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Haemostasis and fibrinolysis
Published in Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland, Manual of Venous and Lymphatic Diseases, 2017
Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland
Control mechanisms exist to localize fibrin formation to the site of injury. Protein C when activated by its cofactor protein S inactivates the cofactors VIIIa and Va. Antithrombin inhibits thrombin and factor Xa as well as FIXa and FXIa. Tissue factor pathway inhibitor and alpha-2macroglobulin inhibit FXa and thrombin. Other serine protease inhibitors are heparin cofactor II (thrombin inhibitor), protein Z-dependent protease inhibitor (FXa inhibitor) and C1-inhibitor (FXIa inhibitor).
Cyclic Nucleotide Metabolism and Action During Senescence
Published in Richard C. Adelman, George S. Roth, Endocrine and Neuroendocrine Mechanisms of Aging, 2017
In addition to the protein inhibitor specific for the catalytic subunit of cyclic AMP-dependent protein kinase, other proteins have now been identified which inhibit cyclic GMP-dependent and cyclic nucleotide-independent protein kinases.97,98 The apparent ability of the "Walsh inhibitor" to regulate in vivo kinase activity under basal con-ditions,72 plus the fact that the inhibitor level in a cell or tissue may change as a function of diet72 or hormonal state,72,98 indicates that assessment of the level of this and other inhibitors is necessary in cases of altered hormonal responsiveness. If basic proteins are used to assay these levels, assay conditions, particularly protein kinase and histone concentrations, must be precisely controlled since the acidic inhibitor protein(s) may bind to the basic protein(s) used as substrate.99
Protein Phosphorylation of Prolactin Target Tissue: Mammary Gland
Published in James A. Rillema, Actions of Prolactin on Molecular Processes, 1987
Cyclic AMP-dependent protein kinases are composed of two catalytic subunits (C) and two regulatory subunits (R). The inactive tetramer (R2C2) is activated by cyclic AMP. Two moles of cyclic AMP are bound per mole of regulatory subunit, allowing dissociation of the regulatory and catalytic subunits.11 The regulatory subunit and holoenzyme are quite acidic, while the catalytic subunit is a basic protein.12 In addition, a heat-stable inhibitor protein of cyclic AMP-dependent protein kinase is found in many tissues. The inhibitor protein binds to the free catalytic subunit and blocks activity.13,14 Similar enzymes are present in mammary tissue, as well as a large number of other tissues.15 A number of substrate proteins for cyclic AMP-dependent protein kinase have been identified.11,16
Peptide foldamer-based inhibitors of the SARS-CoV-2 S protein–human ACE2 interaction
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Violeta Marković, Jeelan Basha Shaik, Katarzyna Ożga, Agnieszka Ciesiołkiewicz, Juan Lizandra Perez, Ewa Rudzińska-Szostak, Łukasz Berlicki
Peptide 27 was further studied in detail using NMR spectroscopy. Based on the TOCSY and NOESY spectra, all resonances were unambiguously identified (Table S4), and numerous nonsequential interproton contacts were identified (Table S5). In particular, 24 medium range i-i + 3 contacts accompanied by i-i + 2 and i-i + 4 interactions were present, indicating that the peptide adopts a helical conformation (Figure 12A). The simulated annealing protocol with NMR-derived restraints provided a well-folded helical structure of peptide 27 (Figure 12B-C). In particular, the fragment between ACPC5 and ACPC16 is fully defined. Moreover, the observed conformation is consistent with the conformations resulting from inhibitor–protein molecular modelling studies, as presented above.
Nuclear factor-kappa B and effector molecules in photoaging
Published in Cutaneous and Ocular Toxicology, 2022
Qiang Zhang, Shiyun Qiao, Chunsheng Yang, Guan Jiang
The NF-κB family consists of five members, including RelA (p65), RelB, c-Rel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52), that function as heterodimeric or homodimeric transcription factors13,17. The most common form of the dimer in the skin is the p50/p65 heterodimer15,18. The NF-κB family can bind to DNA sequences, recognise the regulatory regions of target genes, and induce the transcription of those genes17,19. Each type of NF-κB dimer recognises distinct DNA targets, thereby enhancing the ability of NF-κB subunits to regulate specific gene expression18. These dimers bind to an inhibitor protein family (inhibitory kappa B [IκB] family) and are kept inactive in the cytoplasm20,21. The expression of IκB is also controlled by NF-κB and thus forms a tightly negative feedback loop of expression regulation13.
Modulators of calpain activity: inhibitors and activators as potential drugs
Published in Expert Opinion on Drug Discovery, 2020
Levente Endre Dókus, Mo’ath Yousef, Zoltán Bánóczi
Although it is a rarer event, decreased calpain activity also has a role in pathological conditions (e.g. wound healing in diabetes [31], LGMD2A [42], gastric ulcers [46], tumor survival [81] and diabetes mellitus [47]). Therefore, activation of calpains in these symptoms may compensate these harmful changes. As calpain activity is under strict control; fully active calpain may cleave a dozen of proteins; they are silenced in cells. Besides Ca2+ ions, few partners are known as activators. Ca2+ ions are necessary for the formation of the active site cleft in the case of all calpains, but some of them need further process or interaction to reach their full activity [16]. However, these partners (e.g. phospholipids, kinases, some activator proteins [163,164]) cannot be easily utilized as external activators. In the endogenous inhibitor protein, calpastatin, there are three conserved subdomains, A, B, and C. The A and C subdomains just potentiate the inhibitory effect assisting in the binding to calpain but have no inhibitory activity. It has been demonstrated that peptides corresponding to these subdomains, calpastatins A and C, enhanced the activity of calpain 1 and 2 [165]. Using these peptides as activators is hampered by their low internalization. This was improved by conjugation with cell-penetrating peptide (penetratin [166] and octaarginine [167]). All conjugates retained the calpain activator effect and conjugation with octaarginine boosted the calpain activity. That intensified the neuronal excitability in rat hippocampal slices.