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Coenzyme A (CoA,SHCoA,CoASH) is a coenzyme,notable for its role in the synthesis and oxidation of fatty acids,and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a substrate,and around 4% of cellular enzymes use it (or a thioester) as a substrate. In humans,CoA biosynthesis requires cysteine,pantothenate (vitamin B5),and adenosine triphosphate (ATP).
Glutathione is an organic compound with the chemical formula HOCOCH(NH2)CH2CH2CONHCH(CH2SH)CONHCH2COOH. It is an antioxidant in plants,animals,fungi,and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species,free radicals,peroxides,lipid peroxides,and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.
In chemistry and biology,reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2),water,and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H),superoxide (O2-),hydroxyl radical (OH.),and singlet oxygen. ROS are pervasive because they are readily produced from O2,which is abundant. ROS are important in many ways,both beneficial and otherwise. ROS function as signals,that turn on and off biological functions. They are intermediates in the redox behavior of O2,which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however,ROS are discussed in a biological context,ranging from their effects on aging and their role in causing dangerous genetic mutations.
4-Hydroxynonenal,or 4-hydroxy-2E-nonenal or 4-hydroxy-2-nonenal or 4-HNE or HNE,,is an α,β-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells. 4-HNE is the primary α,β-unsaturated hydroxyalkenal formed in this process. It is a colorless oil. It is found throughout animal tissues,and in higher quantities during oxidative stress due to the increase in the lipid peroxidation chain reaction,due to the increase in stress events. 4-HNE has been hypothesized to play a key role in cell signal transduction,in a variety of pathways from cell cycle events to cellular adhesion.
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Leukotriene C4 (LTC4) is a leukotriene. LTC4 has been extensively studied in the context of allergy and asthma. In cells of myeloid origin such as mast cells,its biosynthesis is orchestrated by translocation to the nuclear envelope along with co-localization of cytosolic phospholipase A2 (cPLA2),arachidonate 5-lipoxygenase (5-LO),5-lipoxygenase-activating protein (FLAP) and LTC4 synthase (LTC4S),which couples glutathione to an LTA4 intermediate. The MRP1 transporter then secretes cytosolic LTC4 and cell surface proteases further metabolize it by sequential cleavage of the γ-glutamyl and glycine residues off its glutathione segment,generating the more stable products LTD4 and LTE4. All three leukotrienes then bind at different affinities to two G-protein coupled receptors:CYSLTR1 and CYSLTR2,triggering pulmonary vasoconstriction and bronchoconstriction.
Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.
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Glutathione S-transferase Mu 4 is an enzyme that in humans is encoded by the GSTM4 gene.
Glutaredoxin 2 (GLRX2) is an enzyme that in humans encoded by the GLRX2 gene. GLRX2,also known as GRX2,is a glutaredoxin family protein and a thiol-disulfide oxidoreductase that maintains cellular thiol homeostasis. This gene consists of four exons and three introns,spanned 10 kilobase pairs,and localized to chromosome 1q31.2–31.3.
Glutathione S-transferase kappa 1 (GSTK1) is an enzyme that in humans is encoded by the GSTK1 gene which is located on chromosome seven. It belongs to the superfamily of enzymes known as glutathione S-transferase (GST),which are mainly known for cellular detoxification. The GSTK1 gene consists of eight exons and seven introns and although it is a member of the GST family,its structure has been found to be similar to bacterial HCCA (2-hydroxychromene-2-carboxylate) isomerases and bacterial disulphide-bond-forming DsbA oxidoreductase. This similarity has later allowed the enzyme GSTK1 to be renamed to DsbA-L. Research has also suggested that several variations of the GSTK1 gene can be responsible for metabolic diseases and certain types of cancer.
The reduction-oxidation sensitive green fluorescent protein (roGFP) is a green fluorescent protein engineered to be sensitive to changes in the local redox environment. roGFPs are used as redox-sensitive biosensors.
The ascorbate-glutathione cycle,sometimes Foyer-Halliwell-Asada pathway,is a metabolic pathway that detoxifies hydrogen peroxide (H2O2),a reactive oxygen species that is produced as a waste product in metabolism. The cycle involves the antioxidant metabolites:ascorbate,glutathione and NADPH and the enzymes linking these metabolites.
Bacterial glutathione transferases are part of a superfamily of enzymes that play a crucial role in cellular detoxification. The primary role of GSTs is to catalyze the conjugation of glutathione (GSH) with the electrophilic centers of a wide variety of molecules. The most commonly known substrates of GSTs are xenobiotic synthetic chemicals. There are also classes of GSTs that utilize glutathione as a cofactor rather than a substrate. Often these GSTs are involved in reduction of reactive oxidative species toxic to the bacterium. Conjugation with glutathione receptors renders toxic substances more soluble,and therefore more readily exocytosed from the cell.
