Glycolysis and gluconeogenesis: mnemonics | epomedicine (2023)

There is no need to memorize every step of the process. We will cover only the most important events.

One meaning:Glyco (Sugar) + Lysis (Breaking or Breaking)

B. Synonym:Embden-Meyerhof-Weg (EM-Weg)

C. Location:cytoplasm

D. Basic concepts of enzymes:

• Kinase – adds or removes phosphate from substrate (uses ADP or ATP)
  • For phosphorylation (ATP is used): enzyme = "substrate" + kinase (e.g. hexokinase)
  • For dephosphorylation (ATP production): enzyme = “product” + kinase (e.g. pyruvate kinase)
• Dehydrogenase: Oxidizes substrate, reduces electron acceptor (NAD+/NADP+ or FAD or FMN)
  • Converts aldehyde to alcohol

E. Key Concepts:

1. 1 molecule of glucose (6 C) is converted into 2 molecules of pyruvate (2 x 3 C; aerobic) or lactate (2 x 3 C; anaerobic).
2. During the initial cracking phase (6 C to 3 C) during the addition of phosphate to the substrate: Energy is consumed
3. After splitting a 6C compound into two 3C compounds: 2 molecules are formed (energy is generated)
4. Substrate phosphorylation consumes ATP: 1 at each step (no cleavage occurred)
   • Glucose zu Glucose-6-Phosphate (Glucokinase/Hexokinase) – 1 ATP
   • Fructose-6-Phosphate to Fructose-1,6-Biphosphate (Phosphofructokinase) – 1 ATP
5. Dehydrogenation reaction (oxidative phosphorylation).: uses NAD to generate NADH (2 at each step - cleavage has already taken place)
   • Glycerinaldehyde-3-phosphate (G3P) zu 1,3-Bisphosphoglycerate (G3P-Dehydrogenase) + 2 NADH
6. Substrate dephosphorylation produces ATP:2 in each step (the division has already been done)
   • 1,3 bisphosphoglycerato (1,3 BPG) zu 3-fosphoglycerato (fosfoglyceratoquinasa) + 2 ATP
   • Phosphoenolpyruvate (PEP) for Pyruvate (pyruvate kinase) + 2 ATP
7. ATP net gain:
   • Aerobic: -1 ATP – 1 ATP + 2 ATP + 2 ATP + 2 NADH = 2 ATP + 2 NADH (1 NADH gives 2.5 ATP in the new concept depending on the shuttle or 3 ATP in the old concept) = 7 to 8 PTA
   • Anaerobic: -1 ATP – 1 ATP + 2 ATP + 2 ATP = 2 ATP (NAD+ is regenerated from NADH by the reduction of pyruvate to lactate by lactate dehydrogenase)
   • ATP generated directly by phosphorylation = substrate-level phosphorylation
8. Irreversible reactions:
   • 3 out of 4 of the "kinase" reactions discussed above are irreversible.
   • Hexokinase/glucokinase, phosphofructokinase, and pyruvate kinase (irreversible due to very large negative ΔG)
   • These are potential sites for regulatory scrutiny (often this is because blockages could result in a pathway elsewhere
     for intermediate accumulation) and substrate availability (in this case glucose) is another general issue for regulation.
   • At each of these three points, glycolytic reactions are circumvented by alternative gluconeogenic reactions:
     • Hexoquinase/Glucoquinase by Glucose-6-Fosfatase
     • Phosphofructokinase during Fructose-1,6-Biphosphatase
     • Pyruvate kinase by pyruvate carboxylase and PEP carboxykinase

How does NADH make ATP?

1. Glycolysis produces NADH in the cytosol.
2. To produce ATP, it must be transferred to the electron transport chain within the mitochondria.
3. NADH itself cannot cross the inner mitochondrial membrane.
4. This is done by the malate-aspartate shuttle: Malate IN - Aspartate OUT (Malate enters and is oxidized to oxaloacetate, producing NADH, but it also cannot cross the mitochondrial membrane and therefore has to produce aspartate via a transamination, of way that aspartate enters the cytosol and regenerates oxaloacetate through the transamination reaction)

Glycolysis is aerobic except under the following conditions (where anaerobic glycolysis occurs):

1. Decreased oxygen supply: renal medulla
2. Few or no mitochondria: red blood cells
3. Large increase in ATP requirement: skeletal muscle during exercise

E. Glucoquinasa (Hexoquinasa IV) vs. Hexoquinasa (Hexoquinasa I-III):

The difference between glucokinase and hexokinase I-III is that glucokinase only works at high concentrations of glucose. The liver, site of glycogen synthesis, has a homologous enzyme called glucokinase. This one has a high Km for glucose. This allows the brain and muscles to use the glucose before storing it as glycogen.

