CO and electron transport chain

[link2swim06]

I was reviewing a practice test and am a little confused on what part of the electron transport chain is most affected during CO poisoning. I choose complex IV (cytochrome oxidase), which was not the correct answer.

Any other ideas which would would be more affected during a one hour history of carbon monoxide poisoning with the usual symptoms (headache, cherry red appearance, etc)?

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[ijn]

Are you referring to the question on NBME 13? The answer is cytochrome C oxidase. It's the last step before transferring electrons to oxygen. They call it cytochrome a and a3 on that exam, but it's the same thing.

 

[link2swim06]

Are you referring to the question on NBME 13? The answer is cytochrome C oxidase. It's the last step before transferring electrons to oxygen. They call it cytochrome a and a3 on that exam, but it's the same thing.

Yep, so what is:

Cyt C --> Cyt a and a3?

 

[AndyRSC]

Which practice test was this?

CO ****s you up in three ways, that I recall:
1. It left-shifts your oxygen-hemoglobin dissociation curve, causing reduced oxygen unloading at tissues.
2. It takes up O2 binding sites on Hgb itself
3. It binds to to Fe+2 in Complex IV, preventing electrons from being passed to O2.

Of the three, if the question specifically asked about the effect on ETC, the last one is the answer. Granted, they'll sometimes use "Cytochrome C oxidase" or "cytochrome a/a3," but it sounds to me like you were correct.

Edit: ijn, you sank my battleship.

 

[ijn]

Yep, so what is:

Cyt C --> Cyt a and a3?

I think that is Cytochrome C reductase (complex III). I also picked that one when I took #13 originally because I saw the C.... tricky bastards.

 

[link2swim06]

Which practice test was this?

CO ****s you up in three ways, that I recall:
1. It left-shifts your oxygen-hemoglobin dissociation curve, causing reduced oxygen unloading at tissues.
2. It takes up O2 binding sites on Hgb itself
3. It binds to to Fe+2 in Complex IV, preventing electrons from being passed to O2.

Of the three, if the question specifically asked about the effect on ETC, the last one is the answer. Granted, they'll sometimes use "Cytochrome C oxidase" or "cytochrome a/a3," but it sounds to me like you were correct.

It was 13, but it was confusing becuase they had cytochrome C into a two step reaction it seemed.

Cyt C --> Cyt a/3

Cyt a/a3 --> O2


I dont really understand what it is trying to show.

 

[luxaeterna]

Co block the transfer of e- to O2.

 

[AndyRSC]

I dont really understand what it is trying to show.

It's trying to get at the mechanism. CO binds to Fe+2, both in RBC Hgb and in Complex IV, preventing electron from being passed to O2.

Just keep in mind that Complex IV can also be named "Cytochrome C oxidase" or "cytochrome a/a3."

 

[Phloston]

It was 13, but it was confusing becuase they had cytochrome C into a two step reaction it seemed.

Cyt C --> Cyt a/3

Cyt a/a3 --> O2


I dont really understand what it is trying to show.

My interpretation is that they're trying to separate out where CO actually plays a role.

As far as I'm aware, CO binds to cytochrome C oxidase, inhibiting it.

Cyanide binds to cytochrome aa3, preventing the transfer of electrons to molecular oxygen.

That distinction is exceedingly high-yield.

I have that annotated into my FA. I can't entirely recall where I had seen that. It may have been FA Q&A, but I specifically remember that CO was the wrong answer regarding "binding to cytochrome C and inhibiting the transfer of electrons to molecular oxygen." That was specifically cyanide, not CO.

All of the following is stuff I had annotated directly into my FA from USMLE Rx and FA Q&A:

Complex I = NADH dehydrogenase
Complex II = succinate dehydrogenase
Complex III = cytochrome bc1 complex (Q-cycle)
Complex IV = cytochrome C oxidase / cytochrome oxidase aa3

Rotenone is a competitive inhibitor of NADH dehydrogenase, the first component of e- transfer in the e- transport chain.

For succinate dehydrogenase, FAD --> FADH2 (requires B2).

Antimycin A binds to cytochrome C reductase and prevents e- transfer from cytochrome b to cytochrome c (I've interpreted this as antimycin A knocking out complex III).

CN- binds to Fe3+ in cytochrome oxidase aa3, preventing transfer of e- to molecular O2.

All of these agents induce lactic acidosis (anion-gap acidosis). Although CN- poisoning may decrease O2 saturation, laboratory studies show near normal O2 saturation. This is in contrast to CO, which has increased affinity for Hb, so O2 saturation would be decreased with CO poisoning. And with CN- poisoning, selectively, there is increased venous O2 saturation, because cells cannot use O2 (decreased venous-arterial O2 difference).

