Module 2 tuts p2.2 krebs, gluconeogenesis , ppp

KREBS CYCLE

Aka Citric Acid cycle, TCA - Tricarboxylic Acid cycle

• Elucidated by Hans Krebs

• Site: Mitochondrial matrix

KREBS CYCLE

1. Acetyl CoA + Oxaloacetate → Citrate

• Citrate synthase

• Condensation reaction

2. Citrate → Isocitrate

• Aconitase

• Isomerization

3. Isocitrate → Alpha-ketoglutarate

• Isocitrate Dehydrogenase

• Oxidative Decarboxylation

4. Alpha-ketoglutarate → Succinyl CoA

• α-Ketoglutarate Dehydrogenase

• Oxidative Decarboxylation

5. Succinyl CoA → Succinate

• Succinate thiokinase; Succinyl-CoA Synthetase

• Hydrolysis & Substrate Level Phosphorylation

6. Succinate → Fumarate

• Succinate Dehydrogenase

• Oxidation Reaction

7. Fumarate → Malate

• Fumarase

• Hydration Reaction

8. Malate → Oxaloacetate

• Malate Dehydrogenase

• Oxidation Reaction

KREBS CYCLE: STEP 1

Step 1

• Acetyl CoA + Oxaloacetate → Citrate/Citric Acid

• Enzyme: Citrate synthase (ligase)

• Reaction: Condensation reaction

• Explanation: Combines a 2-carbon Acetyl CoA with a 4-carbon Oxaloacetate to form 6-carbon Citrate.

KREBS CYCLE: STEP 2

Step 2

• Citrate → Isocitrate

• Enzyme: Aconitase (Isomerase)

• Reaction: Isomerization

• Explanation: Rearranges Citrate into its isomer, Isocitrate, to prepare for oxidation.

KREBS CYCLE: STEP 3

Step 3

• Isocitrate → Alpha-ketoglutarate

• Enzyme: Isocitrate Dehydrogenase (Oxidoreductases)

• Reaction: Oxidative Decarboxylation

• Explanation: Isocitrate is oxidized, releasing CO₂ and forming NADH and Alpha-ketoglutarate; from 6C to 5C

KREBS CYCLE: STEP 4

Step 4

• α-Ketoglutarate → Succinyl CoA

• Enzyme: α-Ketoglutarate Dehydrogenase (Oxidoreductases)

• Reaction: Oxidative Decarboxylation

• Explanation: Another CO₂ is released, and NADH is generated while forming Succinyl CoA; 5C to 4C

KREBS CYCLE: STEP 5

Step 5

• Succinyl CoA → Succinate

• Enzyme:

  • Succinate thiokinase (hydrolase)

• Reaction: Hydrolysis & Substrate Level Phosphorylation

• Hydrolysis

  • Water is added, breaking the high-energy thioester bond between succinyl group and CoA.

  • This releases Succinate and Coenzyme A (CoA-SH) as two separate molecules.

• Substrate Level Phosphorylation

  • The energy released from breaking the Succinyl-CoA bond is used to directly form GTP from GDP + Pi (inorganic phosphate).

  • GTP (guanosine triphosphate) is then quickly converted to ATP

KREBS CYCLE: STEP 6

Step 6

• Succinate → Fumarate

• Enzyme: Succinate Dehydrogenase (Oxidoreductases)

• Reaction: Oxidation Reaction

• Explanation: Succinate is oxidized to Fumarate while FAD is reduced to FADH₂.

KREBS CYCLE: STEP 7

Step 7

• Fumarate → Malate

• Enzyme: Fumarase (Lyase)

• Reaction: Hydration

• Explanation: Water is added across the double bond of fumarate. This breaks the double bond, converting it into a single bond, forming Malate.

