Glycolysis

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The following is not bullshit superfluousness and is literally what you need to know for Step1 for glycolysis:

The irreversible steps are:

1. Glucose → G6P (hexokinase/glucokinase)
2. F6P → F1,6-BP  (PFK-1)
3. PEP → pyruvate (pyruvate kinase)

Pyruvate kinase is a deceitful name because PEP loses a Pi. That’s the only exception on Step1.

Some molecular regulators of glycolysis:

ATP, NADH, citrate, and alanine inhibit glycolysis.

In contrast, AMP and ADP stimulate glycolysis.

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Phosphofructokinase 1 (PFK1) is the rate-limiting enzyme, not hexokinase/glucokinase.

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Hexokinase is the first enzyme of glycolysis everywhere except for the liver and β-islet cells of the pancreas. In the liver + β-cells, glucokinase is the first enzyme.

The USMLE is obsessed with testing hexokinase vs glucokinase.

Enzyme	Where	Km	Vmax	Stimulated by insulin?
Hexokinase	Mostly ubiquitous	↓	↓	No
Glucokinase	Liver + ß-islets of pancreas	↑	↑	Yes

Hexokinase has a higher affinity for glucose (↓ Km) but gets saturated quickly (↓ Vmax).

In contrast, glucokinase has a lower affinity for glucose (↑Km) but can tolerate high amounts of it (↑ Vmax).

This makes sense because most of the time we want glucose to be taken up peripherally, not by the liver for storage. Therefore the liver should have lower affinity for it.

When glucose is high, we want the liver to start storing it as glycogen. In this case, high glucose means high insulin, which then stimulates glucokinase in the liver to start buffering the excess load.

Insulin does NOT stimulate hexokinase. Only glucokinase is stimulated by insulin.

Fasting state → insulin lower → ↓ stimulation of glucokinase in the liver → hexokinase takes up glucose peripherally

Fed state → insulin higher → ↑ stimulation of glucokinase in the liver → liver buffers excess blood glucose → insulin dephosphorylates and activates glycogen synthase → excess glucose stored as glycogen (elaboration in this module)

Holy cow: Although insulin drives glucose into cells by upregulating GLUT4 recruitment to adipocyte and skeletal muscle cell membranes, the dephosphorylation and activation of glycogen synthase + the activation of hepatic glucokinase, perpetuated by insulin, decreases/buffers blood glucose levels by creating additional G6P and shuttling it to G1P for glycogenesis.

In the second half of glycolysis, normally, 1,3-bisphosphoglycerate → 3-phosphoglycerate. However, RBCs have bisphosphoglycerate mutase that allows for them to convert 1,3-bisphosphoglycerate → 2,3-bisphosphoglycerate (2,3-BPG, or 2,3-DPG) → 3-phosphoglycerate.

2,3-BPG (2,3-DPG) decreases the affinity of oxygen for deoxyhemoglobin (i.e., shifts the Hb-O2 dissociation curve to the right).

The bottom line is that if they ask you about what type of cell has an enzyme called bisphosphoglycerate mutase, the answer is RBC, because this enzyme is what creates 2,3-BPG from 1,3-BPG.

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Normally, F6P → F1,6-BP via PFK-1. When the insulin/glucagon ratio is ↑ (i.e., in the fed state), some F6P is instead shunted, via PFK-2, to F2,6-BP.

F2,6-BP then acts as a (+) allosteric regulator of PFK-1, the rate-limiting enzyme of glycolysis, to further stimulate F6P → F1,6-BP.

In other words, F2,6-BP is what stimulates the rate-limiting enzyme of glycolysis.

In contrast, when the insulin/glucagon ratio is ↓ (i.e., in the fasting state), any available F2,6-BP is shunted back to F6P, via F2,6-BPase, and the F6P → F1,6-BP step is not stimulated.

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(If the following comes off confusing, open this post in a separate tab.)

PFK2 is dephosphorylated and activated by ↑ insulin/glucagon.

F2,6-BPase is dephosphorylated and deactivated by ↑ insulin/glucagon.

PFK2 is phosphorylated and deactivated by ↓ insulin/glucagon.

F2,6-BPase is phosphorylated and activated by ↓ insulin/glucagon.

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The final product of glycolysis is 2x pyruvate, from one glucose.

4 ATP are produced. But 2 are consumed. So 2 net ATP are produced.

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Pyruvate dehydrogenase + B1 (and B2, 3, 5, and lipoic acid): pyruvate → acetyl-CoA

Pyruvate carboxylase + B7: pyruvate → OAA (for gluconeogenesis, not glycolysis)

Lactate dehydrogenase: pyruvate + NADH ↔ lactate + NAD⁺

Alanine transaminase (ALT) + B6: pyruvate + glutamate ↔ alanine + α-KG

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