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Sources of the instigators A. Exogenous sources of radicals B. Endogenous NADPH oxidase NADPH P450 oxidor

Redox Biology: Biochemistry David A. Wink and Murali C. Krishna National Institutes of Health National Cancer Institute Radiation Biology Branch Bldg. 10, Room B3-B69 Bethesda, Maryland 20892.

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Sources of the instigators A. Exogenous sources of radicals B. Endogenous NADPH oxidase NADPH P450 oxidor

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  1. Redox Biology: BiochemistryDavid A. Wink and Murali C. KrishnaNational Institutes of HealthNational Cancer InstituteRadiation Biology BranchBldg. 10, Room B3-B69Bethesda, Maryland 20892

  2. Biochemical Lecture I. Sources of the instigators A. Exogenous sources of radicals B. Endogenous NADPH oxidase NADPH P450 oxidoreductases Xanthine oxidase Mitochondria Nitric oxide Synthase Heme oxygenase II. Detoxification: A. Enzymatic SOD, CAT, GPx DT-Diaphorase (2-e transfer) B. Scavenging GSH Ascorbate Tocopherol Biochemical Lecture Sources of the instigators A. Exogenous sources of radicals B. Endogenous NADPH oxidase NADPH P450 oxidoreductases Xanthine oxidase Mitochondria Nitric oxide Synthase Heme oxygenase II. Detoxification: A. Enzymatic SOD, CAT, GPx DT-Diaphorase (2-e transfer) B. Scavenging GSH Ascorbate Tocopherol

  3. ● Formation and Abatement of Oxidants in Redox Biology -Source of Instigators: ●PAO, XO, NOX, Xenobiotic, Catalase/GPX, Prx, LOOH, TrxProtein, GSSG(GR)GSH, NOSNOHbO2 and Cellular Consumption ● NOO2- H2O2 and ●oxidationLOOH, Protein, GSSG - Antioxidant systems Formation and Abatement of Oxidants in Redox Biology NOS uncoupled NO Catalase/GPX HbO2 Cellular Consumption Prx GR GSH Trx Source of Instigators NOX XO PAO Xenobiotic H2O2 O2- SOD oxidation LOOH Proteinox GSSG Antioxidant systems

  4. Reduction of oxygen to O2. and H2O2 ● Outer-sphere electron transfer Thus, the determining factor is E and access ● O2 + e- O2- - 0.33 V O2 + e- + H+ HO2 - 0.46 V ●O2- + e- H2O2 +0.95 V pKa = 4.7● Substance with more negative reduction potential than -0.33 V can spontaneously reduce oxygen to superoxide.● Paraquat/methyl viologen MV+ + O2 MV2+ + O2-ΔE = (+0.45) + (-0.33) = +0.12 MV2+ + O2- Paraquat/methyl viologen MV+ + O2 DE = (+0.45) + (-0.33) = +0.12 Reduction of oxygen to O2- and H2O2 Outer-sphere electron transfer Thus, the determining factor is E and access O2 + e- O2- - 0.33 V O2 + e- + H+ HO2 - 0.46 V pKa = 4.7 O2- + e- H2O2 +0.95 V Substance with more negative reduction potential than -0.33 V can spontaneously reduce oxygen to superoxide.

  5. Redox Cycling to form Reactive Oxygen Species ● Types of Compounds● Ubiquinone (CoQ)● Menidione● Adriamycin (Doxorubicin)● Tocopherol● Quinone● Semi-Quinone (GSH) GS-Q  Prot-SQ● Diphenol● Dopamine derivatives, Catecholic Estrogens● Adrenaline● Quinone● Semi-Quinone● Diphenol OH OH Dopamine derivatives, Catecholic Estrogens Adrenaline Ortho O O O - e- O- + e- Quinone Semi-Quinone Diphenol Redox Cycling to form Reactive Oxygen Species Para Types of Compounds O O2 O O2- OH - e- Ubiquinone (CoQ) Menidione Adriamycin (Doxorubicin) Tocopherol + e- O2- H2O2 O O- OH Quinone Semi-Quinone Diphenol GSH GS-Q Prot-SQ

  6. ●Menadione (Vitamin K3) ● HbO2MetHb● 6-hydroxydopamine to 6-hydroxy dopamine O CH3 Thiol Met Hb + SQ- HbO2 O2- O Menadione (Vitamin K3) CH2CH2NH3+ CH2CH2NH3+ HO O2 OH OH hydroxylase OH OH dopamine 6-hydroxydopamine

