Makindo Medical Notes

Related Subjects: |Enzymes in Humans |Important Metabolic Pathways |DNA replication |DNA structure in Nucleus |Cell Cycle |Mitosis and Meiosis |Ribosomes |Microtubules |Mitochondria |Endoplasmic Reticulum

Important Metabolic Pathways in Humans

The human body relies on various metabolic pathways to convert nutrients into energy, synthesize essential molecules, and eliminate waste products. Below is a comprehensive and detailed list of the most important metabolic pathways, including key enzymes, substrates, products, cofactors, and regulatory mechanisms.

1. Glycolysis

Description: Glycolysis is the process of breaking down glucose into pyruvate, yielding ATP and NADH. It occurs in the cytoplasm of cells.

• Substrates: Glucose, 2 NAD⁺, 2 ADP, 2 Pi
• Products: 2 Pyruvate, 2 NADH, 2 ATP, 2 H₂O, 2 H⁺
• Key Enzymes:
  • Hexokinase/Glucokinase: Phosphorylates glucose to glucose-6-phosphate (G6P).
  • Phosphofructokinase-1 (PFK-1): Converts fructose-6-phosphate to fructose-1,6-bisphosphate; key regulatory step.
  • Pyruvate Kinase: Converts phosphoenolpyruvate (PEP) to pyruvate.
• Cofactors: Mg²⁺, ATP, ADP, NAD⁺
• Regulation:
  • PFK-1 Activation: Activated by AMP, fructose-2,6-bisphosphate.
  • PFK-1 Inhibition: Inhibited by ATP, citrate.
  • Hexokinase Inhibition: Inhibited by its product G6P (feedback inhibition).

2. Citric Acid Cycle (Krebs Cycle)

Description: The citric acid cycle oxidizes acetyl-CoA to CO₂, generating NADH, FADH₂, and GTP. It occurs in the mitochondrial matrix.

• Substrates: Acetyl-CoA, 3 NAD⁺, FAD, GDP (or ADP), Pi, 2 H₂O
• Products: 2 CO₂, 3 NADH, FADH₂, GTP (or ATP), CoA-SH, 3 H⁺
• Key Enzymes:
  • Citrate Synthase: Combines acetyl-CoA and oxaloacetate to form citrate.
  • Isocitrate Dehydrogenase: Converts isocitrate to α-ketoglutarate; produces NADH and CO₂.
  • α-Ketoglutarate Dehydrogenase Complex: Converts α-ketoglutarate to succinyl-CoA; produces NADH and CO₂.
  • Succinate Dehydrogenase: Converts succinate to fumarate; produces FADH₂.
• Cofactors: NAD⁺, FAD, CoA-SH, Mg²⁺, Mn²⁺
• Regulation:
  • Citrate Synthase Inhibition: Inhibited by ATP, NADH, succinyl-CoA, citrate.
  • Isocitrate Dehydrogenase Activation: Activated by ADP, Ca²⁺.
  • Isocitrate Dehydrogenase Inhibition: Inhibited by ATP, NADH.
  • α-Ketoglutarate Dehydrogenase Activation: Activated by Ca²⁺.
  • α-Ketoglutarate Dehydrogenase Inhibition: Inhibited by succinyl-CoA, NADH.

3. Oxidative Phosphorylation (Electron Transport Chain)

Description: Electrons from NADH and FADH₂ are transferred through a series of protein complexes to oxygen, generating a proton gradient used to produce ATP. Occurs in the inner mitochondrial membrane.

• Substrates: NADH, FADH₂, ADP, Pi, O₂
• Products: NAD⁺, FAD, ATP, H₂O
• Key Enzymes/Complexes:
  • Complex I (NADH: Ubiquinone Oxidoreductase): Transfers electrons from NADH to ubiquinone (CoQ).
  • Complex II (Succinate Dehydrogenase): Transfers electrons from FADH₂ to CoQ.
  • Complex III (Cytochrome bc₁ Complex): Transfers electrons from CoQ to cytochrome c.
  • Complex IV (Cytochrome c Oxidase): Transfers electrons from cytochrome c to oxygen, forming water.
  • ATP Synthase (Complex V): Synthesizes ATP using the proton gradient.
• Cofactors: Iron-sulfur clusters, heme groups, CoQ, cytochromes, Cu²⁺
• Regulation:
  • Primarily regulated by the availability of substrates (ADP, Pi, NADH, FADH₂) and oxygen.
  • Inhibited by high ATP/ADP ratio.

4. Gluconeogenesis

Description: The synthesis of glucose from non-carbohydrate precursors, mainly in the liver and to a lesser extent in the kidneys.

