reciprocal substrate processing
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Rhomboid intramembrane proteases regulate pathophysiological processes, but their targeting in a disease context has never been achieved. We decoded the atypical substrate specificity of malaria rhomboid PfROM4, but found, unexpectedly, that it results from "steric exclusion": PfROM4 and canonical rhomboid proteases cannot cleave each other's substrates due to reciprocal juxtamembrane steric clashes. Instead, we engineered an optimal sequence that enhanced proteolysis >10-fold, and solved high-resolution structures to discover that boronates enhance inhibition >100-fold. A peptide boronate modeled on our "super-substrate" carrying one "steric-excluding" residue inhibited PfROM4 but not human rhomboid proteolysis. We further screened a library to discover an orthogonal alpha-ketoamide that potently inhibited PfROM4 but not human rhomboid proteolysis. Despite the membrane-immersed target and rapid invasion, ultrastructural analysis revealed that single-dosing blood-stage malaria cultures blocked host-cell invasion and cleared parasitemia. These observations establish a strategy for designing parasite-selective rhomboid inhibitors and expose a druggable dependence on rhomboid proteolysis in non-motile parasites.
- MeSH
- amidy chemická syntéza chemie farmakologie MeSH
- antimalarika chemická syntéza chemie farmakologie MeSH
- HEK293 buňky MeSH
- inhibitory proteas chemická syntéza chemie farmakologie MeSH
- kyseliny boronové chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- malárie krev farmakoterapie metabolismus MeSH
- molekulární struktura MeSH
- parazitické testy citlivosti MeSH
- peptidy chemická syntéza chemie farmakologie MeSH
- Plasmodium falciparum účinky léků metabolismus MeSH
- proteasy krev metabolismus MeSH
- proteolýza účinky léků MeSH
- protozoální proteiny antagonisté a inhibitory krev metabolismus MeSH
- racionální návrh léčiv * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Zánět mozku představuje jeden z hlavních substrátů farmakorezistentní epilepsie různé etiologie a může přímo ovlivnit neuronální excitabilitu. Neuromodulační schopnosti ně kterých prozánětlivých molekul (cytokinů, chemokinů) mohou být odpovědné za hyperexcitabilitu v neuronálních sítích. Vztah zánětu a epilepsie je reciproční. Zánětlivé procesy v mozku se mohou účastnit na spouštění záchvatové aktivity a zároveň mohou být následkem pokračujících záchvatů. Farmakologické studie na zvířecích modelech cílené na systémy IL-1/IL-1R1, HMGB1/TLR4 a COX-2/prostaglandiny prokazují, že tyto zánětlivé kaskády mají významný podíl na spouštění a opakování záchvatové aktivity. Status epilepticus (SE) vede k rozvoji zánětlivých procesů, které mohou být detekovány v mozkové tkáni, mozkomíšním moku i séru. Prolongované záchvaty a SE vedou k rychlé a dlouhotrvající aktivaci specifických zánětlivých kaskád v těch oblastech mozku, které odpovídají epileptogenní zóně. Pochopení komplexní role zánětu při vzniku a exacerbaci epilepsie a rozvoji farmakorezistence je zásadním předpokladem možnosti identifikace nových molekulárních cílů, které by se mohly uplatnit v léčbě těchto pacientů.
Brain inflammation represents a common substrate of pharmacoresistant epilepsy of different etiologies and it can directly affect neuronal excitability. Neuromodulatory properties of some proinflammatory molecules (cytokines, chemokines) may be responsible for hyperexcitability in neuronal networks. The relation between inflammation and epilepsy is reciprocal. The inflammatory processes in the brain may participate in initiating seizure activity and simultaneously they may be a consequence of the recurrence of the seizures. Pharmacological studies on experimental models focused on IL-1β/ IL-1R1, HMGB1/ TLR4 and COX-2/ prostaglandin systems demostrate that these inflammatory pathways significantly in triggering and recurring seizure activity. Status epilepticus (SE) leads to development of inflammatory processes which can be detected in brain tissue, cerebrospinal fluid and blood serum. Prolonged seizures and SE lead to fast and prolonged activation of specific inflammatory pathways in brain areas accordant with the epileptogenic zone. Understanding the complex role of inflammation in the generation and exacerbation of epilepsy and development of pharmacoresistance in epilepsy is crucial for the identification of new molecular targets for therapeutic intervention in these patients.
- MeSH
- cytokiny fyziologie MeSH
- imunomodulace MeSH
- lidé MeSH
- modely u zvířat MeSH
- mozek patologie MeSH
- refrakterní epilepsie * farmakoterapie imunologie patologie MeSH
- status epilepticus etiologie farmakoterapie patologie MeSH
- zánět * etiologie farmakoterapie patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
... Molecules Along Specific Reaction Pathways -- How Enzymes Find Their Substrates: The Enormous Rapidity ... ... Superhelical Tension 314 -- Transcription Elongation in Eukaryotes Is Tightly Coupled to RNA -- Processing ... ... Spliceosome-Catalyzed RNA Splicing Probably Evolved from -- Self-splicing Mechanisms 324 -- RNA-Processing ... ... Elongation Factors Drive Translation Forward and Improve Its -- Accuracy 343 -- Many Biological Processes ... ... Matrix Produces NADH Mitochondria Have Many Essential Roles in Cellular Metabolism A Chemiosmotic Process ...