  7. Pro-oxidant versus Antioxidant Quinone Pro-oxidant Pro-oxidant: SQ to QuinoneAnti-oxidant: reduce the SQ to QH2. Location is essential and pharmacokinetic stability water versus fat soluble Pro-oxidant versus Antioxidant +e +e SQ QH2 Quinone Fe(III) reduction Pro-oxidant O2- Pro-oxidant: SQ to Quinone Anti-oxidant: reduce the SQ to QH2. Location is essential and pharmacokinetic stability water versus fat soluble

  8. Vitamins Working in Concert. Vitamin E = TcOH forms a free radical TcO, which Is prooxidant in the lipid. Asc forms a free radical Asc. In the cytosol. Caretinoid forms a free radical CarOH. Or CarOOH, which is reduced by Asc. Carentiod CarOH or CarOOL R R Asc Car + OH; LOO CarOH or CarOOL NO2 Asc Car Vitamins Working in Concert Vitamin E = TcOH Pro-oxidant TcOH + OH; LOO or NO2 TcO Lipid Asc Cytosol Asc DHA and Asc

  9. Xenobiotic Metabolism ●Activation of Quinones, Paraquat etc. by NADPH Cytochrome P450 Oxidoreductases adds + 1 electron generating a free radical X-.. Detoxification of Quinones, Paraquat etc. by DT-Diaphorase or Quinone Reductase ( NQ1, P450 reductase super family)adds + 2 electrons to generate XH2. ● Broccoli extracts induce DT-Diaphorase (NQ1) expression Xenobiotic Metabolism Activation of Quinones, Paraquat etc. X X- NADPH Cytochrome P450 Oxidoreductases + 1 electron Detoxification of Quinones, Paraquat etc. DT-Diaphorase or Quinone Reductase ( NQ1, P450 reductase super family) X XH2 + 2 electrons Broccoli extracts induce DT-Diaphorase (NQ1) expression

  10. ●Mitochondrial Sources of ROS. NADH feeds into site I, followed by site II. O2 feeds into Site III to generate superoxide. At site IV O2 is reduced to water by cytochrome C oxidase. Cofactors include ubiquinone, ubisemiquinone and ubiphenol. ● Polarization/depolarization of the mitochondria can effect reductionwhere the proton gradient can be important to reduction of O2. H2O2 O2- -0.04 V Ubiquinone (Q) Ubisemiquinone (SQ) Ubiphenol (H2Q) -0.25 V HO2 O2- O2 pKa = 4.7 Mitochondrial Sources of ROS O2 Site I Site II Site III Site IV H2O Cytochrome c oxidase O2 O2- NADH Polarization/depolarization of the mitochondria can effect reduction where the proton gradient can be important to reduction of O2.

  11. ● Energetics of ROS formation from Site III SQ radical plus O2 leads to Q plus O2.. O2. pluse e- leads to H2O2 catalyzed by MnSOD● Over expression of MnSOD leads to increase DCHF oxidation Energetics of ROS formation from Site III Eo = -0.33 Eo = 0.04 DE = -0.29 DG ~6 kcal K =0.01 SQ +O2 e- Water reduction at Site IV K = 0.01 Aconitase +NO Q +O2- NO3- ONOO- MnSOD e- H2O2 Spin trap Over expression of MnSOD leads to increase DCHF oxidation DHR DCHF

  12. Exampl.s of Inner-sphere reduction of Oxygen Fe(V) or Fe(III)O2H+ transfers e- to form Bleomycin (BLM)Fe(III). BLMFe(III) reacts with O2- to form Fe(II)O2 or Fe(III)O2-. With Prolyl hydroxylase (Fe(O2-) hydroxylates proline resulting in Fe(III). Fe(III) accepts and electron to form Fe(II) with reacts with O2 to form (Fe(II)O2. Prolyl Hydroxylase +e- O2 Fe(III) Fe(II) Fe(II)O2 Hydroxylation of proline +e- Fe(O2-) Fe(III)O2- Examples of Inner-sphere reduction of Oxygen Bleomycin BLMFe(II) e- O2- BLMFe(III) Fe(II)O2 or Fe(III)O2- Substrate oxidation H2O2 e- Fe(V) or Fe(III)O2H+ OH and Fe(IV) 2 electron, oxygen transfer hydroxylation 1 electron oxidants

