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Another redox proxy you never hear about........protein bonds

Discussion in 'Redox Rx' started by Jack Kruse, May 6, 2021.

  1. Jack Kruse

    Jack Kruse Administrator

    Disulfide bonds move over, there's a new link in town. N-O-S.

    Disulfide-bond formation on secreted proteins is tightly regulated by oxidoreductases in the endoplasmic reticulum (ER), including members of the protein disulfide isomerase (PDI) family

    Disulfide bonds are essential to the structural stability of many proteins within the secretory pathway and can exist as intramolecular or inter-domain disulfides. The proper formation of these bonds often relies on folding chaperones and oxidases such as members of the protein disulfide isomerase (PDI) family. Many of the PDI family members catalyze disulfide-bond formation, reduction, and isomerization through redox-active disulfide, and perturbed PDI activity is characteristic of carcinomas and neurodegenerative diseases. In addition to catalytic function in oxidoreductases, redox-active disulfides are also found on a diverse array of cellular proteins and act to regulate protein activity and localization in response to oxidative changes in the local environment. These redox-active disulfides are either dynamic intramolecular protein disulfides or mixed disulfides with small-molecule thiols generating glutathionylation and cysteinylation adducts. The oxidation and reduction of redox-active disulfides are mediated by cellular reactive oxygen species and the activity of reductases, such as glutaredoxin and thioredoxin. Dysregulation of cellular redox conditions and resulting changes in mixed disulfide formation are directly linked to diseases such as cardiovascular disease and Parkinson’s disease.


    https://www.nature.com/articles/d41586-021-01135-3
     
    Penny, JanSz and John Schumacher like this.
  2. Disulfide bond uses the electrons from donated hydrogen.
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    • As disulfide bonds can be reversibly reduced and re-oxidized, the redox state of these bonds has evolved into a signaling element. In chloroplasts, for example, the enzymatic reduction of disulfide bonds has been linked to the control of numerous metabolic pathways as well as gene expression. The reductive signaling activity has been shown, thus far, to be carried by the ferredoxin thioredoxin system, channeling electrons from the light reactions of photosystem I to catalytically reduce disulfides in regulated proteins in a light dependent manner. In this way chloroplasts adjust the activity of key processes such as the Calvin–Benson cycle, starch degradation, ATP production and gene expression according to light intensity. Additionally, It has been reported that disulfides plays a significant role on redox state regulation of Two-component systems (TCSs), which could be found in certain bacteria including photogenic strain. A unique intramolecular cysteine disulfide bonds in the ATP-binding domain of SrrAB TCs found in Staphylococcus aureus is a good example of disulfides in regulatory proteins, which the redox state of SrrB molecule is controlled by cysteine disulfide bonds, leading to the modification of SrrA activity including gene regulation.
    Even though this is an old article from the American Institute of Biological Sciences – “The Ferredoxin/Thioredoxin System: A Key Element in the Regulatory Function of Light in Photosynthesis” by Bob B. Buchanan Jun3 1984 - https://sci-hub.se/10.2307/1309730
    Back then 1984, we did not know much about melanin’ role in human photosynthesis, but we can reverse engineer the process.

    First off -> Mammalian thioredoxin reductases [NADPH + H+ + thioredoxin-S2 ⇋ NADP+ + thioredoxin] is a dimeric flavo-enzyme. As a pyridine nucleotide-disulfide oxidoreductase it is closely related to glutathione reductase. - https://www.sciencedirect.com/topics/medicine-and-dentistry/thioredoxin-reductase
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    The ferredoxin/thioredoxin system is central to the regulation of biosynthetic and degradatory enzymes of oxygen-evolving photosynthetic system,

    Thioredoxins, with a dithiol/disulfide active site (CGPC) are the major cellular protein disulfide reductases; they therefore also serve as electron donors for enzymes such as ribonucleotide reductases, thioredoxin peroxidases (peroxiredoxins) and methionine sulfoxide reductases. Glutaredoxins catalyze glutathione-disulfide oxidoreductions overlapping the functions of thioredoxins and using electrons from NADPH via glutathione reductase. - https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1432-1327.2000.01701.x

