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MTC Block 3 > 1 - Redox Biology and Oxidative Stress > Flashcards

1 - Redox Biology and Oxidative Stress Flashcards

1
Q

What does the term “redox” mean?

What does redox state or redox poise mean?

A

Reactions that involve the change in reduction/oxidation state, and in particular those involving oxidative damage to biological molecules and the corresponding cellular response.

Indicates how well a cell is able to withstand oxidative attack.

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2
Q

What is photosynthesis? What are the two major consequences? How is solar energy captured?

A

A redox reaction that removes electrons from water and passes them to carbon.

  1. Reduced forms of carbon can form polymers which are used to build complex structures
  2. Oxidizing gas (oxygen) is generated and released.

Solar energy captured by pushing redox rxn away from equilibrium.

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3
Q

What is a consequence of all the oxygen from photosynthesis being put into the atmosphere? What is an example of this?

A

Biosphere is a long way from equilibrium and if an appropriate route back to equilibrium can be found, then the trapped energy will be released.

Forest fires are a release of this stored energy.

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4
Q

What stops everything from just combusting or from forest fires from spontaneously occurring? How do our bodies use this energy?

A

There is not a kinetic route; The energy can’t be tapped into without the proper activation energy.

Our bodies can tap into this energy gradient and capture the released energy for biological processes without triggering uncontrolled oxidation of our own molecules.

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5
Q

What is the function of cellular respiration? When is oxygen involved?

A

It extracts solar redox energy and converts it to chemical energy of ATP/ADP with as few “leaks” as possible.

Electrons are placed on oxygen at complex 4 (cyt C oxidase) of ETC.

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6
Q

When is oxygen used NOT at the end of the ETC?

A

Some metabolic enzymes use oxygen for introducing functional groups into molecules.

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7
Q

How do enzymes that use oxygen work?

A

By trapping oxygen as the ligand of a metal ion - often as part of a heme group.

Oxygen is then reduced by NADPH , and can then directly oxidizes the carbon polymer.

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8
Q

What is the risk involved in enzymes that use oxygen?

A

Unsafe kinetic mechanism for the reduction of oxygen.

The partial reduction or “leakage” of electrons onto oxygen outside of the safe complex 4 can give rise to radicals and oxidants.

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9
Q

What is the sequential reduction of O2 to H2O? Name the intermediates.

A

O2 -(loses 1e)-> O2.-

-(loses 1e and gains 2H)-> H2O2 -(loses 1e)-> .OH -(loses 1e)-> H2O.

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10
Q

Describe each of the intermediates between O2 and H2O?

A

O2.- is a superoxide: free radical but not a strong oxidant.

H2O2 strong oxidant found in bleach, can oxidize some biological molecules.

.OH is the strongest oxidant in biology, will oxidize almost all carbon polymers, initial chain reactions of oxidations, and cause DNA oxidation/mutation. Also involved in ionizing radiation induced cell death.

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11
Q

What is oxidative stress? What causes it?

A

When more oxidants are being generated than can be handled by cellular defense systems.

Caused by oxidative stressors: anything that can tap into the energy by overriding the Ae.

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12
Q

What is paraquat?

A

A herbicide that can take e- from NADPH and use them to reduce paraquat to cationic free radical.

Usually done by hijacking cyt p450 reductase.

Paraquat radical can then reduce oxygen by one e- to make a superoxide.

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13
Q

What are reactive oxygen species (ROS)? What can they attack?

A

Partially reduced forms of oxygen and some of their oxidative products.

Can attack biolocial molecules such as PUFAs to cause damage and potential cell death.

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14
Q

What are reactive nitrogen species (RNS)?

A

Arise from nitric oxide through oxidation. Potentially damaging agents.

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15
Q

What happens when RNS and ROS interact?

A

They form other oxidative species.

NO can react with superoxide to form peroxynitrite, an oxidant with similar reactivity to the hydroxyl radical.

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16
Q

What are the two protection mechanisms for dealing with ROS and RNS?

A

Enzymatic system and a small molecule vitamin antioxidant system.

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17
Q

What is central to most enzymatic mechanisms to handle ROS and RNS?

A

Tripeptide made of glu-cys-gly, which can exist as the oxidized GSSG or reduced by two electrons to form GSH.

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18
Q

What is the function of glutathione peroxidases (GPx)?

A

Catalyze the reaction between H2O2 and GSH to removal H2O2 and form GSSG.

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19
Q

What recycles GSSG back to GSH?

A

Glutathione reductase (GR), which uses electrons from NADPH.

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20
Q

What is the role of superoxide dismutase? What happens to those products?

A

Takes two superoxide molecules and transfers one electron between them to make oxygen and H2O2.