  13. Different reduction mechanism of O2 by P450 system●Cytochrome P450 F3(III) accepts an e- to form Fe(II). Fe(II) reacts with O2 plus e- to form Fe(III)-O2- using the peroxide shunt. Fe(III)-O2- is metabolized to Fe(V)=O. The P450 reductase uses NADPH, FAD and FMN as cofactors. Different reduction mechanism of O2 by P450 system Cytochrome P450 Fe2+ + O2 Fe2+O2 +e- +e- Resting state Peroxide shunt Fe3+ -O22- Fe3+ +H2O2 Substrate oxidation H2O Fe5+=O 1.4 -1.6 V P450 reductase NADPH FAD FMN P450 O2 Q SQ

  14. Enzymatic generation of Reactive Oxygen Species Purpose: ●As an antimicrobial agent ● as a by product of metabolism ● Part of signal transduction mechanisms Enzymatic generation of Reactive Oxygen Species • Purpose: • As an antimicrobial agent • as a by product of metabolism • Part of signal transduction mechanisms

  15. Examples of Hydrogen peroxide formation ● Glucose Oxidase (Glc oxidase: Bacterial) ● O2 + Glucose --> gluconolactone + H2O2 ● Polyamine oxidase (PAO) O2 + spermine ---> acrolein + putrescine + H2O2●Xanthine Oxidase (XO) ● O2 + Xanthine --> Urate and O2-/H2O2 ● O2 + Hypoxanthine --> Xanthine and O2-/H2O2 ● NADPH oxidase (NOX) ● NADPH + 2 O2 --> 2 O2- + NADP+ Examples of Hydrogen peroxide formation Glucose Oxidase (Glc oxidase: Bacterial) O2 + Glucose --> gluconolactone + H2O2 Polyamine oxidase (PAO) O2 + spermine ---> acrolein + putrescine + H2O2 Xanthine Oxidase (XO) O2 + Xanthine --> Urate and O2-/H2O2 O2 + Hypoxanthine --> Xanthine and O2-/H2O2 NADPH oxidase (NOX) NADPH + 2 O2 --> 2 O2- + NADP+

  16. Xanthine Oxidase ●Purpose: Purine metabolism Secretion of milk dropsDetoxification of AldehydesGeneration of ROS. Xanthine is metabolized under normal condidions by XD to uric acid and NADH. Xanthine is metabolized in disease and injury by XO to Uric acid and O2./H2O2. Xanthine Oxidase Purpose: Purine metabolism Secretion of milk drops Detoxification of Aldehydes Generation of ROS XD Normal (XD) Uric acid + NADH Xanthine Uric acid + O2-/H2O2 Disease and injury (XO) XO XO HX --> X + ROS

  17. Xanthine Oxidase ●The homodimer which forms urate is inhibited by allopurinol (abundant in goats milk) to urate plus FAD.●Mouse utilizes XO more than humans Xanthine Oxidase Homodimer Inhibited by allopurinol (abundant in goats milk) HX or X Mo O2 FAD FADH2 Urate Fe2S2 O2-/H2O2 S O Mo Mouse utilizes XO more than humans S O H2O H S H N N 3-O3PO O N Moco H

  18. NADPH oxidase (NOX) ●Purpose:AntimicrobialRegulation of cell-surface signalingregulation of physiological function ● NOX-1 colon VSMC, prostate● NOX-2 innate immune system● NOX-3`inner ear● NOX-4 kidney● NOX-5 spleen (human only)● Vascular NOX● Phagocytic (Phox) ● Membrane bound ● gp91phox p21phox● Cytosolic regulators ● p47phox ● p67phox● p40phox ● Small GTPase/rac1/Rac2 NADPH oxidase (NOX) Purpose: Antimicrobial Regulation of cell-surface signaling regulation of physiological function Phagocytic (Phox) Membrane bound gp91phox NOX-1 colon VSMC, prostate NOX-2 innate immune system NOX-3`inner ear NOX-4 kidney NOX-5 spleen (human only) p21phox Cytosolic regulators p47phox p67phox p40phox Small GTPase/rac1/Rac2 Vascular NOX