In molecular biology,the glutaredoxin 2 family is a family of bacterial glutaredoxins. Unlike other glutaredoxins,glutaredoxin 2 (Grx2) cannot reduce ribonucleotide reductase. Grx2 has significantly higher catalytic activity in the reduction of mixed disulphides with glutathione (GSH) compared with other glutaredoxins. The active site residues (Cys9-Pro10-Tyr11-Cys12,in Escherichia coli Grx2,which are found at the interface between the N- and C-terminal domains are identical to other glutaredoxins,but there is no other similarity between glutaredoxin 2 and other glutaredoxins. Grx2 is structurally similar to glutathione-S-transferases,but there is no obvious sequence similarity. The inter-domain contacts are mainly hydrophobic,suggesting that the two domains are unlikely to be stable on their own. Both domains are needed for correct folding and activity of Grx2. It is thought that the primary function of Grx2 is to catalyse reversible glutathionylation of proteins with GSH in cellular redox regulation including the response to oxidative stress. These enzymes are not related to GLRX2.
Reductive stress (RS) is defined as an abnormal accumulation of reducing equivalents despite being in the presence of intact oxidation and reduction systems. A redox reaction involves the transfer of electrons from reducing agents (reductants) to oxidizing agents (oxidants) and redox couples are accountable for the majority of the cellular electron flow. RS is a state where there are more reducing equivalents compared to reductive oxygen species (ROS) in the form of known biological redox couples such as GSH/GSSG,NADP+/NADPH,and NAD+/NADH. Reductive stress is the counterpart to oxidative stress,where electron acceptors are expected to be mostly reduced. Reductive stress is likely derived from intrinsic signals that allow for the cellular defense against pro-oxidative conditions. There is a feedback regulation balance between reductive and oxidative stress where chronic RS induce oxidative species (OS),resulting in an increase in production of RS,again.
Kenneth D. Tew is a Scottish-American pharmacologist,academic and author. He is a professor in the Department of Cell &Molecular Pharmacology and the John C. West Endowed Chair in Cancer Research at the Medical University of South Carolina.
References
- 1 2 "Faculty Directory | MUSC". education.musc.edu.
- 1 2 "Browse journals and books | ScienceDirect.com". www.sciencedirect.com.
- ↑ Townsend, Danyelle; Tew, Kenneth (February 9, 2003). "Cancer drugs, genetic variation and the glutathione-S-transferase gene family". American Journal of Pharmacogenomics: Genomics-Related Research in Drug Development and Clinical Practice. 3 (3): 157–172. doi:10.2165/00129785-200303030-00002. PMC 9086716 . PMID 12814324.[ non-primary source needed ]
- ↑ "College of Pharmacy Faculty Directory". pharmacy.musc.edu.
- ↑ "COBRE Members". medicine.musc.edu.
- ↑ "Hollings Cancer Center > Profiles". admin.hcc.musc.edu.
- ↑ "Danyelle Townsend". scholar.google.com.
- ↑ Townsend, Danyelle M.; Tew, Kenneth D.; Tapiero, Haim (May 1, 2003). "The importance of glutathione in human disease". Biomedicine & Pharmacotherapy. 57 (3): 145–155. doi:10.1016/S0753-3322(03)00043-X. PMC 6522248 . PMID 12818476.[ non-primary source needed ]
- ↑ Townsend, Danyelle M.; Tew, Kenneth D. (October 9, 2003). "The role of glutathione-S-transferase in anti-cancer drug resistance". Oncogene. 22 (47): 7369–7375. doi:10.1038/sj.onc.1206940. PMC 6361125 . PMID 14576844.[ non-primary source needed ]
- ↑ Townsend, Danyelle M.; Deng, Mei; Zhang, Lei; Lapus, Maia G.; Hanigan, Marie H. (January 2003). "Metabolism of Cisplatin to a Nephrotoxin in Proximal Tubule Cells". Journal of the American Society of Nephrology. 14 (1): 1–10. doi:10.1097/01.ASN.0000042803.28024.92. PMC 6361148 . PMID 12506132.[ non-primary source needed ]
- ↑ Ye, Zhi-Wei; Zhang, Jie; Townsend, Danyelle M.; Tew, Kenneth D. (August 1, 2015). "Oxidative stress, redox regulation and diseases of cellular differentiation". Biochimica et Biophysica Acta (BBA) - General Subjects. 1850 (8): 1607–1621. doi:10.1016/j.bbagen.2014.11.010. PMC 4433447 . PMID 25445706.[ non-primary source needed ]
