A basic biochem question.

[Old Style Nanny]

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How does increased ammonia deplete alpha-keto glutarate?

Is it because free ammonia combines with alpha keto glutarate? (an internet search vaguely suggests this is the reason)

Or does it have something to do with glutamate / ammonium transport?

I guess what I am asking is, does ammonemia by itself deplete alpha KG or is it depleted during the body's attempt to clear it off as urea in the liver?

Thanks.

 

[Phloston]

How does increased ammonia deplete alpha-keto glutarate?

Is it because free ammonia combines with alpha keto glutarate? (an internet search vaguely suggests this is the reason)

Or does it have something to do with glutamate / ammonium transport?

I guess what I am asking is, does ammonemia by itself deplete alpha KG or is it depleted during the body's attempt to clear it off as urea in the liver?

Thanks.

Alpha-KG + alanine <--> glutamate + pyruvate

This is the same as: alpha-KG + NH3 <--> glutamate + H2O

To answer your question: increased ammonia on its own can deplete alpha-KG.

In liver disease, decreased hepatic arginase synthesis leads to decreased BUN (increased BUN is kidney disease) and hyperammonaemia. This depletes your alpha-KG, shutting down your TCA cycle, leading to encephalopathy, etc. You'd also get increased glutamate synthesis, leading to neuroexcitotoxicity.

 

[Old Style Nanny]

Alpha-KG + alanine <--> glutamate + pyruvate

This is the same as: alpha-KG + NH3 <--> glutamate + H2O

To answer your question: increased ammonia on its own can deplete alpha-KG.

In liver disease, decreased hepatic arginase synthesis leads to decreased BUN (increased BUN is kidney disease) and hyperammonaemia. This depletes your alpha-KG, shutting down your TCA cycle, leading to encephalopathy, etc. You'd also get increased glutamate synthesis, leading to neuroexcitotoxicity.

Thanks. A couple of follow up questions.

How does increased glutamate cause neuroexcitation? Doesn't it form GABA which is a (-) NT?

So, you are saying ammonia combines with alpha-KG to form glutamate regardless of the intention of the body to convert that glutamate to urea right?

 

[Old Style Nanny]

And as long as we are on the subject of biochemistry, could you clarify my other very basic doubt?

I understand as far as the fact that neutral particles cross membranes easier than charged ones. This is the basis for acidifying urine to eliminate basic products and alkalanizing urine to eliminate acidic products, trapping them in urine.

And similarly, lactulose is used to acidify GIT to trap ammonium which is basic in GIT, preventing absorption.

My question is how does this translate to amino acids?

In cystinuria, lysine and arginine are not absorbed. They are both basic amino acids. So what is the logic behind using acetazolamide for treatment which alkalanizes urine?

 

[Old Style Nanny]

And finally, how does lactic acidosis cause increased urine pH? (von Gierke -> gout)

What is the basic chemistry concept here?

TIA

 

[Phloston]

Thanks. A couple of follow up questions.

How does increased glutamate cause neuroexcitation? Doesn't it form GABA which is a (-) NT?

So, you are saying ammonia combines with alpha-KG to form glutamate regardless of the intention of the body to convert that glutamate to urea right?

Glutamate, via glutamate decarboxylase and vitamin B6, can form GABA, but the glutamate is still formed in excess, hence the neuroexcitotoxicity.

And as long as we are on the subject of biochemistry, could you clarify my other very basic doubt?

I understand as far as the fact that neutral particles cross membranes easier than charged ones. This is the basis for acidifying urine to eliminate basic products and alkalanizing urine to eliminate acidic products, trapping them in urine.

And similarly, lactulose is used to acidify GIT to trap ammonium which is basic in GIT, preventing absorption.

My question is how does this translate to amino acids?

In cystinuria, lysine and arginine are not absorbed. They are both basic amino acids. So what is the logic behind using acetazolamide for treatment which alkalanizes urine?

Ammonium is acidic, not basic. NH4+ doesn't transcytose the enterocytes and therefore remains in the lumen.

Cystinuria is associated with COLA malabsorption (cysteine, ornithine, lysine, arginine), which are the basic amino acids. If you alkalinize the urine by using acetazolamide, then I'd assume you'd make it easier to reabsorb the basic amino acids because there'd be a decreased proclivity for them to protonate.

And finally, how does lactic acidosis cause increased urine pH? (von Gierke -> gout)

What is the basic chemistry concept here?

TIA

If you have metabolic acidosis via lactic acidosis, you should have decreased urine pH.

 

[Old Style Nanny]

Ammonium is acidic, not basic. NH4+ doesn't transcytose the enterocytes and therefore remains in the lumen.

My mistake. I meant to type "trap ammonium from ammonia which is basic". But I get the idea. NH4+ by virtue of being a charged molecule doesn't enter enterocytes.

Glutamate, via glutamate decarboxylase and vitamin B6, can form GABA, but the glutamate is still formed in excess, hence the neuroexcitotoxicity.

To add on to that, this is what I read: Incr glutamate -> incr opening of Ca2+ channels -> excitation.

Cystinuria is associated with COLA malabsorption (cysteine, ornithine, lysine, arginine), which are the basic amino acids. If you alkalinize the urine by using acetazolamide, then I'd assume you'd make it easier to reabsorb the basic amino acids because there'd be a decreased proclivity for them to protonate.

I don't think that may be possible? Isn't the problem in cystinuria a defect in the transporter protein? Would changing pH of urine magically make them work? I think it may be a symptomatic treatment as in if the urine is also basic (alkaline), the amino acids won't form the stones (won't precipitate that is). Because I guess if urine was acidic, acid+base will form a salt, a.k.a. stone?

If you have metabolic acidosis via lactic acidosis, you should have decreased urine pH.

You're right. Clearly an error then. Also found out that gout in von gierke is because uric acid competes with lactic acid for excretion, and nothing to do with urine pH at all.

 

[Phloston]

I don't think that may be possible? Isn't the problem in cystinuria a defect in the transporter protein? Would changing pH of urine magically make them work? I think it may be a symptomatic treatment as in if the urine is also basic (alkaline), the amino acids won't form the stones (won't precipitate that is). Because I guess if urine was acidic, acid+base will form a salt, a.k.a. stone?

Yeah, I'm pretty sure it is a transporter defect. We were on the topic of charged vs uncharged molecules and their propensities for reabsorption vs excretion, which is why I was relating acetazolamide to possible increased reabsorption if that could possibly happen to any degree. I'm not saying it actually does. And you're right about the decreased stone formation with increased urine basicity. Good call.