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Lecture 39 April 26,2017 Radicals ROS/NOS.

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1 Lecture 39 April 26,2017 Radicals ROS/NOS

2 Introduction 1. What we have found that is new is that weak magnetic fields can change the recombination rates of radical pairs. 2. These weak magnetic field are modifying the concentrations of O2‾,H2O2, NADPH, Ca++ 3. These are signaling molecules that can activate a verity of biological processes. 4. They can also do damage.

3 Introduction 3. We also know that we have feedback paths that occur with a time delay that reduces the concentrations of H2O2 by the generation of SOD. 4. We have changes in membrane potentials that are associated with changes in growth rates for cancer cells.

4 Introduction 5. We have data that shows we can both accelerate and inhibit the growth of some cancer cells. 6. The problem is to figure out how the signaling system works so we can define exposure conditions so as to get what we want to happen.

5 Introduction 7. The signals must be specific enough to differentiate a verity of different biological processes. 8. The signaling involves chemical reactions and electron transfer. 9. When ever we have an odd number of electrons we have a radical and the possibility that magnetic fields can affect the reaction rate.

6 Background 1 Cells operate in a reducing environment.
2. This means that there is an electrochemical gradient needed for electron flow. 3. There are an array of redox couples that are responsible for the electron transfer.

7 DEFINITIONS OF OXIDATION AND REDUCTION (REDOX) Multiple Definitions
Oxidation and reduction in terms of oxygen transfer Definitions Oxidation is gain of oxygen. Reduction is loss of oxygen. For example, in the extraction of iron from its ore: Because both reduction and oxidation are going on side-by-side, this is known as a redox reaction.

8 Oxidising and reducing agents
An oxidising agent is substance which oxidises something else. In the above example, the iron(III) oxide is the oxidising agent. A reducing agent reduces something else. In the equation, the carbon monoxide is the reducing agent. Oxidising agents give oxygen to another substance or removes hydrogen from it. Reducing agents remove oxygen from another substance or gives hydrogen to it.

9 Oxidation and reduction in terms of electron transfer
This is easily the most important use of the terms oxidation and reduction at A' level. Definitions Oxidation is loss of electrons. Reduction is gain of electrons.

10 A simple example The equation shows a simple redox reaction which can obviously be described in terms of oxygen transfer. Copper(II) oxide and magnesium oxide are both ionic. The metals obviously aren't. If you rewrite this as an ionic equation, it turns out that the oxide ions are spectator ions and you are left with:

11 Redox State and Redox Environment
1. Redox State is used to define the ratio interconvertible oxidized and reduced forms of a redox couple. 2. Example NADN+/NADH is a redox pair NADP+ +2e‾ +H+ →NADPH 3. The redox state of a redox couple is defined by the half-cell reduction potential of the reducing capacity of that couple.

12 Redox State and Redox Environment
The redox environment of a linked set of redox couples as found in a biological fluid, organelle, cell, or tissue is the summation of the products of the reduction potential and the reducing capacity of the linked redox couples present. Reducing capacity refers to the size of the pool (concentration) of reducing equivalents available, i.e. the strength of the redox buffer. Ability to pick up electrons.

13 The Nernst Equation 1. Electronic from for K= potassium concentrations
Chemical Form Where Δ G is the Gibbs energy change, n is the number of electrons exchanged, F is the Faraday constant Is the electromotive force under standard conditions. Eo

14 The Nernst Equation 1. The E0 are different for different redox couples. 2. Eo! Is referenced for a pH=7 2. The oxidation potential is defined as Red→Ox+ne− As a half reaction 3. For ΔE= 0 there is no net electron flow

15 Two-Electron Reduction Potentials
Redox Couple Eo!/mV at 25oC Xanthine/hyporxanthine, H NAD+,H+/NADPH NADP+,H+/NADPH O2,2H+/H2O NO3-/NO H2O2,2H+/2H2O Schafer and Buettner Chapter 1 in Signal Transduction by Oxygen and Nitrogen Species Forman, Fukuto, and Torres 2003

16 Redox Potentials 1. Redox potential differences are the drivers for many chemical reactions. 2. Most redox reactions involve 2 electron transfers so you do not get radical intermediaries with unpaired electrons. 3. Example NADPH/NADP+ ratio is about 100/1 in tissue and this leads to Ehc= -374mV This is a major force in maintaining a reducing environment in cells and tissues.