  19. ● NADPH oxidase ●cytochrome b558 GP91 interacts with rac, pg67, p22, p47 and p40 subunits to metabolize lOs to O2- using NADPH and FAD. O2- NADPH oxidase O2 cytochrome b558 -Fe- -Fe- gp91phox FAD gp91 NADPH p22 P rac p47 gp67 P p40 P P

  20. Nitric Oxide Synthase ● Homodimer ● NOS-1 nNOS or neuronal NOS and NOS-3 eNOS or endothelial NOS is consttuitive and calcium insensitive. ● NOS-2 iNOS is inducible and calcium insensitive NOS ● P450 reductase domain requires NADPH, FMN and FAD to bind calmodulin ● Heme oxidase domain uses O2 and Arginine/N-hydroxyarginine (NOHA) Nitric Oxide Synthase Homodimer NOS-1 nNOS or neuronal NOS NOS-3 eNOS or endothelial NOS NOS-2 iNOS or inducible NOS Constitutive and calcium sensitive Induced and calcium insensitive P450 reductase domain Heme oxidase domain Calmodulin binding NADPH FMN FAD O2 Arginine/N-hydroxyarginine (NOHA)

  21. Nitric Oxide Synthase using Arginine and O2 as substrates to generate citrulline and NO. Calmodullin (Cm) interacts with NADPH-dependent P450 reductase (NOSred) which uses NADPH, FMN and FAD as cofactors. Heme oxygenase uses BH4 as a cofactor. ●In cells can exist as monomers which then are converted to dimers Nitric Oxide Synthase 130kd Arginine Reductase domain Heme oxygenase Cm BH4 BH4 Heme oxygenase BH4 BH4 Citrulline + NO Reductase domain Cm FMN FAD NOSox NADPH NOSred NADPH-dependent P450 reductase In cells can exist as monomers which then are converted to dimers

  22. NOS Biochemistry. Arginine, O2 and NADPH use calcium and BH4 to generate NO, NOHA, O2-, H2O2 and HNO. NOS interacts with PZT and HSP90 with Fe(NO) forming Fe(II) plus NO. NO prefers iNOS relative to nNOS or eNOS. O2 prefers eNOS relative to iNOS or nNOS. NOS Biochemistry NO Arginine Oxygen NADPH NOS NOHA O2- Calcium PZT BH4 HSP90 H2O2 HNO Fe(NO) Fe(II) + NO NO iNOS>> nNOS or eNOS Ki O2 Km eNOS > iNOS > nNOS

  23. Heme Oxygenase (HO-1 or HO-2)● Heme is degraded to Biliverdin and CO which can activate guanylyl cyclase ● Biliverdin plus NADPH is metabolized to Bilirubin which is an Antioxidant N N N N N N N N Heme Oxygenase HO-1 HO-2 Heme M M V M V M V V + CO O O Guanylyl cyclase H H H NADPH Biliverdin NADP+ M M V M V M V V Antioxidant O O H H H H Bilirubin

  24. ●Biochemistry of Prevention of Oxidative or Nitrosative stress ● Different classes ● Preventive -Inhibition of production of instigators ● Interception and Quenching -Scavenging of reactive intermediates formed 1) Want the product to be innocuous2) The product could be biologically recycled3) Prevent chain reactions from occurring (chain breaking) Biochemistry of Prevention of Oxidative or Nitrosative stress Different classes Preventive Inhibition of production of instigators Interception and Quenching Scavenging of reactive intermediates formed Want the product to be innocuous The product could be biologically recycled 3) Prevent chain reactions from occurring (chain breaking)

  25. Biochemistry of Reactive Oxygen Species NOSunc, XO and NOX produce O2. Peroxidases use Cl-, Br- and NO2. to form HOCl, HOBr and NO2 which are antimicrobial. H2O2 goes thru the Fenton reaction to LOOH, Aconitase inhibition, COX, LipOX, MAPK NFκB and p53. Biochemistry Reactive Oxygen Species XO NOX Peroxidases O2- NOSunc NO2- Cl- Br- NO2 HOCl HOBr Fenton H2O2 Antimicrobial LOOH MAPK NFkB p53 Aconitase inhibition COX LipOX

