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11.
Aryl Hetaryl Ketones and Thioketones as Efficient Inhibitors of Peptidyl‐Prolyl cis‐trans Isomerases
Thomas Hediger Walter Frank Michael Schumann Gunter Fischer Manfred Braun 《化学与生物多样性》2012,9(11):2618-2634
A series of 18 differently substituted new aryl hetaryl ketones and thioketones were synthesized in four to six steps from commercial starting materials. The new ketones were evaluated as inhibitors of the peptidyl‐prolyl cis‐trans isomerase hPin1 with Ki values ranging in the one‐digit micromolar to sub‐micromolar numbers. A crystal structure revealed the non‐planar arrangement of the aryl residues at the carbonyl compound and supports the hypothesis that the new compounds might mimic the transition state of the enzymatic conversion. 相似文献
12.
Bettina Schmidt Thomas Tradler Jens-U. Rahfeld Birgit Ludwig Bunty Jain Karlheinz Mann K. Peter Rücknagel Bernhard Janowski Angelika Schierhorn Gerhard Küllertz Jörg Hacker Gunter Fischer 《Molecular microbiology》1996,21(6):1147-1160
Legionella pneumophila is the causative agent of a severe form of pneumonia in humans (Legionnaires’disease). A major virulence factor, the Mip protein (FK506-binding protein, FKBP25mem), belongs to the enzyme family of peptidyl-prolyl cis/trans isomerases (PPIases). Here we show that L. pneumophila Philadelphia I possesses an additional cytoplasmic PPiase at a level of enzyme activity comparable to that of FKBP25mem. The N-terminal amino acid sequence of the purified protein was obtained by Edman degradation and showed that the protein is a member of the cyclophilin family of PPIases. The Icy gene (Legionella cycophn) was cloned and sequenced. It encodes a putative 164-amino-acid protein with a molecular mass of 17 968 Da called L. pneumophila cyclophilin 18 (L. p. Cyp18). Amino acid sequence comparison displays considerable similarity to the cytoplasmic and the periplasmic cyclophilins of Escherichia coll with 60.5% and 51.5% identity, respectively. The substrate specificity and inhibition by cyclosporin A revealed a pattern that is typically found for other bacterial cyclophilins. An L. pneumophila Cyp18 derivative with a 19-amino-acid polypeptide extension including a 6-histi-dine tag and an enterokinase cleavage site exhibits 相似文献
13.
The human genetic material is packed hierarchically within the metaphase chromosome: the DNA moleculet together with histone proteins form 11 nm diameter nucleosomes, which are then ordered into the 30 nm thick chromatin fiber. Little is known about the packing of this fiber within the chromosome. We have developed a tracking algorithm with which we followed its path within a three-dimensional reconstruction of a human chromosome computed from a series of electron micrographie projections. Fiber segments were seen to form loops of 100–350 nm diameter. Our observations indicate that these loops — which themselves show no preferred orientation — are organised into regions of roughly 200 nm axial extent. 相似文献
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MT113, a nonphotosynthetic mutant of Rhodobacter capsulatus previously characterized as lacking cytochrome c2 is shown to lack also cytochrome c1, the Rieske iron-sulfur cluster and the antimycin sensitive semiquinone Qc, all components of the cytochrome bc1 complex. Although MT113 contained b-type cytochromes and other iron-sulfur clusters at nearly wild-type level, it lacks c-type cytochromes. Based on antibody detection, c2 apoprotein was absent in MT113, however the apoproteins corresponding to the cytochromes b and c1 and the Rieske iron-sulfur cluster were present in reduced amounts. Genetic analysis indicated that the lesion appears to be due to a single mutation which is not localized in the structural genes of cytochrome c2 or the bc1 complex. These data taken together suggest that the pleiotropic mutation in MT113 might be related to the biosynthesis of c-type cytochromes. 相似文献
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Glycation reactions resulting in the generation and accumulation of advanced glycation endproducts (AGEs) are potential mechanisms by which bone protein may be altered in vivo. AGEs accumulate in the bone increasingly with age come into close contact with osteoblasts or osteoclasts. The direct effect of AGEs on bone cells has not been thoroughly investigated. This study aimed to examine whether glycated bovine serum albumin (AGE - BSA) as an AGE modulate the mRNA expression of various genes in primary human osteoblast cultures. The following parameters were included: RAGE (receptor for AGEs), alkaline phosphatase, osteocalcin, osterix and RANKL (receptor activator of nuclear factor-kappaB ligand). Primary human osteoblast cultures were obtained from bone specimens of six patients with osteoarthrosis. Human osteoblasts were treated in AGE - BSA or control-BSA (non-glycated BSA) containing medium (5 mg/ml each) over a time course of seven days. After RT-PCR the mRNA expression was measured by real-time PCR. Related to control - BSA exposure, the mRNA expression of RAGE, RANKL and osterix increased during AGE - BSA treament. For alkaline phosphatase and osteocalcin a tendency of down-regulation was found. In summary, the study presents evidence that advanced glycation end products accumulated in bone alter osteoblasts by activation the AGE - RAGE pathway (RAGE mRNA up-regulation), inducing enhanced osteoclastogenesis (RANKL mRNA up-regulation) and impaired matrix mineralization (down-regulation of alkaline phosphatase and osteocalcin mRNA). Thus, AGEs may play a functional role in the development of bone diseases (e.g. osteoporosis). 相似文献
18.
We report on the second case of a reed warbler × great reed warbler hybrid (Acrocephalus scirpaceus and A. arundinaceus). The bird was captured during a standardised ringing session in Belgium in autumn 1999, and fell between the parental species in all measurements. Molecular analyses of two microsatellite loci verified that the bird was a female that had a reed warbler father and a great reed warbler mother. 相似文献
19.
Hung-Chun Yu Jennifer L. Sloan Gunter Scharer Alison Brebner Anita M. Quintana Nathan P. Achilly Irini Manoli Curtis R. Coughlin II Elizabeth A. Geiger Una Schneck David Watkins Terttu Suormala Johan L.K. Van Hove Brian Fowler Matthias R. Baumgartner David S. Rosenblatt Charles P. Venditti Tamim H. Shaikh 《American journal of human genetics》2013
20.