• Substrates: Lactate, glycerol, amino acids (especially alanine), propionate
• Products: Glucose, ADP, GDP, Pi
• Key Enzymes:
  • Pyruvate Carboxylase: Converts pyruvate to oxaloacetate; requires biotin and ATP.
  • Phosphoenolpyruvate Carboxykinase (PEPCK): Converts oxaloacetate to phosphoenolpyruvate; requires GTP.
  • Fructose-1,6-bisphosphatase: Converts fructose-1,6-bisphosphate to fructose-6-phosphate.
  • Glucose-6-phosphatase: Converts glucose-6-phosphate to glucose; only present in liver and kidneys.
• Cofactors: Biotin (for pyruvate carboxylase), ATP, GTP, NADH
• Regulation:
  • Fructose-1,6-bisphosphatase Activation: Activated by ATP, inhibited by AMP, fructose-2,6-bisphosphate.
  • Pyruvate Carboxylase Activation: Activated by acetyl-CoA.
  • Regulated reciprocally with glycolysis to prevent futile cycles.

5. Glycogen Metabolism

Description: Glycogenesis is the synthesis of glycogen from glucose; glycogenolysis is the breakdown of glycogen to glucose-1-phosphate.

• Substrates:
  • Glycogenesis: Glucose-6-phosphate, ATP, UTP
  • Glycogenolysis: Glycogen
• Products:
  • Glycogenesis: Glycogen, ADP, UDP
  • Glycogenolysis: Glucose-1-phosphate, glucose (from debranching)
• Key Enzymes:
  • Glycogen Synthase: Adds glucose units to glycogen chain; key enzyme in glycogenesis.
  • Branching Enzyme: Creates α(1→6) linkages for branching.
  • Glycogen Phosphorylase: Removes glucose units from glycogen; key enzyme in glycogenolysis.
  • Debranching Enzyme: Removes branches to allow glycogen phosphorylase to continue.
• Cofactors: Pyridoxal phosphate (for glycogen phosphorylase)
• Regulation:
  • Glycogen Synthase Activation: Activated by insulin, glucose-6-phosphate.
  • Glycogen Phosphorylase Activation: Activated by glucagon (liver), epinephrine (muscle), AMP (muscle).
  • Regulated by phosphorylation: Glycogen synthase is inactivated by phosphorylation; glycogen phosphorylase is activated by phosphorylation.

6. Fatty Acid β-Oxidation

Description: The breakdown of fatty acids to acetyl-CoA units, which enter the citric acid cycle. Occurs in the mitochondrial matrix.

• Substrates: Fatty acyl-CoA, NAD⁺, FAD
• Products: Acetyl-CoA, NADH, FADH₂
• Key Enzymes:
  • Carnitine Palmitoyltransferase I (CPT I): Transfers fatty acyl groups to carnitine for transport into mitochondria.
  • Acyl-CoA Dehydrogenase: Catalyzes the first step in β-oxidation; produces FADH₂.
  • Enoyl-CoA Hydratase: Hydrates the double bond to form hydroxyacyl-CoA.
  • Hydroxyacyl-CoA Dehydrogenase: Oxidizes hydroxyacyl-CoA to ketoacyl-CoA; produces NADH.
  • Thiolase: Cleaves ketoacyl-CoA to acetyl-CoA and a shortened acyl-CoA.
• Cofactors: NAD⁺, FAD, CoA-SH, carnitine
• Regulation:
  • CPT I Inhibition: Inhibited by malonyl-CoA (prevents simultaneous fatty acid synthesis and degradation).
  • Regulated by the availability of free fatty acids and energy demands.

7. Fatty Acid Synthesis

Description: The synthesis of fatty acids from acetyl-CoA, primarily occurs in the cytoplasm of liver and adipose tissue cells.

• Substrates: Acetyl-CoA, malonyl-CoA, NADPH, ATP
• Products: Palmitate (C16 fatty acid), NADP⁺, ADP, Pi, CO₂
• Key Enzymes:
  • Acetyl-CoA Carboxylase (ACC): Converts acetyl-CoA to malonyl-CoA; rate-limiting step.
  • Fatty Acid Synthase Complex: Multi-enzyme complex that elongates fatty acid chain.
• Cofactors: Biotin (for ACC), NADPH
• Regulation:
  • ACC Activation: Activated by citrate (allosteric activator), insulin (induces dephosphorylation).
  • ACC Inhibition: Inhibited by palmitoyl-CoA, glucagon, epinephrine (induce phosphorylation).
  • Regulated by hormonal control and energy status.

8. Pentose Phosphate Pathway (Hexose Monophosphate Shunt)

Description: Provides NADPH for biosynthetic reactions and ribose-5-phosphate for nucleotide synthesis. Occurs in the cytoplasm.