Sixth edition xxxiv, 1430 stran v různém stránkování : ilustrace (převážně barevné) ; 29 cm
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- molekulární biologie, molekulární medicína
- NLK Publikační typ
- učebnice vysokých škol
The paper describes a pilot remediation test combining two Cr(VI) geofixation methods - chemical reduction by nanoscale zero-valent iron (nZVI) and subsequent biotic reduction supported by whey. Combination of the methods exploited the advantages of both - a rapid decrease in Cr(VI) concentrations by nZVI, which prevented further spreading of the contamination and facilitated subsequent use of the cheaper biological method. Successive application of whey as an organic substrate to promote biotic reduction of Cr(VI) after application of nZVI resulted in a further and long-term decrease in the Cr(VI) contents in the groundwater. The effect of biotic reduction was observed even in a monitoring well located at a distance of 22 m from the substrate injection wells after 10 months. The results indicated a reciprocal effect of both the phases - nZVI oxidized to Fe(III) during the abiotic phase was microbially reduced back to Fe(II) and acted as a reducing agent for Cr(VI) even when the microbial density was already low due to the consumed substrate. Community analysis with pyrosequencing of the 16S rRNA genes further confirmed partial recycling of nZVI in the form of Fe(II), where the results showed that the Cr(VI) reducing process was mediated mainly by iron-reducing and sulfate-reducing bacteria.
- MeSH
- chemické látky znečišťující vodu chemie MeSH
- chrom chemie MeSH
- fosfolipidy analýza MeSH
- mikrobiologie vody MeSH
- monitorování životního prostředí MeSH
- oxidace-redukce MeSH
- pilotní projekty MeSH
- podzemní voda chemie MeSH
- redukční činidla chemie MeSH
- regenerace a remediace životního prostředí metody MeSH
- RNA ribozomální 16S chemie genetika MeSH
- syrovátka chemie MeSH
- železité sloučeniny chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
... Carbon-13 NMR Spectroscopy 158 -- 3.5.1 General Set-up 160 -- 3.5.2 Metabolic Modeling 162 -- 3.5.3 Substrates ... ... Pre-localization 368 -- 7.5.3 Methods Utilizing Spatial Prior Knowledge 371 -- 7.6 Spectroscopic Imaging Processing ... ... Spectral Quantification 445 -- 9.1 Introduction 445 -- 9.2 Data Acquisition 446 -- 9.3 Data Pre-processing ... ... -- 10.5.2 RF Coil Performance 519 -- 10.5.3 Spatial Field Properties 521 -- 10.5.4 Principle of Reciprocity ... ... I 526 -- 10.5.5 Principle of Reciprocity II 529 -- 10.6 Radiofrequency Coil Types 530 -- 10.6.1 Combined ...
2nd ed. xxi, 570 s., [8] s. obr. příl. : il. ; 25 cm
... the -- Synthesis of ATP 31 -- 2.3.5 Molecular Oxygen* a Toxic By-Product of Some -- Photosynthetic Processes ... ... 5 -- 8.4.3 Most Biochemical Reactions Include Multiple -- Substrates 207 -- 8.4.4 Allosteric Enzymes ... ... Such As Blood Clotting and Vision 219 -- Appendix: Vmax and Km Can Be Determined by -- Double-Reciprocal ... ... Modification 287 -- 10.5.8 Hemophilia Revealed an Early Step in Clotting 288 -- 10.5.9 The Clotting Process ... ... Regulated 456 -- 16.4.1 Substrate Cycles Amplify Metabolic Signals and -- Produce Heat 457 -- 16.4.2 ...
5th ed. xvii, 974 s. : il., tab., grafy ; 32 cm
... organism - including the human body - develops in accordance with its own genetic blue print -- 3 The process ... ... of DNA duplication to RNA is called transcription 7 -- 4 The process of proteosynthesis is called translation ... ... Dyadic system is designed to form an interpersonal information channel for the transmission of a reciprocal ... ... The first to mature is the child’s right hemisphere, the dominant one for emotional information processing ... ... attachment, insecure resistant attachment, insecure avoidant attachment 46 -- 45 The biological substrate ...
Acta Universitatis Carolinae. Medica - monographia, ISSN 0567-8250 146, 2001
87 s. : il. ; 26 cm
- MeSH
- biologická psychiatrie MeSH
- duševní poruchy prevence a kontrola terapie diagnóza MeSH
- vývojová biologie MeSH
- Publikační typ
- monografie MeSH
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- neurovědy
- psychiatrie
... CHAPTER -- 62 -- Macromolecules: Structure, 62 Shape, and Information -- 63 Molecular Recognition Processes ... ... Motions Not Only Bring Molecules Together -- 65 But Also Pull Them Apart -- Molecular Recognition Processes ... ... Summary 127 -- Protein Function 127 -- A Protein’s Conformation Determines Its Chemistry 128 -- Substrate ... ... Recombination Usually Involves a Cross-Strand Exchange -- General Recombination Aids DNA Repair Processes ... ... by Antibodies -- Cross-linked Membrane Proteins Are Actively Swept to One Pole of the Cell in the Process ...
xxxix, 1146 s. : il., tab. ; 28 cm
- MeSH
- biologie buňky MeSH
- molekulární biologie MeSH
- Publikační typ
- monografie MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- biologie
- cytologie, klinická cytologie
... Definition of “trophic processes” and “nervous regulation of trophic processes” -- (“trophic influence ... ... Components of innervation affecting trophic processes a) The trophic function of the motoneuron b) The ... ... The role of specific muscle function in regulation of trophic processes -- 3. ... ... Character and basis of energy metabolism of muscle after denervation 254 a) Disturbances in substrate ... ... supply 254 b) Disturbances of substrate utilization 254 aa) Fibrillation activity 255 bb) Formation ...
486 s. : il., tab.