- ↑ Tapiero, H; Townsend, D. M; Tew, K. D (January 3, 2004). "The role of carotenoids in the prevention of human pathologies". Biomedicine & Pharmacotherapy. 58 (2): 100–110. doi:10.1016/j.biopha.2003.12.006. PMC 6361147 . PMID 14992791.[ non-primary source needed ]
- ↑ Townsend, Danyelle M. (December 9, 2007). "S-Glutathionylation: Indicator of Cell Stress and Regulator of the Unfolded Protein Response". Molecular Interventions. 7 (6): 313–324. doi:10.1124/mi.7.6.7. PMC 6361142 . PMID 18199853.[ non-primary source needed ]
- ↑ Grek, Christina L.; Zhang, Jie; Manevich, Yefim; Townsend, Danyelle M.; Tew, Kenneth D. (September 2013). "Causes and Consequences of Cysteine S-Glutathionylation". Journal of Biological Chemistry. 288 (37): 26497–26504. doi: 10.1074/jbc.R113.461368 . PMC 3772197 . PMID 23861399.[ non-primary source needed ]
- ↑ Tew, Kenneth D.; Manevich, Yefim; Grek, Christina; Xiong, Ying; Uys, Joachim; Townsend, Danyelle M. (July 15, 2011). "The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer". Free Radical Biology and Medicine. 51 (2): 299–313. doi:10.1016/j.freeradbiomed.2011.04.013. PMC 3125017 . PMID 21558000.[ non-primary source needed ]
- ↑ Zhang, Leilei; Kim, Seok-Hyung; Park, Ki-Hoon; Townsend, Danyelle M.; Tew, Kenneth D.; Zhi-wei, Ye; Jie, Zhang (April 9, 2021). "Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish". The Journal of Pharmacology and Experimental Therapeutics. 377 (1): 121–132. doi:10.1124/jpet.120.000417. PMC 8047768 . PMID 33514607.[ non-primary source needed ]
- ↑ Xiong, Ying; Uys, Joachim D.; Tew, Kenneth D.; Townsend, Danyelle M. (July 9, 2011). "S-Glutathionylation: From Molecular Mechanisms to Health Outcomes". Antioxidants & Redox Signaling. 15 (1): 233–270. doi:10.1089/ars.2010.3540. PMC 3110090 . PMID 21235352.[ non-primary source needed ]
- ↑ Zhang, Jie; Ye, Zhi-Wei; Chen, Wei; Culpepper, John; Jiang, Haiming; Ball, Lauren E.; Mehrotra, Shikhar; Blumental-Perry, Anna; Tew, Kenneth D.; Townsend, Danyelle M. (November 20, 2020). "Altered redox regulation and S-glutathionylation of BiP contribute to bortezomib resistance in multiple myeloma". Free Radical Biology & Medicine. 160: 755–767. doi:10.1016/j.freeradbiomed.2020.09.013. PMC 7704679 . PMID 32937189.[ non-primary source needed ]
- ↑ Townsend, Danyelle M.; Manevich, Yefim; He, Lin; Hutchens, Steven; Pazoles, Christopher J.; Tew, Kenneth D. (January 2009). "Novel Role for Glutathione S-Transferase π". Journal of Biological Chemistry. 284 (1): 436–445. doi: 10.1074/jbc.M805586200 . PMC 2610519 . PMID 18990698.[ non-primary source needed ]
- ↑ Zhang, Jie; Ye, Zhi-Wei; Janssen-Heininger, Yvonne; Townsend, Danyelle M.; Tew, Kenneth D. (2020). "Development of Telintra as an Inhibitor of Glutathione S-Transferase P". Reactive Oxygen Species. Handbook of Experimental Pharmacology. Vol. 264. pp. 71–91. doi:10.1007/164_2020_392. ISBN 978-3-030-68509-6. PMC 8963531 . PMID 32767141.[ non-primary source needed ]
- ↑ Bräutigam, Lars; Zhang, Jie; Dreij, Kristian; Spahiu, Linda; Holmgren, Arne; Abe, Hiroshi; Tew, Kenneth D.; Townsend, Danyelle M.; Kelner, Michael J.; Morgenstern, Ralf; Johansson, Katarina (July 9, 2018). "MGST1, a GSH transferase/peroxidase essential for development and hematopoietic stem cell differentiation". Redox Biology. 17: 171–179. doi:10.1016/j.redox.2018.04.013. PMC 6006721 . PMID 29702404.[ non-primary source needed ]
- ↑ Mathuram, Theodore L.; Townsend, Danyelle M.; Lynch, Vincent J.; Bederman, Ilya; Ye, Zhi-Wei; Zhang, Jie; Sigurdson, Wade J.; Prendergast, Erin; Jobava, Raul; Ferruzza, Jonathan P.; D’Angelo, Mary R.; Hatzoglou, Maria; Perry, Yaron; Blumental-Perry, Anna (6 April 2022). "A Synthetic Small RNA Homologous to the D-Loop Transcript of mtDNA Enhances Mitochondrial Bioenergetics". Frontiers in Physiology. 13. doi: 10.3389/fphys.2022.772313 . PMC 9020786 . PMID 35464086.[ non-primary source needed ]
- ↑ Bartolini, Desirée; Wang, Yanzhong; Zhang, Jie; Giustarini, Daniela; Rossi, Ranieri; Wang, Gavin Y.; Torquato, Pierangelo; Townsend, Danyelle M.; Tew, Kenneth D.; Galli, Francesco (February 9, 2019). "A seleno-hormetine protects bone marrow hematopoietic cells against ionizing radiation-induced toxicities". PLOS ONE. 14 (4): e0205626. Bibcode:2019PLoSO..1405626B. doi: 10.1371/journal.pone.0205626 . PMC 6488049 . PMID 31034521.[ non-primary source needed ]
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