• Substrates: Glucose-6-phosphate, NADP⁺
• Products: NADPH, ribose-5-phosphate, CO₂, glycolytic intermediates
• Key Enzymes:
  • Glucose-6-phosphate Dehydrogenase (G6PD): Converts G6P to 6-phosphogluconolactone; produces NADPH.
  • 6-Phosphogluconate Dehydrogenase: Converts 6-phosphogluconate to ribulose-5-phosphate; produces NADPH and CO₂.
  • Transketolase and Transaldolase: Catalyze reversible reactions to produce glycolytic intermediates.
• Cofactors: NADP⁺, thiamine pyrophosphate (for transketolase)
• Regulation:
  • G6PD Activation: Activated by NADP⁺.
  • G6PD Inhibition: Inhibited by NADPH (feedback inhibition).

9. Urea Cycle

Description: Converts toxic ammonia to urea for excretion. Occurs primarily in the liver, both in mitochondria and cytoplasm.

• Substrates: Ammonia (NH₃), aspartate, CO₂, ATP
• Products: Urea, fumarate, ADP, Pi
• Key Enzymes:
  • Carbamoyl Phosphate Synthetase I (CPS I): Combines NH₃ and CO₂ to form carbamoyl phosphate; rate-limiting step.
  • Ornithine Transcarbamylase: Converts carbamoyl phosphate and ornithine to citrulline.
  • Argininosuccinate Synthetase: Combines citrulline and aspartate to form argininosuccinate.
  • Argininosuccinate Lyase: Converts argininosuccinate to arginine and fumarate.
  • Arginase: Converts arginine to urea and ornithine.
• Cofactors: N-acetylglutamate (activator for CPS I)
• Regulation:
  • CPS I Activation: Activated by N-acetylglutamate, which is synthesized when amino acid levels are high.
  • Overall activity increases during high protein intake or starvation (when protein catabolism increases).

10. Amino Acid Metabolism

Description: Involves transamination, deamination, and conversion of amino acids into other compounds or energy. Occurs in various tissues.

• Substrates: Amino acids, α-ketoglutarate, NAD⁺, FAD
• Products: α-Keto acids, glutamate, NADH, FADH₂, ammonia
• Key Enzymes:
  • Aminotransferases (Transaminases): Transfer amino groups between amino acids and α-keto acids; require pyridoxal phosphate.
  • Glutamate Dehydrogenase: Converts glutamate to α-ketoglutarate and releases NH₃; can use NAD⁺ or NADP⁺.
  • Phenylalanine Hydroxylase: Converts phenylalanine to tyrosine; requires tetrahydrobiopterin.
• Cofactors: Pyridoxal phosphate (vitamin B₆), NAD⁺/NADP⁺, tetrahydrobiopterin
• Regulation:
  • Regulated based on dietary amino acid intake and the body's needs for protein synthesis and energy.
  • Deficiencies or defects in specific enzymes can lead to metabolic disorders (e.g., phenylketonuria).

11. Cholesterol Synthesis

Description: The synthesis of cholesterol from acetyl-CoA, important for membrane structure and precursor of steroid hormones. Occurs in the cytoplasm, mainly in the liver.

• Substrates: Acetyl-CoA, NADPH, ATP
• Products: Cholesterol, NADP⁺, ADP, Pi
• Key Enzymes:
  • HMG-CoA Reductase: Converts HMG-CoA to mevalonate; rate-limiting step.
• Cofactors: NADPH
• Regulation:
  • HMG-CoA Reductase Inhibition: Inhibited by cholesterol (feedback inhibition), statin drugs, glucagon.
  • HMG-CoA Reductase Activation: Activated by insulin.
  • Regulated by gene expression, degradation rate, and phosphorylation state of the enzyme.

12. Nucleotide Metabolism

Description: Synthesis and degradation of purine and pyrimidine nucleotides for DNA, RNA, and energy carriers like ATP. Occurs in the cytoplasm and mitochondria.

• Substrates: Ribose-5-phosphate, amino acids (glycine, glutamine, aspartate), CO₂, ATP
• Products: Nucleotides (AMP, GMP, UMP, CMP), ADP, Pi
• Key Enzymes:
  • Ribonucleotide Reductase: Converts ribonucleotides to deoxyribonucleotides.
  • Thymidylate Synthase: Converts dUMP to dTMP; requires folate derivative.
  • Amidophosphoribosyltransferase: First committed step in purine synthesis.
• Cofactors: Folate derivatives (tetrahydrofolate), NADPH
• Regulation:
  • Feedback inhibition by end products (e.g., ATP, GTP inhibit their own synthesis pathways).
  • Regulated by availability of substrates and energy status.

Conclusion

The above metabolic pathways are central to human physiology, enabling energy production, biosynthesis of essential molecules, and maintenance of homeostasis. A detailed understanding of these pathways, including the enzymes, substrates, cofactors, and regulatory mechanisms involved, is crucial for assessing metabolic functions and diagnosing metabolic disorders.