F. Entry of other sugars into glycolysis:

1. fructose:
   • Fructose is phosphorylated by fructokinase (liver) or hexokinase (fat) at positions 1 and 6, respectively.
   • Fructose-6-phosphate is an intermediate product of glycolysis.
   • An aldolase-like enzyme acts on fructose-1-phosphate to produce DHAP and glyceraldehyde.
   • DHAP is an intermediate of glycolysis and glyceraldehyde can be phosphorylated to glyceraldehyde-3-P.
2. Glycerin:It is phosphorylated to G-3-P, which is then converted to glyceraldehyde-3-phosphate.
3. Galactose:
   • It has a somewhat complicated multi-step pathway to convert to glucose-1-phosphate.
   • gal → gal-1-P → UDP-gal → UDP-glc → glc-1-P.
   • When this pathway is interrupted due to a defect in one or more enzymes involved in the conversion of gal to glc-1-P, galactose accumulates in the blood and the subject suffers from galactosemia.

F. Regulation of Glycolysis:

1. Hexoquinasa:

• Inhibition by accumulation of glucose-6-phosphate (feedback inhibition).
• Glucose-6-phosphate is required for other metabolic pathways, including pentose phosphate shunting and glycogen synthesis. Therefore, the hexokinase step is not inhibited unless G-6-P accumulates (without regulation by downstream intermediates/metabolites).

2. Glucoquinasa:

• No direct feedback inhibition as with hexokinase.
• Induced by insulin and blood sugar and inactivated by glycogen.
• Inactivated indirectly by fructose-6-phosphate (through induction of a protein that binds to and suppresses glucokinase).
• Excessive consumption of fructose can cause an imbalance in liver metabolism, indirectly depleting ATP from liver cells.

3. Phosphofructokinase:

• speed limit step
• PFK-1 controls the entry of G6P into glycolysis; when the PFK-1 rate is reduced, G6P accumulates and is directed to glycogen synthesis or to the pentose phosphate pathway.
• PFK-1 is allosterically regulated by:
  • Fructose-2,6-Bisphosphate: "well-fed" signal that stimulates PFK-1 in the liver (synthesized from F6P by PFK-2 when insulin levels are high; glucagon inhibits insulin and stimulates fructose bisphosphatase -two)
  • AMP: stimulates PFK-1 in muscle (inhibits fructose bisphosphatase and gluconeogenesis)
  • ATP and citrate: slow glycolysis when energy is plentiful (activates fructose bisphosphatase to form glucose)
• Its equivalent enzyme (fructose biphosphatase-1) is the rate-limiting enzyme of gluconeogenesis.

4. Pyruvatequinase:

• Innovative Stimulation: Fructose 1,6 Bisphosphate (prevents metabolic blockade when PFK is active)
• Allosteric inhibition: ATP and alanine (biosynthetic product of pyruvate; mobilized from fasting muscle) - enable PEP accumulation and gluconeogenesis

Hormonal regulation:

1. Insulin (well-nourished state): Lowers blood sugar (stimulates glycolysis and inhibits glycolysis)

(Video) Glycolysis TRICK - How to remember GLYCOLYSIS FOREVER !!!

• Stimulate glucokinase, PFK and pyruvate kinase (not hexokinase)
• Inhibit the counterenzymes of gluconeogenesis, d. h glucose-6-phosphatase, fructose biphosphatase, pyruvate carboxylase and PEP carboxykinase

2. Glucagon (starvation): increase in blood sugar (inhibiting glycolysis and stimulating gluconeogenesis)

• Inhibits glucokinase, PFK and pyruvate kinase (not hexokinase)

fasting state:↑ Glucagon → ↑ cAMP → ↑ Protein kinase A → ↑ FBPase-2, ↓ PFK-2
State:↑ Insulin → ↓ cAMP → ↓ Protein kinase A → ↓ FBPase-2, ↑ PFK-2

