Biochemistry

Gluconeogenesis

by MEHLMANMEDICAL

 

The pink enzymes are gluconeogenic. This diagram might look “scary” at first. But if you wrap your head around this annoying pathway stuff, you’ve honestly knocked out the “hardest” biochemistry for Step 1 (and it’s really not that bad!). You can see I only included the stuff you need to know for the USMLE. No superfluousness with endless cofactors, etc.

First learn the following four reactions in order. If you want to make a good comparison with glycolysis, open this post in a separate tab:

1) Pyruvate carboxylase

  • Converts pyruvate → OAA
  • Biotin (vitamin B7)-dependent enzyme.
  • As I talk about in this post, acetyl-coA is a (+) regulator of pyruvate carboxylase, which is why carnitine or acyl-CoA (not acetyl-CoA) dehydrogenase deficiency leads to hypoketotic hypoglycemia.

2) PEP carboxykinase

  • Converts OAA back to PEP. Then PEP can work its way back up to glucose.

3) Fructose-1,6-bisphosphatase

  • Rate-limiting enzyme of gluconeogenesis.

4) Glucose-6-phosphatase

  • Enables G6P to go back to glucose.
  • Deficiency causes von Gierke disease (glycogen storage disease type I).
  • G6Pase is not found in skeletal muscle, which is why skeletal muscle does not partake in gluconeogenesis.
  • G6Pase is found predominantly in the liver.

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So far so good?

Now we can look at another way to get back to glucose:

Whereas even-chain FAs only yield 2-carbon acetyl-CoAs, odd-chain FAs are terminally catabolized to a 3-carbon molecule called propionyl-CoA. (If you want more detail on this, open this post in a separate tab).

Propionyl-CoA carboxylase converts propionyl-CoA → methylmalonyl-CoA via biotin (B7).

Methylmalonyl-CoA mutase then converts methylmalonyl-CoA to succinyl-CoA in the TCA cycle. This reaction requires vitamin B12.

Same as how vitamins B6 and B7 are involved in decarboxylase and carboxylase reactions, respectively, vitamin B12 is involved in isomerase reactions. Methylmalonyl-CoA mutase is a type of isomerase.

Buildup of methylmalonyl-CoA in B12 deficiency is what leads to myelin toxicity and subacute combined degeneration, which is the name of the neurological condition seen in B12 deficiency.

The involved tracts are the corticospinal tract, dorsal columns, and spinocerebellar tract.

Sounds pedantic, but trust me, they ask specifically for those three tracts.

I find an easy way to remember which three are affected is to start by saying, “The spinothalamic tract is not involved.”

So that’s the highest-yield information regarding gluconeogenesis for Step 1. The aim of this post wasn’t to give you a superfluous and unabridged biochemistry lecture regarding bullshit detail that will never show up. If you know the content on this page, you’re solid. You might also want to take a look at this HY post on glycogen metabolism.

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1. Which of the following are gluconeogenic enzymes? (Select all that apply)

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2. What are the two biotin (B7) dependent enzymes in gluconeogenesis?

3. a) Which gluconeogenic enzyme notably requires vitamin B12?

b) Which substrate does B12 deficiency therefore cause a buildup of?

c) Why does the buildup of this substrate matter?

4. Which three neurologic tracts are affected in B12 deficiency. And what is this condition called?

5. Acetyl-CoA is a positive allosteric regulator of which enyzme?

6. What is the rate-limiting enzyme of gluconeogenesis?

7. How many carbons is propionyl-CoA? And where is it derived from? (Name four things)

8. Methylmalonyl-CoA is converted to what gluconeogenic substrate?

9. What is the substrate and product of the pyruvate carboxylase reaction?



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