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Cutting to the chase. Key factoids:
Pyruvate dehydrogenase (PDH) is thiamine-dependent, and absence or dysfunction of this enzyme causes severe lactic acidosis and increased serum alanine. Why?
| Buildup of pyruvate means increased shunting to:
Lactate (pyruvate + NADH ↔ lactate + NAD+) Alanine (pyruvate + glutamate ↔ α-ketoglutarate + alanine) |
Tx with ↑ dietary ketogenic nutrients (e.g. leucine, lysine and healthy oils; all → acetyl-CoA, not pyruvate).
| USMLE says: a patient has severe acidosis and ↑↑ serum alanine. The answer is pyruvate dehydrogenase deficiency. |
Arsenic inhibits PDH.
| Arsenic poisoning causes garlic-smelling breath. |
Isocitrate dehydrogenase is the rate-limiting enzyme of the TCA cycle.
| The USMLE is occasionally known to test rate-limiting enzymes. It’s a weird/obscure enzyme name, but the TCA cycle is so high-yield for pathway biochemistry that you should know this enzyme regardless. |
α-ketoglutarate dehydrogenase, like PDH, is thiamine-dependent.
| The four thiamine-dependent enzymes are pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase, and transketolase. |
Pyruvate, instead of going to acetyl-CoA via PDH and B1, can also go to OAA via pyruvate carboxylase and vitamin B7 (biotin).
| Pyruvate dehydrogenase (anabolic enzyme) = B1-dependent = takes pyruvate into the TCA cycle
Pyruvate carboxylase (catabolic enzyme) = B7-dependent = takes pyruvate backwards to glucose (via OAA in order to get to PEP) |
The ↑ NADH/NAD+ ratio caused by alcohol increases OAA → malate, thereby depleting OAA to be shuttled to PEP for gluconeogenesis.
| Fasting hypoglycemia in alcoholism is partially due to impaired gluconeogenesis because of shunting of OAA to malate. |
Succinyl-CoA (of TCA cycle) can be produced from methylmalonyl-CoA (not in TCA cycle) via vitamin B12. It is inhibition of this step in B12-deficiency that is responsible for neurologic dysfunction and myelin sheath abnormalities.
| Impaired methylmalonyl-CoA → succinyl-CoA is responsible for the neurologic dysfunction in B12-deficiency. |
Succinyl-CoA → succinate is the step where GTP is produced. Succinate → fumarate is the step where FADH2 is produced and vitamin B2 is a cofactor.
| The only thing you need to know about vitamin B2 for the USMLE (and in life essentially) is that it’s called riboflavin and is used in the above reaction. |
The TCA cycle produces lots of NADH and a molecule of FADH2, which are ultimately used to drive protons into the intermembrane space of the mitochondria in order to generate ATP. The HY factoids for this process (electron transport chain) are discussed here.
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