• DAP forms glycerol-3-phosphate (G3P) by G3P dehydrogenase; G3P is involved in triglyceride synthesis and electron transport
• In red blood cells: 2-3-BPG mutase forms 2,3-DPG from 1,3-BPG, which binds to the β chains of HbA and reduces oxygen affinity; shifts the oxygen dissociation curve to the right
• Enolase is inhibited by fluorine.
• PK deficiency: hemolytic anemia, elevated 2,3-BPG, absence of Heinz bodies (red blood cells lack mitochondria and rely on anaerobic glycolysis; PK deficiency results in decreased ATP, resulting in:
  • Loss of biconvex shape, which is destroyed in the spleen
  • decreased activity of the Na + K + ATPase pump, leading to loss of ionic balance and causing osmotic embrittlement

Gluconeogenesis begins 4 to 6 hours after the last meal and becomes fully active when liver glycogen stores are depleted, peaking after 5 to 7 days of fasting (it is not a source of energy for the liver; hepatocytes use beta oxidation to provide the energy needed for gluconeogenesis).

In gluconeogenesis, glucose is synthesized from non-carbohydrate precursors such as:

1. Glycogenic amino acids (all except leucine and lysine)
2. Lactate (produced by muscles during anaerobic glycolysis)
3. Glycerin (produced by adipose tissue)
4. Propionate (from odd-chain fatty acid beta oxidation, isoleucine oxidation, and cholesterol side chain)

The (large) liver and kidneys are important gluconeogenic tissues; the kidney contributes up to 40% of the total glucose synthesis in the fasted state and more in the fasted state. It does not occur in muscles because muscles lack glucose-6-phosphatase, so free glucose cannot be released.

Acetyl-CoA (produced by beta-oxidation of fatty acids in the liver after lipolysis during fasting) cannot be used as a substrate for gluconeogenesis, but is an allosteric activator of pyruvate carboxylase (converts pyruvate to oxaloacetate). for use in gluconeogenesis) and pyruvate dehydrogenase inhibitor (converts pyruvate to acetyl-CoA to enter the TCA cycle), pushing pyruvate towards gluconeogenesis.

Cahill cycle (alanine-glucose cycle): Glutamate (containing amino groups toxic due to breakdown of muscle protein) can be transported to the liver via conversion to glutamine, or it can transfer its amino group to pyruvate (product of glycolysis) via from the action of ALT (SGPT) to form alanine, which is then transported to the liver. In the liver, alanine is deaminated back to pyruvate. The amino group enters the urea cycle and the pyruvate enters gluconeogenesis. The glucose thus formed is transported back to the muscle for use.

Cori Cycle (lactic acid cycle):

First, the reaction of LDH to form lactate requires NADH and produces NAD.⁺which is then available for use by the glyceraldehyde-3-phosphate dehydrogenase reaction of glycolysis. Therefore, these two reactions are closely linked during anaerobic glycolysis. Second, the lactate produced by the LDH reaction is released into the bloodstream and transported to the liver, where it is converted to glucose. Glucose is then returned to the blood, where it is used by muscles for energy and glycogen stores are replenished. This cycle is calledheart cycle.

In muscle, glycolysis leads to the production of two units of ATP. However, the liver uses six units of ATP to carry out the process of gluconeogenesis. Cori's cycle also requires the initial supply of oxygen, without which it cannot start. Therefore, muscles eventually need a fresh supply of glucose and oxygen.

When physical activity is very strenuous, muscle energy requirements exceed the ability of the Cori cycle to regenerate glucose from lactate. This leads to a condition known as lactic acidosis.

Difficulty:

It involves cytosolic and mitochondrial enzymes.

The irreversible steps of glycolysis must be avoided with special gluconeogenic enzymes.

1. Pyruvate-carboxylase (mitochondrial):

In mitochondria, pyruvate is converted to oxaloacetate via pyruvate carboxylase. But, as mentioned above, the inner mitochondrial membrane is impermeable to oxaloacetate, so oxaloacetate must be converted to malate (through a malate-aspartate transport) to leave the mitochondria and reach the cytosol.

Activated by acetyl-CoA.

2. PEP carboxykinase (mitochondrial and cytosolic):

Activated by glucagon and cortisol.

3. Fructose-1,6-Biphosphatase (zytosolisch)

4. Glucose-6-phosphatase (hepatocyte ER)