 

[AndyRSC]

CO binds to cytochrome C oxidase, inhibiting it.

Cyanide binds to cytochrome aa3, preventing the transfer of electrons to molecular oxygen.

That distinction is exceedingly high-yield.

Kaplan diverges on this. The biochemist in Kaplan lectures states that cyanide prevents electron flow to the Complex IV iron, as cyanide binds to it in the +3 state. CO, on the other hand, binds to Complex IV iron in +2 state, just as it’s reduced by electrons, preventing them from being passed to O2.

If I'm understanding link2swim's post, the NBME may support the Kaplan version.

 

[Phloston]

Kaplan diverges on this. The biochemist in Kaplan lectures states that cyanide prevents electron flow to the Complex IV iron, as cyanide binds to it in the +3 state. CO, on the other hand, binds to Complex IV iron in +2 state, just as it's reduced by electrons, preventing them from being passed to O2.

If I'm understanding link2swim's post, the NBME may support the Kaplan version.

That's interesting that you say that. Once CO binds to Hb in the lungs, its 240x greater affinity for it would prevent the unloading of O2 at the tissues due to increased Hb-R-configuration (as we already know). Therefore, the inhibition of the complex IV conversion of 1/2O2 (g) + 2H+ (aq) + 2e- --> 1H2O (l) would be less a result of direct Fe2+ binding to CO as much as it would be due to loss of the downstream complex IV substrate (i.e. oxygen); in other words, I wouldn't doubt that the former occurs, but the proclivity for the latter is greater based on CO's overwhelming affinity for Hb (which they want us to know). In relation to cyanide, it strictly functions via direct binding and inhibition of e-transfer.

I'm not trying to stir another heated debate. Both CN- and CO, given that they each inhibit complex IV, would ultimately chasten the O2 electron transfer, but in terms of the USMLE, they want cyanide as the agent that prevents electron transfer to oxygen. My guess is because the CO-spectrum of effects is shifted upstream relative to CN-'s.

 

[link2swim06]

That's interesting that you say that. Once CO binds to Hb in the lungs, its 240x greater affinity for it would prevent the unloading of O2 at the tissues due to increased Hb-R-configuration (as we already know). Therefore, the inhibition of the complex IV conversion of 1/2O2 (g) + 2H+ (aq) + 2e- --> 1H2O (l) would be less a result of direct Fe2+ binding to CO as much as it would be due to loss of the downstream complex IV substrate (i.e. oxygen); in other words, I wouldn't doubt that the former occurs, but the proclivity for the latter is greater based on CO's overwhelming affinity for Hb (which they want us to know). In relation to cyanide, it strictly functions via direct binding and inhibition of e-transfer.

I'm not trying to stir another heated debate. Both CN- and CO, given that they each inhibit complex IV, would ultimately chasten the O2 electron transfer, but in terms of the USMLE, they want cyanide as the agent that prevents electron transfer to oxygen. My guess is because the CO-spectrum of effects is shifted upstream relative to CN-'s.

Right the main effect is at oxygen loading on hemoglobin. NBME questions agree with that...

However, this particular question specifically asked what within the eletron transport cycle was blocked.

ijn said that he though cyt c means complex III, after a little googling I saw he is correct.

Wikipedia: Complex 3 is also called "The coenzyme Q : cytochrome c — oxidoreductase, sometimes called the cytochrome bc1 complex, and at other times complex III"



In short, the NBME was being nasty and expected you to know a/a3 is complex 4 and then also know complex 3 has a bunch of names. Up till this question I always called complex 3 "Cytochrome bc1" but apparently cyt c is an abbreviation the NBME will use.

 

[Celtikman]

Right the main effect is at oxygen loading on hemoglobin. NBME questions agree with that...

However, this particular question specifically asked what within the eletron transport cycle was blocked.

ijn said that he though cyt c means complex III, after a little googling I saw he is correct.

Wikipedia: Complex 3 is also called "The coenzyme Q : cytochrome c — oxidoreductase, sometimes called the cytochrome bc1 complex, and at other times complex III"



In short, the NBME was being nasty and expected you to know a/a3 is complex 4 and then also know complex 3 has a bunch of names. Up till this question I always called complex 3 "Cytochrome bc1" but apparently cyt c is an abbreviation the NBME will use.

I know I am years late to this party. But I had to dig up my SDN password to clear this up. (Almost) Everything in ETC has "cytochrome c" as part of the name because of newton's law of alliteration. COQ:CytC oxidoreductase, Cytochrome BC1, Cytochrome C oxidase.

All preceding explanations, other than the response mentioning Complex IV = cytochrome a+a3, are just complicating what is very simple and most tweens probably know the answer to.

Cytochrome C (proper) shuttles the electron from complex III to complex IV.
Please see this middle school "science class" illustration for clarification.