    All mammalian thioredoxin reductase isozymes are homologous to glutathione reductase and contain a conserved C-terminal elongation with a cysteine±selenocysteine sequence forming a redox-active selenenylsulfide/selenolthiol active site.
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    An important function in cell signaling and the defense against oxidative damage and stress is the function of thioredoxin as an electron donor for the ubiquitous family of thioredoxin peroxidases or peroxiredoxins (at least six members in mammalian cells) that catalyze the reduction of H2O2.

    Although glutathione peroxidases and catalase reduce H2O2, it was demonstrated that at least one of the thioredoxin peroxidases (human TPxII) when overexpressed in cells could inhibit induction of apoptosis by decreasing H2O2 levels, thereby constituting a thioredoxin-dependent regulatory step of apoptosis upstream that of Bcl-2.

    Human thioredoxin was found as a secreted protein upregulating the IL-2 receptor and having co-cytokine activity from HTLV-I transformed T-lymphocytes, where it was initially called adult T-cell leukemia-derived factor. It was subsequently shown that this factor and human thioredoxin are the same protein, and it is now clear that the functions of extracellular human thioredoxin are many. Secretion of thioredoxin under conditions of oxidative stress and inflammation has been observed fro many normal or neoplastic cells.

    Thioredoxin has been shown to act as a chemotactic protein causing migration of neutrophils, monocytes and T-cells with a potency similar to known chemokines including IL-8.

    Thioredoxins have a structure (the thioredoxin fold), containing a central core of five b strands surrounded by four a helices and the archetypical active site sequence -Cys-Gly-Pro-Cys.

    The low redox potential of thioredoxin (-270 mV) ensures that thioredoxin is the major dithiol reductant in the cytosol.
    Human thioredoxin may form an inactive homodimer via a disulfide between the structural surface located Cys73 implicated to have a regulatory function.

    Human thioredoxin reductase is a selenoprotein resulted in much interest and intimately linked the thioredoxin system with the selenium status and function in cells.

    It is believed that - Selenodiglutathione may function as a hydrogen donor system for the selenoprotein plasma glutathione peroxidase or as a lipid hydroperoxide reductase.

    However, I am of the opinion that it is the electron chain transport process of human photosynthesis from the melanosome’s melanin stored capacitance which is the primary donor of free electrons from the split of hydrogen from the surrounding structured water within the cell. https://forum.jackkruse.com/index.php?threads/what-is-food.25698/#post-297547

    Is it possible for other secondary processes to donate a hydrogen molecule? <- Yes
    However, these are not as effective and come with oxidative by-products.

    This purpose of this thread is not to prove human photosynthesis nor disproved mitochondria cytochrome c oxidase.
    What interest me about human thioredoxin process is the exosome cytokine transformation in the form of T-lymphocytes which are produced from a “healthy” cell. https://forum.jackkruse.com/index.php?threads/redox-rx-and-the-exosome.20444/

    One of these (exosomes) has been categorize in “medical science” as the human prostaglandin system. Unlike most hormones, which are produced by glands and transported in the bloodstream to act on distant areas of the body, the prostaglandins are produced at the site where they are needed. Prostaglandins are produced in nearly all cells and are part of the body’s way of dealing with injury and illness.

    Prostaglandins act as signals to control several different processes depending on the part of the body in which they are made. Prostaglandins are made at sites of tissue damage or infection, where they cause inflammation, pain and fever as part of the healing process. PTGS creates ATP for the surrounding cells through cyclooxygenase (COX) isoenzymes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081099/

    It is my belief that when the human thioredoxin process is stimulated by sunlight, specifically red and infrared spectrum, the disulfide bonds can properly form stable structures.

    It is the exosomes which can then be formed within a cell which carryout the “healing power” to our human system. example: http://website60s.com/upload/files/333_1.pdf
     
    Last edited: May 8, 2021
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