• Non hydrolytic bond cleavage

KREBS CYCLE: STEP 8

Step 8

• Malate → Oxaloacetate

• Enzyme: Malate Dehydrogenase (Oxidoreductases)

• Reaction: Oxidation Reaction

• Explanation: Malate is oxidized - loses 2 electrons (2e⁻) and 1 hydrogen ion (H⁺)

• These are accepted by NAD⁺, reducing it to NADH

KREBS CYCLE: PRODUCTS

1 NADH = 2.5 ATP’s

1 FADH₂ = 1.5 ATP’s

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2 Acetyl CoA’s:

• 6 NADH × 2.5 = 15

• 2 FADH₂ × 1.5 = 3

• 2 ATP’s via SLP = 2

• TOTAL: 20 ATP’s

KREBS CYCLE: ENZYMES and REACTION SUMMARY

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Step 1

• Reaction: Acetyl CoA + Oxaloacetate → Citrate

• Enzyme: Citrate synthase (Ligase)

• Reaction: Condensation reaction

Step 2

• Reaction: Citrate → Isocitrate

• Enzyme: Aconitase (Isomerase)

• Reaction: Isomerization

Step 3

• Reaction: Isocitrate → Alpha-ketoglutarate

• Enzyme: Isocitrate Dehydrogenase (Oxidoreductases)

• Reaction: Oxidative Decarboxylation

Step 4

• Reaction: Alpha-ketoglutarate → Succinyl CoA

• Enzyme: α-Ketoglutarate Dehydrogenase (Oxidoreductases)

• Reaction: Oxidative Decarboxylation

Step 5

• Reaction: Succinyl CoA → Succinate

• Enzyme: Succinate thiokinase (hydrolase)

• Reaction: Hydrolysis & Substrate Level Phosphorylation

Step 6

• Reaction: Succinate → Fumarate

• Enzyme: Succinate Dehydrogenase (Oxidoreductases)

• Reaction: Oxidation Reaction

Step 7

• Reaction: Fumarate → Malate

• Enzyme: Fumarase (Lyase)

• Reaction: Hydration

Step 8

• Reaction: Malate → Oxaloacetate

• Enzyme: Malate Dehydrogenase (Oxidoreductases)

• Reaction: Oxidation Reaction

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KREBS CYCLE: STEP 9

Step 9: Additional in some references for krebs (gluconeogenesis step)

• Pyruvate → Oxaloacetate

• Enzyme: Pyruvate Carboxylase (Ligase)

• Reaction: Carboxylation reaction

• Explanation: In gluconeogenesis, pyruvate in the mitochondria is converted to oxaloacetate by adding CO₂.

• From 3C pyruvate to 4C oxaloacetate

• This step requires biotin as a cofactor and ATP as an energy source.

GLUCONEOGENESIS

Glucose + New + Formation

• Formation of new glucose from non-carbohydrate precursors

• Happens in starvation and prolonged fasting

GLUCONEOGENESIS

Precursors:

1. Glycerol from fats

   • Fats are esters of glycerol and 3 fatty acids

2. Glucogenic Amino Acids like alanine

3. Pyruvate or pyruvic acid

4. Lactate or lactic acid

Ketone bodies

When fats breakdown, ketone bodies are produced

1. Acetone

2. Acetoacetic acid

3. B-hydroxy butyric acid - most abundant

They are used by our brain cells and heart cells for energy (KETOSIS)

Glycogen

A branched glucose polymer (polysaccharide) that serves as the body's short-term energy reserve.

Catabolism

Breaks down complex molecules into simpler ones, releasing energy.

• Glycogen to glucose units - glycogenolysis

Anabolism

Uses energy to build complex molecules from simpler ones.

• Glucose to glycogen - Glycogenesis

GLYCOGEN METABOLISM

• GLYCOGENESIS

• GLYCOGENOLYSIS

GLYCOGENESIS

• Generation or formation of glycogen from glucose units (anabolism)

GLYCOGENOLYSIS

• Breakdown of glycogen to form glucose units (catabolism)

• Formation of glucose from glycogen

HORMONES THAT REGULATE GLYCOGEN METABOLISM

• Glucagon

• Insulin

• Epinephrine

True

• Insulin responds to excess glucose by signaling for its storage as glycogen in the liver and muscles, lowering blood sugar.

• Glucagon and epinephrine counter this by promoting glycogenolysis (glycogen breakdown to glucose) to raise blood glucose levels, with epinephrine also initiating fatty acid release to provide alternative fuel.

