99.12.4449. |
Blood |
A new platelet polymorphism Duv(a+), localized within the RGD binding domain of glycoprotein IIIa, is associated with neonatal thrombocytopenia
Abstract
- We report here the identification and characterization of a new platelet alloantigen, Duv(a+), implicated in a case of neonatal thrombocytopenia. Immunochemical studies demonstrated that the epitope was localized on glycoprotein (GP) IIIa. Sequencing of the exons 2 to 15 of GP IIIa gene polymerase chain reaction products from both parents revealed a single base substitution 517C>T (complementary DNA) present in a heterozygous state in DNA from the father leading to amino acid substitution Thr140Ile (ACC>ATC) within the Arg-Gly-Asp binding domain of GP IIIa. Flow cytometry and immunoprecipitation studies of IIb-C517 or T517 IIIa transfected Cos cells allowed us to demonstrate this mutation was responsible for expression of the Duv(a+) epitope. By polymerase chain reaction-single-strand conformational-polymorphism analysis, the mutated allele could not be detected in a population of 100 healthy unrelated donors, indicating a low frequency of occurrence. The Thr140/Ile dimorphism, localized 3 amino acids upstream from the Arg143 involved in the expression of HPA-4a, did not interfere with the binding of an anti-HPA-4a antibody in flow cytometry. Results of functional analysis of wild-type or mutated transfected CHO cells-(1) aggregation in the presence of Ca(++) and soluble fibrinogen after complex activation by dithiothreitol, (2) adhesion on coated fibrinogen, (3) binding of monoclonal antibody PAC-1 or LIBS antibody D3, and (4) outside-in signaling-all suggest that the Thr140Ile polymorphism localized in the Arg-Gly-Asp binding domain of GP IIIa does not affect significantly, if at all, the integrin function. We have shown that the anti-Duv(a+) antibody may inhibit platelet GP IIb-IIIa function.
|
| 12045349 |
New cyclic peptides from Citrus medica var. sarcodactylis SWINGLE |
10.1248/cpb.50.857. |
Chem Pharm Bull (Tokyo) |
New cyclic peptides from Citrus medica var. sarcodactylis SWINGLE
Abstract
- Two new cyclic peptides were isolated from the fruit peels of Citrus medica var. sarcodactylis SWINGLE. Their structures were elucidated as cyclo(-Gly-Asp-Leu-Thr-Val-Tyr-Phe-) and cyclo(-Gly-Leu-Pro-Trp-Leu-Ile-Ala-Ala-) by intensive two-dimensional (2D) NMR analysis and chemical evidence.
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