pyruvate [x] deficiency question

[quietude]

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I have memorized the glycolysis/TCA cycle until my eyes hurt, but am not so great at identifying obscure metabolic disorders based on physical exam alone. Too bad for me that's how the USMLE likes to write the biochem questions. Will some biochem major help me out?

Why is pyruvate carboxylase deficiency equally as fatal as pyruvate dehydrogenase deficiency? I get that a lack of PDH would be a problem with fatty acid synthesis and the major route into the TCA cycle. What I don't understand is why PC deficiency is also fatal...you should still have a working PDH enzyme that would feed into the TCA cycle, and you could presumably make up your oxaloacetate deficiency from shuttles, etc.

And along those lines: why is pyruvate kinase deficiency not a bigger issue in non-RBC cells? I'm assuming this has to do with having mitochondria for FA oxidation, but confirmation would be nice.

 

[hooperg]

When approaching these types of questions, the key to getting them right is finding either: 1. The substrate with the greatest amount of accumulation or 2. The Deadliest Substrate that accumulates. If you know #2, bingo. If you know #1, just follow the pathways out until you get to #2.

Example: PC is needed to create OAA for gluconeogenesis. PC deficiency leads to excess Pyruvate, which zooms back and forth to Lactate. Excess lactate coupled with the lacking ability to generate glucose = doomed.

Memorization is good only if you can apply the physiologic principles of each step.
Not what, why! Not what, why! ~Goljan

Addendum: Yes, it is because RBCs do not have mitochondria. If they are unable to utilize glycolysis due to PK deficiency, then they are unable to generate energy period (no mito = no ox phos). As a result, they are unable to maintain biconcave shape and get destroyed in the spleen.

 

[quietude]

When approaching these types of questions, the key to getting them right is finding either: 1. The substrate with the greatest amount of accumulation or 2. The Deadliest Substrate that accumulates. If you know #2, bingo. If you know #1, just follow the pathways out until you get to #2.

Example: PC is needed to create OAA for gluconeogenesis. PC deficiency leads to excess Pyruvate, which zooms back and forth to Lactate. Excess lactate coupled with the lacking ability to generate glucose = doomed.

Thanks, but it's still not that clear. There are other pathways for the creation of OAA. Why wouldn't they take over in this case, and PDH get rid of the excess pyruvate?

I did at least just figure out that asp --> OAA takes place in the cytosol, so I understand why that's not an alternative. But there are also plenty of things that go into malate (or fumarate, same thing in the end), which can enter the mitochondria and go to OAA in the TCA.