  26. Chemical Biology of Nitric Oxide ●Direct. NOS makes NO which causes inhibition of respiration, guanylyl cyclase activation, radical scavenging antioxidant properties and inhibition of P450 ●Indirect effects from O2. include ONOO-, + NO to form NO2 and N2O3 leading to antitumor and antipathogen activities, Oxidation nitration and nitrosation Chemical Biology of Nitric Oxide Direct NOS Radical scavenging Antioxidant properties Inhibition of Respiration Guanylyl cyclase Inhibition of P450 NO O2- Indirect +NO N2O3 NO2 ONOO- Antitumor Antipathogen Nitrosation Oxidation Nitration

  27. Preventive Mechanisms. O2. is metabolized by SOD to H2O2 which can be metabolized by catalase, a heme protein peroxisome or Peroxiredoxin (Prx) Isoforms: Prx1-6 which contain a reactive thiol. Prx1-4 have 2 cysteine whereas Prx 5,6 have one cysteine. H2O2 can also be metabolized by Glutathione Peroxidase (GPX), a selenium containing protein in the cytosol and mitochondria. Catalase Heme protein peroxisome Peroxiredoxin (Prx) Isoforms: Prx 1-6 Contains reactive thiol 1-4 two cys one cys one cys Location Cytosol Mitochondria Peroxisome plasma Glutathione peroxidase (GPX) Selenium containing protein Cytosol and mitochondria LOOH Preventive Mechanisms O2- SOD H2O2

  28. ● Scavenging of NO. (Prevention of RNOS formation). The NOS product NO has a general cellular consumption by a mechanism to be determined (mitochondria?). NO. is metabolized to NO3- by HBO2 or MBO2. NO. is metabolized to NO2- by Fe=O with a k > 107 M-1s-1. ● Critical to compartmentalizing NO effects Scavenging of NO (Prevention of RNOS formation) NOS General Cellular Consumption Mechanism to be determined HbO2 MbO2 NO3- NO Fe=O Mitochondria? k > 107 M-1 s-1 NO2- Critical to compartmentalizing NO effects

  29. Biochemistry of Glutathione Peroxidase. Prot-Se-OH reacts with GSH to form Prot-SeSG + H20. Prot-SeSG is metabolized by GPX to form Prot-Se- plus GSSG. GSSG is metabolized by Glutathione Reductase (GR) to GSH. Prot-Se- reacts with H2O2, LOOH or ONOO- to form Prot-Se-OH. ●Selenium compound Eblselen Biochemistry of Glutathione Peroxidase NADPH Glutathione reductase (GR) GPX H2O2 LOOH ONOO- GSSG Prot-Se- GSH H2O LOH NO2- Prot-Se-OH + Prot-SeSG + H2O GSH Selenium compound Eblselen

  30. Peroxiredoxin (Prx)reacts with H2O2 to form a disulfide. Thioredoxin (ER) = Trx reacts with PrxS-S to form Prx(SH)2 + Trx (S-S). Trx(S-S) is reduced by thioredoxin reductase (FAD) = Trxred. Trxred + NADPH reduces Trx(S-S) to Trx(SH)2. ● Both GR and Trxred use hydride transfer to reduce the disulfides to sulfides Peroxiredoxin (Prx) SH Prx Prx (1-4) SH H2O2 Trx(S-S) S Prx NADPH Trxred S Trx(SH)2 Trx = Thioredoxin (ER) Trxred = thioredoxin reductase (FAD) FADH2 Reduced S-S NADPH Both GR and Trxred use hydride transfer to reduce the disulfides to sulfides

  31. Reduction of a seleno-cysteine. TrxR has FAD, SeH and (SH)3 reacts with NADPH to form TrxR-SeH(SH)3 FADH2. This can be oxidized by Trx(S-S) to TrsR-Se-S(SH)2FADH2 plus Trx(SH)2. The cycle is completed with the formation of TrxR-she(SH)(S-S)FADH2. AA selenylsulfide in a protein is reduced by a cysteine-exchange reaction and the resulting disulfide is then reduced by electron transfer. This example shows the reduction of thioredoxin (Trx) by thioredoxin reductase (TrxR).●Jacob C, Giles GI, Giles NM, Sies H. (2003) Sulfur and Selenium: The Role of Oxidation State in Protein Structure and Function.Angewandte Chemie International Edition. 42: 4742-4758. Reduction of a seleno-cysteine A selenylsulfide in a protein is reduced by a cysteine-exchange reaction and the resulting disulfide is then reduced by electron transfer. This example shows the reduction of thioredoxin (Trx) by thioredoxin reductase (TrxR). Jacob C, Giles GI, Giles NM, Sies H. (2003) Sulfur and Selenium: The Role of Oxidation State in Protein Structure and Function.Angewandte Chemie International Edition. 42: 4742-4758.

