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Glycolysis & Gluconeogenesis

Master the pathways that power your cells — and what happens when they go wrong

Catabolic State: Breaking Down for Energy

Catabolic = breaking down for energy = starvation state

The Nervous System Takes Over

Sympathetic nervous system controls catabolic pathways. Enzymes work hardest when PHOSPHORYLATED.

The Catabolic Hormones

Starvation signals these hormones to wake up:

Second Messenger: cAMP

These hormones activate adenylyl cyclase → cAMP increases → Phosphorylates catabolic enzymes to turn them ON.

Location Matters

Mitochondria is catabolic HQ (TCA, oxidative phosphorylation, β-oxidation). Exception: Glycolysis happens in cytoplasm.

Where Your Energy Comes From

GLUCOSE

40% of diet

4 kcal/g

FATS

30% of diet

9 kcal/g

PROTEINS

30% of diet

4 kcal/g

KETONES

Last resort

> 36 hours starvation

Which Organ Prefers What Fuel?

Click a stress level to see what changes:

Organ Normal: Preferred Fuel Why This Matters (Board Alert!)
Brain Glucose Hypoglycemia destroys the brain first. Seizures, coma, death.
Heart FFAs (60% of ATP) In stress, heart DEMANDS glucose. Explains why acute MI + cardiogenic shock = give dextrose IV.
Muscles Glucose + FFAs During long fasts, muscles break down → FFAs, but also catabolized for gluconeogenesis (loss of mass).
RBCs ALWAYS Glucose RBCs have NO mitochondria. Only pathway = glycolysis (+ pentose phosphate for NADPH). Hypoglycemia → hemolytic anemia in 36h.

The Starvation Timeline

When glucose runs out, your body runs this playbook:

1

Plasma Glucose: 2–4 hours

Fed state → normal blood glucose

2

Liver Glycogen: 24–28 hours

Glycogenolysis maxed out, then depleted

3

Lipolysis: > 36 hours

Break down fat → FFAs → gluconeogenesis, ketogenesis

4

Ketogenesis: > 36 hours

Brain shifts to ketones, muscle finally spares glucose

⚠️ The RBC Connection: Why Hypoglycemia Kills Fast

RBCs only eat glucose via glycolysis. They have NO mitochondria → can't use FFAs, ketones, amino acids.

The Pentose Phosphate Pathway (The Other RBC Need)

RBCs need NADPH to protect themselves from oxidative damage. Only source: pentose phosphate pathway (happens in cytoplasm, requires glucose as substrate).

Board Alert: Hemolytic Anemia at 36+ Hours

Severe hypoglycemia (< 36h starvation) → RBCs lose NADPH protection → oxidative stress → hemolytic anemia. This is why treating hypoglycemia ASAP is life-saving.

Glycolysis: The Assembly Line

Click each step to reveal the enzyme, substrate, product, and ATP cost/gain.

ATP Counter

0
+4 created−2 used = +2 net

The Net Yield

4 ATP created2 ATP invested = +2 ATP net

⚠️ Also produces 2 NADH per glucose (crucial for energy in the electron transport chain).

NADH: The Niacin (B3) Connection

Every NADH contains Niacin (Vitamin B3). Glycolysis makes 2 NADH per glucose.

Board Alert: Pellagra

Niacin deficiencyPellagra → The 4 Ds:

Hartnup's Syndrome

Defective renal transport of tryptophan (can't reabsorb from urine) → tryptophan not available to make niacin → presents like pellagra.

2,3-DPG: The RBC Oxygen Delivery Driver

A branch off glycolysis (at G1,3DP) makes an RBC secret weapon:

What 2,3-DPG Does

2,3-DPG binds hemoglobin → lowers its O₂ affinity → hemoglobin more likely to DROP oxygen in tissues → tissues get MORE oxygen when they need it most.

The Stored Blood Problem

Stored blood loses its 2,3-DPG over time → hemoglobin grips O₂ too tightly → tissues get less O₂ → why transfusions can paradoxically worsen hypoxia if you give old blood.

The Fix: Inosine

Additive inosine to stored blood → helps RBCs regenerate 2,3-DPG → shelf life extends from 21 days → 45 days.

🔑 Sticky Mnemonics (Tap to Reveal)

🚪 The Bouncer (PFK-1)
PFK-1 is the RATE-LIMITING ENZYME — the bouncer at glycolysis' nightclub. Citrate tells it "we're full, slow down." F2,6DP says "let them in!" During exercise, PFK-1 gets too slow → F6P builds up → alternative pathway activates (F6P → F2,6DP via PFK-2) → F2,6DP activates PFK-1. Genius feedback loop.
⚗️ Mercury Loves Sulfur
Mercury blocks G3P Dehydrogenase (step 6) because Hg binds sulfur in the active site. Remember: Mad Hatter disease (mercury poisoning). In adults: tuna contamination. In kids: thermometer biting. Either way, step 6 dies → glycolysis stops → no ATP → cellular death.
🦷 Fluoride's White Teeth Clue
Fluoride blocks Enolase (step 9). Clue: fluoride = beautiful white teeth + strong bones (too much of a good thing → toxic). Enolase blocked → PEP can't form → pyruvate never forms → glycolysis stops at step 9.
🚚 2,3-DPG: The Delivery Driver
2,3-DPG is hemoglobin's delivery driver — makes it DROP oxygen off in tissues. Stored blood loses its driver (2,3-DPG degrades). Inosine = roadside assistance — helps RBCs regenerate the driver. Without it, tissues get O₂-starved from transfusion of old blood.
👮 Gluconeogenesis: 4 Bouncers
Gluconeogenesis needs 4 special bouncers to reverse glycolysis: Pyruvate Carboxylase → PEP Carboxykinase → F1,6DPase → G6Pase. Only liver (90%) and adrenal cortex (10%) have all 4 bouncers. Muscle can store glycogen but CAN'T do gluconeogenesis. Boom: that's why during starvation, muscle eats itself to feed the brain.
🔒 G6P: Glucose Trap
Glucose → G6P (step 1) is the FIRST REGULATORY STEP. G6P is charged (phosphorylated) → can't cross the cell membrane → glucose is TRAPPED inside the cell. This is how cells "capture" glucose. In the liver, G6Pase REMOVES the phosphate → glucose can escape → bloodstream gets fed.

Gluconeogenesis: Reverse Glycolysis (With Detours)

Making glucose from non-glucose sources during starvation. Only liver (90%) and adrenal cortex (10%) can do this.

Control & Signals

Triggered by epinephrine + glucagon → second messenger cAMP ↑ → activates Pyruvate Carboxylase (the rate-limiting enzyme).

The Pathway (7 Steps, 4 Bypasses)

Pyruvate OAA (Oxaloacetate)
Pyruvate Carboxylase*

⚠️ OAA can't cross membrane from mitochondria to cytoplasm.

↓ Solution: AST shuttle (OAA → Aspartate → shuttle out → back to OAA)

OAA PEP
PEP Carboxykinase*

PEP ... (reversible glycolysis steps)

F1,6DP F6P
F1,6DPase*

F6P G6P

G6P GLUCOSE
G6Phosphatase* (only liver!)

* Bypass enzymes — unique to gluconeogenesis, not found in glycolysis.

Board-Style Vignettes

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