[Eschjelderup]

Hi there
 
I need some help with a "clinical detective story" on my med studies.

My task is:
 
alpha-ketoisocaproic acid: highly elevated
alpha-ketoisovaleric acid: highly elevated
 
Describe the chemical structure of these acids.
Are these acids common in our body?
If yes, how are they produced in our body?
If not, from what substances can our body alternatively create them?
 
I'm not really sure where to look. Found something about metabolism of leucine, but not too much. Can anyone help me out here, and give me a direction where to look for information and stuff?

Thanks

[Babcock_Hall]

When leucine, isoleucine, or valine are broken down, what is the first chemical step?  What two functional groups are present, and in what relative orientation?

[Babcock_Hall]

I meant to write what are the two functional groups present in both alpha-ketoisovaleric acid and alpha-ketoisocaproic acid and how close are they to each other in the two compounds.  You can deduce them from the names of the compounds, or you can look at their structures.

[Eschjelderup]

well, I can see that the two kheto groups and the hydroxy group have identical positions to each other in both acids. My problem is that I really don't have the knowledge (nor time to get it) about what to tell about them, from the questions I got.

Are these acids common in our body ?
If yes, how are they produced in our body ?
If not, from what substances can our body alternatively create them ?

This is the part where Im pretty lost. I understand that both the acids is part of the metabolism of Leucine and Valine, and Leucine and Valine can't be produced in the body. But are they still common in the body, because of intake from food?

And, is there any link between these acids and low pH values of blood in a new born baby? In the clinical detective case the problem is that a baby have several problems:
dehydrated (estimated to lose 5% body water) and almost did not react. He was pale and had blue lips and fingertips. His heart rate was 170/min and a respiratory rate was 60/min. Blood pressure was low. His liver was enlarged. Reflexes were reduced and he was hypotonic in general.

Laberatory values:
Ammonia 100 µM (normal values 30 – 60µM )
pH 7.15 (normal values 7.36 – 7.44)
Glucose 3.6 mmol/l  (normal values 3.3 – 5.6 mmol/)
Lactate 1.3 mmol/l (normal values 0.5 – 1.5 mmol/l)
Semi-quantitative chemical analysis of urine revealed the increased amount of acids.

Found results on detailed examination:
alpha-ketoisocaproic acid: highly elevated
alpha-ketoisovaleric acid: highly elevated

And my part of the task is to anwer the questions I wrote over, and preferably with a link to the values over here. I really don't see the link myself, so maybe some of you can help me out?

Anyway, thank you, I really appreciate it!

[Babcock_Hall]

If you don't have a good general biochemistry textbook (such as Lehninger's Principles of Biochemistry), then you should obtain one.  The ketone group and the carboxylic acid group are on adjacent carbons.  Thus, these compounds are called alpha-ketoacids.  A hydroxyl group is understood to be a portion of a carboxylic acid group, but it can be confusing to talk about the hydroxyl group separately.  Do the R groups of these amino acids have anything in common with each other, and do they look familiar at all?  When acids in the blood are elevated, it can cause the blood pH to drop.  This is a serious medical situation, inasmuch as the pH of blood must be tightly regulated.

If we take in more protein in our diet than we need, we must break the amino acids down.  The first step in breaking down an amino acid is usually transamination, catalyzed by one of the aminotransferase enzymes.  Suppose that valine and pyruvate were the substrates for alanine-valine aminotransferase.  What would the two products be?

[Yggdrasil]

Since you've identified the metabolites as derivatives of amino acids, that could point to some disorder of amino acid metabolism.  Since it is appearing in a newborn, it is likely congenital.  You can use these facts to look through some known diseases and see if they match the symptoms observed.

[Eschjelderup]

Ok, so as I understand, there must be a disorder that "stops" the catabolism of Valine and Leucine when it reaches the first step; alpha-Ketoisovaleric acid and alpha-Ketoisocaproic acid? What can the disorder be? Lack of enzyme that would normally catalyze the reaction, or?

Both of the acids are common in body, but both of them are derivates of essential AA, which is not produced in body. Would it then be wrong to say that the a-keto acids are made in the body? I mean, the acids (or the reaction that makes the a-keto acids) happens inside the body, although the AA themselves are not.

Does this problem have anything to do with a "wrong" diet, eg too much proteins or anything else that makes the body "over produce" these keto-acids? Or is it just the disorder that can be the reason?

Thank you so much for the help btw.

[Babcock_Hall]

Valine and isoleucine are essential amino acids, not derivatives of essential amino acids.  They enter the body through the diet, and the conversion to α-keto acids occurs in the body, in a process called transamination that I discussed above.  If you look at the R-groups, you can figure out which amino acid is related to which ketoacid.

If you put a dam into a river, where will the river rise, in front of the dam or behind it?

A special diet is part of the treatment of this disease, not the cause.

[Eschjelderup]

Of course, I was a little bit unclear there. I ment the keto acids are derivatives of the essential amino acids Leucine and Valine.

So if I understand it right:

The problem is that the BCKDC complex doesn't work properly when breaking down amino acids in skeletal muscle, and cant manage to catalyze the metabolic (catabolic?) reaction any further, and therefor it becomes a accumulation of the keto acids. The accumulation of keto acids is the reason why the pH value of blood is a bit low compared to the expected value.

So over to my first questions:

Are these acids common in our body?
Yes, both of them are a part of our metabolism.

If yes, how are they produced in our body?
If not, from what substances can our body alternatively create them?
The amino acids themselves are not produced in or body. They are essential amino acids, so both of them have to be taken up via food.
The keto-acids are produced as a part of the metabolic breakdown (catabolic) of the two amino acids. The reaction is called transamination, and is the first step on the break down of leucine and valine (and isoleucine).

[Babcock_Hall]

BCKDH is the more common abbreviation for the enzyme complex you are probably thinking of.

[Eschjelderup]

Thank you very much!