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You need to know fatty acids are broken down into two-carbon units called acetyl-CoA.
If you have a six-carbon fatty acid, that will be broken down into three acetyl-CoAs. (Rocket science)
However what if the fatty acid is odd-chain?
We will never get one-carbon units. But we will get three-carbon units, called propionyl-CoA.
If our fatty acid is, e.g., seven carbons, we’ll therefore get two acetyl-CoA + one propionyl-CoA.
| Fatty acid is 6 carbons → becomes 3 acetyl-CoA
Fatty acid is 7 carbons → becomes 2 acetyl-CoA + 1 propionyl-CoA. Then, Propionyl-CoA → methylmalonyl-CoA → succinyl-CoA in the TCA cycle. |
You also need to know that carnitine is necessary for degradation of fatty acids into acetyl-CoA. Just memorize it.
Carnitine sits in the inner mitochondrial membrane and is inhibited by malonyl-CoA.
Malonyl-CoA is normally a molecule that is produced when fatty acids are synthesized. So if the goal is to make more fatty acids and malonyl-CoA levels subsequently go up, then carnitine will naturally be inhibited.
| The USMLE will literally ask you which molecule is responsible for negatively regulating the breakdown of fatty acids, and the answer is malonyl-CoA. |
| What inhibits fatty acid breakdown? Malonyl-CoA |
This is important because the USMLE assesses carnitine deficiency.
If carnitine is deficient, then the patient will have hypoketotic hypoglycemia, but no acyl-CoA (not the same as acetyl-CoA) buildup in the mitochondria.
| Hypoketotic hypoglycemia. Acyl-CoAs present in mitochondria? No. → carnitine deficiency
Hypoketotic hypoglycemia. Acyl-CoAs present in mitochondria? Yes. → acyl-CoA dehydrogenase deficiency |
The above lines are what you need to memorize, but if you want more explanation:
Fatty acids are first converted to acyl-CoAs in the cytosol before being shuttled into the mitochondria via carnitine. The acyl-CoAs then disassemble in the mitochondria and are converted to acetyl-CoAs.
If acyl-CoAs are found in the mitochondria, then it’s not possible that carnitine is deficient because the acyl-CoAs wouldn’t have been able to enter.
So if you have hypoketotic hypoglycemia with acyl-CoA buildup in the mitochondria, you instead of acyl-CoA dehydrogenase deficiency, since this enzyme enables the breakdown of acyl-CoAs in the mitochondria.
One of the highest yield, but seemingly weird, biochemistry points on USMLE Step1:
| Acetyl-CoA is a (+) regulator of pyruvate carboxylase, an enzyme necessary for PEP → OAA in gluconeogenesis. Therefore ↓ production of acetyl-CoA = ↓ gluconeogenesis = ↓ glucose production |
| ↓ acetyl-CoA → ↓ OAA production → ↓ PEP production → ↓ glucose production → forces available/limited acetyl-CoA to be used for ketogenesis |
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Reye syndrome (never give aspirin to children with fever, especially if suspected viral etiology) is caused by disrupted fatty acid beta-oxidation in the mitochondria of virus-infected cells.
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