17 Redox Background 1. The background concentrations of the absorber can cancel out a signal. 2. These reactions are temperature, concentration and pH dependent. 3. These can vary over the interior of a cell. 4. H2O2 is the most common oxidant in vivo. 5. H2O2 reactions are catalyzed by enzymes to speed up the reaction between a metastable compounds to the specific desired result.

18 Redox Regulation 1. Enzyme reaction usual work unidirectionally
2. Use this to control the metabolic rate. 3. You need a sensor to regulate or set a level. 4. A redox sensor is Thioredoxin and in the ASK-1 system it can trigger apoptosis. 5. Redox modifications of proteins and their reversal are suited for regulatory circuits .

19 NADPH 1. We have seen changes in NADPH concentrations with magnetic fields. 2. This is coupled with taking O2- to H2O2 3. NADPH+H++Trx-S2→ NADP++Trx(SH)2 Trx(SH)2+rNDP→dNDP→→dNTP→DNA 4. This shows we can modify DNA

20 NO Nitric Oxide. 1. NO has electron and nuclear spin states and is a radical

21 NO 1. NO has a roll in vasodilation and its target is guanylate cyclase. 2. It diffuses over relatively large distances and has a short lifetime and it can diffuse through membranes in about 1ms 3. It and its derivatives serve a wide verity of biological functions.

22 NO 1. Reactions with NO involve stabilization of an electron.
2. It occurs with a transition metal ion and with other radicals. 3. It reacts with O2 to form NO2 and N2O3 and many other Nox’ s

23 NOx 1. Nox 1 and NOx4 in fibroblasts lead to the increased generation of O2- and H2O2 2. NO is a radical and also a signaling molecule that is good for communications between cells because of its ability to diffuse through membranes. 3. It can induce conformational changes in large molecules.

24 NO 1. NO reacts to inhibit cytochrome c oxidase and deplete ATP levels. 2. Interacts with metal sites in enzymes 3. It is part of the control circuit for the metabolic processes in the mitochondria. 4. A questions is do magnetic fields change its ability to either diffuse or react chemically?

25 H2O2 1. H2O2 is generated in as a result of normal metabolic activity.
2. Electrons leak from the mitochondria to form O2- which goes to H2O2 often with the help of NADPH oxidase complexes. 3. Then H2O2 goes to OH- with the Fenton reaction via Fe or Cu. OH- leads to oxidative damage that is irreversible. 4. H2O2 is also a signaling molecule

26 H2O2 1. H2O2 is generated by a large number of chemical reactions
2. It is a signaling molecule at low concentrations and damaging at high concentrations. 3. Its signaling function can be blocked by PDGF , EGF and agiostensin II

27 H2O2 1. H2O2 is relatively mild oxidant, however it oxidizes cysteine (Cys-SH) residues in proteins to Cys sulfenic acid or disufide which can be converted back (Cys-SH) 2. Reversibility is important for a signaling molecule.

28 H2O2 1.H2O2 also signals the generation of SOD which reduces the concentration of H2O2 2. Some other experiments show time to bring H2O2 concentrations up and back to resting level took 40 minutes. 3. So depending on process we have time constants from less than a second to an hour or so. 4. H2O2 is shown to have a roll in signaling the generation of growth factor through the inactivation of PTPs and PTEN

29 H2O2 1. Over all H2O2 can be both a signaling molecule and destructive. 2. As a signaling molecule it can activate the defense system for oxidative stress. 3. Oxidative stress can lead to aging, cancer and Alzheimer's


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