Catalase takes two H2O2 molecules and pass two electrons from one to another to make water and oxygen. (requires two H2O2 so its not good at getting rid of small amts of H2O2).

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21
Q

What is a peroxyredoxin? What is the electron source?

A

H2O2 metabolizing enzymes that work similarly to glutathione peroxidases, except the thiol reaction occurs on a protein and the recycling occurs via thioredoxin and thioredoxin reductase.

NADPH is still the source of the electrons.

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22
Q

What are examples of small molecule vitamin antioxidants? What is each of their functions?

A

Vitamin E and C: both able to react with and scavenge ROS.

Vit E is lipid soluble and thought to protect lipid membranes from oxidation.

Vit C can help by repairing and recycling vit E.

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23
Q

How is superoxide production part of innate immunity?

A

Phagocytes contain NADH-oxidase, which generates large amounts of superoxides during the respiratory (oxidative) burst to kill invading pathogens.

24
Q

What is the role of NADPH-oxidase?

A

Takes e- from NADPH and puts them on oxygen to make a superoxide.

In combo with myeloperoxidase (MPO) it can generate hyperchlorous acid (HOCl), a strong oxidant that can oxidize phagocytosed pathogens to kill and degrade them.

25
Q

What is chronic granulomatous disease (CGD)? What is the consequence?

A

Inherited deficiency in NADPH oxidase, and thus lack of the ability to make superoxide in innate immunity.

Increased susceptibility to infection.

26
Q

Is NADPH oxidase (NOX) a single enzyme? What do phagocytes mainly use?

A

No, it is a multienzyme complex, several isoforms exist in mammals.

They are under tight control to limit amount of radicals.

NOX4 makes H2O2 directly, the rest of them make superoxide.

Phagocytes use NOX2 mainly.

27
Q

What is re-perfusion injury?

A

Damage caused by the re-introduction of oxygen to ischemic tissue, where a burst of oxidant formation has been most closely linked to damage.

28
Q

What is one mechanism of reperfusion injury?

A

Proteolytic damage to the enzyme xanthine dehydrogenase to form xanthine oxidase, which directly reduces oxygen to superoxide.

29
Q

What is a clinical scenario in which reperfusion injury is common? How is this issue combatted?

A

Transplant surgery.

Use of antioxidants in storage and reperfusion solutions (containing glutathione and allopurinal-inhibitor of xanthine oxidase): these mitigate the effects of the burst of oxidants during re-oxygenation/perfusion.

30
Q

Can oxygen be dangerous without being reduced? When does this occur?

A

Normally oxygen doesn’t react with carbon polymers because it’s ground state is a triplet.

When supplied with energy, a singlet state of oxygen can be formed, which is a strong oxidant.

31
Q

What can cause oxygen electrons to go into the singlet state?

A

UV light or by visible light in the presence of a photosensitizer such as protoporphyrin IX.

32
Q

What effect does singlet oxygen have on the body?

A

Reacts with unsaturated lipids to form hydroperoxides.

Reacts with aas (histidine) to form hydroperoxides or endoperoxides.

Reacts with protein sulfydryls to form sulfonic acid.

33
Q

What is porphyria?

A

Defective heme synthesis causes excessive formation of 1O2 in the presence of sunlight.

Porphyrins accumulate in the skin and sun exposure causes blistering and swelling.

34
Q

What is a therapeutic use of singlet oxygen?

A

Phototdynamic therapy - selective destruction of tumor cells in the presence of a sensitizer (dye), visible light, and oxygen.

35
Q

What is another good way that 1O2 can be used?

A

MC540/PDT therapy

Used ex-vivo to purge bone marrow of cancer cells, making use of selective uptake of photosensitizing dye by cancer cells.

Merocyanine-540 selectively binds to PM of leukemia cells.

36
Q

What is Nitric oxide?

A

A diatomic, lipophilic diffusible free radical that is a gas in pure form.

Belongs to a class of signaling molecules (gasotransmitters).

37
Q

When was nitrous oxide finally used as a surgical anesthetic?

A

1844, nitrous oxide (N2O) used surgically after being previously named ‘laughing gas’ due to its recreational use at carnivals.

38
Q

What was the role of Alfred Nobel?

A

Industrial chemist that used nitroglycerin to generate dynamite.

Explosives based on multiple nitrate ester groups.

39
Q

What was the contribution of Thomas Lauder Brunton? What was significant about this?

A

Use of amyl nitrite, a nitrite ester, to relieve angina.

First use of nitrovasodilator to decrease blood pressure and relieve a clinical symptom.

40
Q

What are five nitrovasodilators? What is the disadvantage to using them?

A
  1. Nitroglycerin
  2. amyl nitrite
  3. erythrityl tetranitrate
  4. isosorbide dinitrate
  5. pentaerythriton tetranitrate.