PENTOSE PHOSPHATE PATHWAY

AKA Hexose Monophosphate Shunt (HMP)

PENTOSE PHOSPHATE PATHWAY

PRODUCTS:

• Hexoses → Pentoses

  • Glucose is converted to ribose, ribulose, xylulose

  • For synthesis of nucleic acid - RNA, and DNA

• NADPH → reduced form of Nicotinamide Adenine Dinucleotide PHOSPHATE

  • Keeps glutathione reduced

  • Important in fatty acid synthesis (CO-ENZYME)

• PENTOSES → ribose

Glutathione

• Must remain in its reduced form (GSH) to neutralize harmful reactive oxygen species (ROS) and prevent cellular damage.

• NADPH from PPP is required to keep glutathione reduced.

Role of G6PD (Glucose-6-Phosphate Dehydrogenase)

• Catalyzes the first committed step: Glucose-6-phosphate → 6-Phosphogluconolactone.

• Produces NADPH from NADP⁺ during this reaction.

Importance of NADPH

• Maintains reduced glutathione for protection against oxidative damage.

• Provides reducing power for biosynthetic reactions (e.g., fatty acid synthesis).

G6PD Deficiency

• Low NADPH production leads to oxidative damage in red blood cells (RBCs).

• Damaged RBCs break down prematurely

  • Hemolytic anemia, surviving less than 120 days.

G6PD Deficiency

CI to these drugs: THESE ARE OXIDANTS so these might worsen the case of people who have G6PD deficiency

1. Sulfonamides like Co-Trimoxazole (SULFAMETHOXAZOLE+ TRIMETHOPRIM)

2. Anti-malarials like Primaquine, Chloroquine

3. Nitrofurans like Nitrofurantoin

4. Quinolones like Nalidixic acid

5. High dose of ASA

6. Naphthalene or moth balls

Transketolase

• Catalyzes transketolation

• Co enzyme: TPP - Thiamine Pyrophosphate (Vit B1) ⭐

Thiamine deficiency

• No TPP produced → decrease in transketolase activity

True

Remember:

• NAD - Vit B3 (Niacin)

• FAD - Vit B2 (Riboflavin)

• Transketolation - Vit B1 (Thiamine)

CARBOHYDRATE METABOLISM DISORDERS

• Ketosis

• Diabetes Mellitus Type I

Ketosis

• Develops when the body is starved with glucose during prolonged fasting or starvation

• Normal, controlled response to low glucose

Blood pH

7.35 to 7.45

• Acidosis - Decrease in pH blood

• Alkalosis - Increase in pH blood

Diabetic ketoacidosis (DKA)

• Common in DM type I

• The body overproduces ketone bodies for energy.

• Excess ketones lower blood pH, leading to metabolic acidosis.

• Fruity-smelling breath (acetone).

• Leads to CNS depression if not treated

Diabetes Mellitus Type I

• Insulin Dependent Diabetes Mellitus / Juvenile-Onset DM

• Beta cells of the pancreas are gone. No insulin is produced.

• This condition is controlled by daily injections of insulin

• Autoimmune

Insulin

Source: Animal (can cause allergic rxn)

1. Porcine Insulin - pig

2. Bovine Insulin - cattle

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Humulin

Eli Lilly manufactures _____, the first commercially available biosynthetic human insulin, which was created using recombinant DNA technology in E. coli bacteria ⭐

• No allergic rxn

Diabetes Mellitus Type 2

• Non-Insulin Diabetes Mellitus / Adult-Onset DM

• A normal amount of insulin is produced, either it is not released fast enough when blood sugar rises or the target tissues have a reduced responsiveness

Diabetes Mellitus Type 2

Oral Hypoglycemic Agents

• Commonly used in Type 2 DM

• Targets insulin resistance

Insulin injection

• Only if there's still high blood sugar level after taking OHAs

Diabetes Insipidus

• A pituitary disorder that directly affects kidney function; no unusual level of glucose in the urine is observed

• Absence of antidiuretic hormone or vasopressin

• Can excrete up to 20L/day

Desmopressin

• Drug used to manage Diabetes Insipidus