Search results for "precursor"
showing 10 items of 490 documents
Proenzyme Structure and Activation of Astacin Metallopeptidase
2010
Proteolysis is regulated by inactive (latent) zymogens, with a prosegment preventing access of substrates to the active-site cleft of the enzyme. How latency is maintained often depends on the catalytic mechanism of the protease. For example, in several families of the metzincin metallopeptidases, a >cysteine switch> mechanism involves a conserved prosegment motif with a cysteine residue that coordinates the catalytic zinc ion. Another family of metzincins, the astacins, do not possess a cysteine switch, so latency is maintained by other means. We have solved the high resolution crystal structure of proastacin from the European crayfish, Astacus astacus. Its prosegment is the shortest struc…
Upregulation of the α-secretase ADAM10 - risk or reason for hope?
2010
A decade ago, a disintegrin and metalloproteinase 10 (ADAM10) was identified as an alpha-secretase and as a key proteinase in the processing of the amyloid precursor protein. Accordingly, the important role that it plays in Alzheimer's disease was manifested. Animal models with an overexpression of ADAM10 revealed a beneficial profile of the metalloproteinase with respect to learning and memory, plaque load and synaptogenesis. Therefore, ADAM10 presents a worthwhile target with respect to the treatment of a neurodegenerative disease such as Morbus Alzheimer. Initially, ADAM10 was suggested to be an enzyme, shaping the extracellular matrix by cleavage of collagen type IV, or to be a tumour n…
The Alzheimer’s disease associated bacterial protease RgpB from P. gingivalis activates the alternative β-secretase meprin β thereby increasing Aβ ge…
2019
AbstractAlzheimer’s disease (AD) is the most common type of dementia and characterized by tau hyperphosphorylation, oxidative stress, reactive microglia and amyloid-β (Aβ) deposits. A recent study revealed that Porphyromonas gingivalis infection is associated with amyloid β generation in Alzheimer’s disease. Increased Aβ levels, tau degradation and neuronal toxicity were observed as a consequence of ginigipain R (RgpB) activity, a cysteine protease constitutively secreted by P. gingivalis. Of note, we previously identified RgpB as a potent activator of the metalloproteinase meprin β. Interestingly, meprin β is an alternative β-secretase of the amyloid precursor protein (APP), which together…
ADAM10, myelin-associated metalloendopeptidase
2013
Publisher Summary This chapter discusses the structural chemistry and the biological aspects of ADAM10. Originally, ADAM10 was characterized as a myelin-associated metalloproteinase. After cloning the bovine ADAM10 cDNA, the deduced amino acid sequence indicated that the enzyme belonged to the reprolysin subfamily and therefore was named MADM (mammalian disintegrin metalloprotease). The mammalian reprolysin subfamily has been named ADAM (a disintegrin and metalloproteinase) and MADM has been designated ADAM10. The ADAM10 homologs in Drosophila melanogaster and Caenorhabditis elegans are named kuzbanian and sup-17, respectively. The enzymatic activity of isolated ADAM10 can be monitored in v…
Changing fate
2020
Abstract The alpha-secretase A disintegrin and metalloproteinase 10 (ADAM10) and the beta-secretase beta-APP cleaving enzyme 1 (BACE-1) compete in neurons to cleave the amyloid precursor protein (APP). The reaction started by BACE-1, designated the amyloidogenic pathway, leads to formation of neurotoxic amyloid beta peptides (A-betas), while alpha-secretase prevents this and gives rise to an alternative cleavage product (APPs-alpha, nonamyloidogenic pathway). The latter is also known to have neurotrophic and neuroprotective properties. Therefore, identification of mechanisms that lead to a switch in APP processing from the amyloidogenic to the nonamyloidogenic pathway is an attractive avenu…
Functional and structural insights into astacin metallopeptidases
2012
The astacins are a family of multi-domain metallopeptidases with manifold functions in metabolism. They are either secreted or membrane-anchored and are regulated by being synthesized as inactive zymogens and also by colocalizing protein inhibitors. The distinct family members consist of N-terminal signal peptides and pro-segments, zincdependent catalytic domains, further downstream extracellular domains, transmembrane anchors, and cytosolic domains. The catalytic domains of four astacins and the zymogen of one of these have been structurally characterized and shown to comprise compact ~200-residue zinc-dependent moieties divided into an N-terminal and a C-terminal sub-domain by an active-s…
Measurement of cerebral ABCC1 transport activity in wild-type and APP/PS1-21 mice with positron emission tomography
2020
Previous data suggest a possible link between multidrug resistance-associated protein 1 (ABCC1) and brain clearance of beta-amyloid (Aβ). We used PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) to measure cerebral ABCC1 transport activity in a beta-amyloidosis mouse model (APP/PS1-21) and in wild-type mice aged 50 and 170 days, without and with pretreatment with the ABCC1 inhibitor MK571. One hundred seventy days-old-animals additionally underwent [11C]PiB PET scans to measure Aβ load. While baseline [11C]BMP PET scans detected no differences in the elimination slope of radioactivity washout from the brain (kelim) between APP/PS1-21 and wild-type mice of both age groups, PET scans after MK…
Hepatocytes of double-transgenic mice expressing high levels of hepatitis B virus e antigen and interferon-gamma are not injured by HBeAg specific au…
2000
Seroconversion from HBeAg to alphaHBe of persons chronically infected by HBV is usually associated with a transient exacerbation of liver disease and subsequent normalization of liver histology. It is speculated that these clinico-pathological features may be due to the activation of cytodestructive mechanisms by alphaHBe antibodies. The aim of the present study was to investigate the pathogenic potential of alphaHBe antibodies in a transgenic mouse model. Therefore, alphaHBe autoantibodies were elicited in double-transgenic mice expressing high amounts of HBeAg and interferon-gamma in the liver. Interferon-gamma has reviously been shown to play an important role in the development of hepat…
Association between antifungal prophylaxis and rate of documented bacteremia in febrile neutropenic cancer patients.
2001
Published data have suggested a correlation between antifungal prophylaxis and bacteremia in febrile neutropenia. This correlation was investigated among 3002 febrile neutropenic patients enrolled in 4 trials during 1986-1994. Globally, 1322 patients (44%) did not receive antifungal prophylaxis; 835 (28%) received poorly absorbable antifungal agents and 845 (28%) received absorbable antifungal agents. The rates of bacteremia for these groups were 20%, 26%, and 27%, respectively (P=.0001). In a multivariate model without including antifungal prophylaxis, factors associated with bacteremia were: age, duration of hospitalization, duration of neutropenia before enrollment, underlying disease, p…
Factores predictivos de desarrollo y evolución de infección activa por citomegalovirus en el transplante alogénico de precursores hematopoyéticos
2021
Citomegalovirus (CMV) es una causa elevada de morbimortalidad en el receptor de trasplante alogénico de precursores hematopoyéticos (alo-TPH). Con la introducción de fármacos específicos frente al virus el riesgo de sufrir enfermedad orgánica por CMV de estos pacientes se ha reducido notablemente; siendo el tratamiento anticipado la estrategia terapéutica más extendida en el manejo de la infección por CMV en el alo-TPH. Sin embargo, esta estrategia es mejorable. En este sentido, nos propusimos analizar una serie de factores que influyen en la monitorización virológica, la cual es inherente a la estrategia de tratamiento anticipado. Dada la elevada variación inter-ensayo e intercentro de las…