Tolerance can be developed.

41
Q

What was the contribution of Robert Furchgott?

A

Showed that blood vessels wouldn’t dilate to Ach if the endothelium was removed, showing that endothelium produces a substance that can diffuse through smooth muscle to trigger relaxation.

Called it “endothelium-derived relaxing factor” or EDRF

42
Q

What was the contribution of salvador moncada

A

First proved that EDRF was indeed NO.

Later showed NO is synthesized from L-arginine by nitric oxide synthase.

43
Q

How is NO generated from arginine? What enzymes are used?

A

L-arginine uses NADPH and oxygen to make N-hydroxyl-L-arginine. High uses half of NADPH to make L-citruline and NO.

Three isoforms of NOS enzyme:

  1. nNOS - neuronal
  2. iNOS - inducible, innate immunity
  3. eNOS - endothelial
44
Q

What is the structure of NOS?

A

Has a reductase domain that binds NADPH and flavin cofactors, which pass e- to oxygenase domain that contains heme and BH4.

Heme site is the active site where arginine binds.

Also contains calmodulin.

45
Q

What is the EDRF pathway?

A

A stimulant increases calcium levels, which triggers NOS to generate NO.

No binds guanylyl cyclase to activate it and convert GTP to cGMP, which acts on PKG to stimulate smooth muscle relaxation.

46
Q

What is another action of cGMP? What degrades cGMP?

A

Interact with phosphodiesterases in the cAMP pathway and create cross-talk between cyclic nucleotide signaling pathways.

Degraded to GMP by PDE5.

47
Q

What is the clinical significance of NO and cGMP signaling?

A

Impaired relaxation of smooth muscle of corpus cavernosum causes erectile dysfunction.

NO and cGMP mediate relaxation in response to stimulation of nonadrenergic, noncholinergic neurons.

Led to birth of sildenafil, which blocks PDE5 (cGMP can’t be degraded).

48
Q

What groups are the primary transducers of redox signals? What?

A

Thiols, becuase they are the most easily oxidized and their reactivity can be tuned by the environment.

There’s a large variety of thiol modifications that can result in recruitment of common responses from different stresses.

49
Q

What amino acid is the most reactive? Why is this?

A

Cysteine, because it can act as a site in proteins that can be modified and thus provide a signal that oxidants are being generated.

50
Q

What is a redox signaling mechanism found in prokaryotes?

A

OxyR, a detector protein, is oxidized to being a direct TF.

OxyR has a vicinal dithiol that can be oxidized to disulfide and then bind to DNA and stimulate transcription of protective enzymes.

OxyR is reduced back to inactive form by glutaredoxin using NADH.

51
Q

Why is the vicinal dithiol motif common in redox signaling mechanisms? What is it made up of?

A

Because different oxidants can trigger the same signaling response.

Made of a reactive cysteine and a resolving cysteine.

52
Q

Describe the reactive cysteine and the resolving cysteine in a vicinal dithiol? Does the type of oxidant make a difference to the signal produced?

A

Reactive: reacts with oxidant to generate cysteine adduct

Resolving: reacts with adduct to generate a disulfide.

Always end up with a disulfide (and thus signal) no matter what the oxidant was.

53
Q

What is the YAP1/Orp1 system in yeast?

A

Orp1 acts as a detector and YAP1 acts as TF.

Orp1 consumes H2O2 and be reduced by the thioredoxin system (TRX uesing NADPH e-).

54
Q

What happens when Orp1 can’t keep up and oxidized Orp1 accumulates?

A

It can cross-react with YAP1 to make an ORP/YAP disulfide.

The resolving cysteine of YAP1 then kicks off Orp1 to leave a YAP1 disulfide and then acts as a TF to transcribe more protective mechanisms.

55
Q

Describe the roles of Keap1 and Nrf 2 in the signaling system. What happens under steady-state conditions?

A

Keap1 detector and Nrf2 is the TF.

Both sequestered by Cul3, which recruits Ub enzymes to ubiquinate Nrf2 for degradation under steady-state conditions (futile cycle).

56
Q

What effect do oxidants of electrophiles have on the cysteine residues on keap1?

A

They modify them to release Nrf2, which can build up and be translocated to the nucleus where it binds to ARE to induce protective genes, which help detoxify the body.

57
Q

How can redox signaling cross-talk with other biological signaling mechanisms? Give an example.

A

MAPKKK ASK1 is bound to thioredoxin (TRX) and inactive.

Once Trx gets oxidized, it relases ASK1, which can trigger a phosphorylation signaling cascade through its kinase activity.

Re-reduction of ASK1 by thiodoxin reductase/NADPH allows it to rebind and inactivate ASK1 again.

MTC Block 3 (20 decks)

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