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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Proprotein convertases activate inactive proproteins thereby releasing the active protein. PCSK9 (first described by Seidah et al., 2003 who characterized the gene; see also Seidah et al., 2014) is a 692–amino acid proteinase K–like serine protease enzyme that degrades the LDL receptor; hence decreasing the number of LDL receptors on the surface of liver cells is tantamount to an increase in plasma concentration of LDL-C and apoB. The structure of PCSK9 (opposite scheme) has been elucidated by Cunnigman et al., 2007). The formation of the mature form of PCSK9 occurs by cleaving its signal peptide (aa 1–30) in the ER and by further self-cleavage into the mature PCSK9 (aa 153–692) and a prosegment (aa 32–152) that remains non-covalently bound to the catalytic site of PCSK9 to give an inactive complex, secreted into the blood stream. For regulation of the LDL level by PCSK9 it binds to a LDL receptor to form a PCSK9-LDL receptor-LDL complex that is taken up by the liver cell for degradation so that the LDL receptor is prevented from being recycled back to the cell surface and hence is no longer available for LDL-binding accompanied by an increase in LDL levels in the plasma (e.g., Nassoury et al., 2007).
FRET Reporter Molecules for Identification of Enzyme Functions
Published in Grunwald Peter, Biocatalysis and Nanotechnology, 2017
Jing Mu, Hao Lun Cheong, Bengang Xing
Proprotein convertases are the subfamily of subtilases, which belongs to the family of subtilisin-like serine proteases. These convertases associate with the activation of cellular and pathogenic precursor proteins like polypeptide hormones, growth factors and bacterial pathogens, etc. They consist of nine family members: convertase 1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme 4 (PACE4), PC7, subtilisin kexin isozyme 1 (SKI-1) and proprotein convertase subtilisin kexin 9 (PCSK9) (Seidah et al., 2012). Currently, proprotein convertases are considered to be attractive targets due to their important functions in the progression of various diseases such as cancer, inflammation and pathogenic infections (Seidah et al., 2012). Recently, Mu et al. (2014) utilized a small molecule based FRET reporter to realtime monitor furin activities (Fig. 13.15). They designed the probe by using furin recognizable cleaving peptide sequence (RVRRSVK) as the framework for their probe. Using a FRET pair fluorescein (FITC) and quencher 4-(dimethylaminoazo)benzene- 4-carboxamide (Dabcyl) in the probe, they were able to observe a “turn-on” fluorescence effect upon furin cleavage. In addition, the lipid membrane anchor was designed to effectively immobilize the unique reporter onto the cell surface. Using this system, they tested it on various furin positive and negative cells lines. It was observed that the probe was selective to furin expressed cell lines. Furthermore, the probe was capable of staining the cell membrane for relatively quite long time (up to 2 h). In addition, they used the probe in two-photon imaging to prove the utility of the probe in monitoring living cells or tissues. The successful mouse’s ear tissues imaging proved the potential of the probe in monitoring furin activities in vivo and clinic trials.
Longitudinal association between moderate to vigorous physical activity and lipid profile indicators in adolescents
Published in European Journal of Sport Science, 2023
Arthur Oliveira Barbosa, Juliana Maria da Penha Freire Silva, Diego Júnio Silva, Tayse Guedes Cabral, Felipe Moreira de Jesus, Gerfeson Mendonça, Alcides Prazeres Filho, Ially Rayssa Dias Moura, Eduarda Cristina da Costa Silva, Sandro Raniel da Silva Rocha, José Cazuza Farias Júnior
The mechanisms that explain the influence of PA on lipid profile indicators, have yet to be fully elucidated, especially with respect to intensity. However, more PA contributed to reducing TC levels by increasing reverse cholesterol transport levels, and those of LDL-C by lowering proprotein convertase subtilisin/kevin type 9 (PCSK9) activity, which inhibits hepatic LDL-C receptor activity (Wang & Xu, 2017). The decline in TG levels associated with PA may be explained by the increase in lipase enzyme (LPL) activity, which is responsible for hydrolysis of TG-rich lipoproteins (very low density lipoproteins – VLDL-C) (Wang & Xu, 2017), greater use of TG as energy source during PA, especially aerobic and moderate intensity exercises (Noland, 2015), and greater insulin sensitivity (lower TG production in the liver) (Zanella, Souza, & Godoy, 2007).