  32. Glutathione Metabolism. GHS oxidizes with OH/Fe=O, NO2) to GS.. GS. reacts with GSH to form GSSG which reacts with O2 to form O2- which is metabolized by SOD to H2O2 and GPX to H2O. GSSG + NADPH is metabolized by GR to GSH. GS. Can react with O2 to form GSOO. which further reacts with O2 to form GSOH + O2-. GSH reacts with ONOO- to form GSOH which reacts with GSH to GSSG. Glutathione Metabolism SOD GPX H2O H2O2 O2- GSSG O2 NADPH GR GSH GSSG GSH GSH ---> GS ONOO- Oxidant OH/Fe=O NO2 GSH O2 GSSG GSOO GSOH SOD GPX H2O O2 H2O2 O2-

  33. ●Abatement of Nitrosative Stress. NO reacts with O2 to form N2O3 which reacts with GSH to form GSNO. GSNO reacts with Cu(I)ZnSOD to form GSH + NO. GSNO reacts to form ProteinS-SG or Protein SNO + GSH. GSNO reacts with GHS to form GSSG _HNO which further reacts to form GSNOH. GSNOH reacts with GSH to form GSSG which is reduced by GR to form GSH. Also, GSNOH forms GS(O)NH2. ● Both NO and HNO toxicity is abated by GSH Abatement of Nitrosative Stress NO Both NO and HNO toxicity is abated by GSH O2 N2O3 GSH Cu(II)ZnSOD Cu(I)ZnSOD GSH + NO GSNO GSH ProteinS-SG GSSG +HNO Protein SNO +GSH GSH GSH GR GS(O)NH2 GSH GSNOH GSSG NH2OH

  34. Glutathione and Ascorbate Pools Communicate. GSSG is metabolized by Protein disulfie isomerase (PDI) with glutaredoxin (cytosol). DHA is metabolized to AscH- which can reduce metals and increase metal-mediated oxidation. AscH- can react with radicals (Y.) to Asc. which metabolizes to DHA. Glutathione and Ascorbate Pools Communicate 2 GSH GSSG Protein Disulfide Isomerase (PDI) Glutaredoxin (cytosol) Trxred NADPH Y Asc AscH- DHA -0.28 +0.17 Reduce metals Increase Metal-mediated Oxidation

  35. ●Human Plasma 0.2-0.4 mM ●Urate and Uric Acid. Xanthine is metabolized by XD or XO to uric acid. Uric Acid reacts with OH (>109) or NO2 (107)and forms urea and HOC-CHO. Glyoxylic acid may then form oxalic acid. UH3 picks up electrons to form UH2- and UH2-. Urate and Uric Acid Human Plasma 0.2-0.4 mM Xanthine XD or XO OH NO2 107 Urea and HOC-CHO >109 Glyoxylic acid Oxalic acid

  36. ●Interaction of NO and ROS . HO-1 is metabolized to CO and bilirubin. HO-1 inhibits NOS and NOX resulting in less NO and O2-. NO inhibits ferrochelatase. O2- is metabolized by SOD to H2O2 which can be metabolized by GPX or Prx. H2O2 can form LOOH which leads to lipid oxidation. LOOH is metabolized by GPX and Prx to ROH. O2- leads to RNOS which is oxidized to GSSG which is metabolized by GR to GSH. ● Heme and iron regulation is critical to the redox balance Interaction of NO and ROS ? CO and Bilirubin HO-1 Heme NOX Lipid Peroxidation NOS NO O2- SOD LOOH H2O2 RNOS Ferrochelatase Ox GPX Prx GSSG GPX Prx GR ROH GSH Heme and iron regulation is critical to the redox balance

  37. ●All enzymes require Oxygen and NADPH . O2 is metabolized by XO, NOX, NOS and HO. ● NADPH versus NADH ● Metabolism of iron, oxygen and glucose will be critical factors in the cellular redox state ● Now the adventure begins in biology All enzymes require Oxygen and NADPH O2 HO XO NOS NOX NADPH versus NADH Metabolism of iron, oxygen and glucose will be critical factors in the cellular redox state Now the adventure begins in biology

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