Human Metabolism Essentials: Pathways & Disorders

Posted on Aug 10, 2025 in Biochemistry

Carbohydrate Metabolism Fundamentals

Glycolysis: Key Outputs

  • Products: 2 Pyruvate, 2 ATP, 2 NADH

Carbohydrate Classification

  • Monosaccharides: Glucose, Fructose, Galactose
  • Disaccharides:
    • Lactose (Glucose + Galactose)
    • Sucrose (Glucose + Fructose)
  • Polysaccharides: Glycogen, Starch

Glycosylation vs. Glycation

  • Glycosylation: Enzymes add carbohydrates to proteins.
  • Glycation: Non-enzymatic attachment of glucose to proteins (e.g., HbA1c = glycated hemoglobin).

Blood Glucose Regulation

  • Low Blood Glucose: Glucagon activates cAMP, cAMP activates PKA, PKA phosphorylates Pyruvate Kinase (PK).
  • Insulin: Released in response to high blood glucose.
  • Glucagon: Released in response to low blood glucose.

Pyruvate Kinase Deficiency

  • Red Blood Cells (RBCs) become hypotonic because potassium (K+) leaves the cell.
  • High 2,3-Bisphosphoglycerate (BPG) leads to low hemoglobin affinity for oxygen.
  • Low ATP levels.

TCA Cycle in Carbohydrate Metabolism

  • Overall: Acetyl-CoA (AcCoA) is oxidized to 2 CO2 + 2 H2O, producing NADH, FADH2, and GTP.
  • First Step: Acetyl-CoA + Oxaloacetate → Citrate.

Anaerobic Glycolysis

  • Produces Lactate and NAD+.
  • Pyruvate is converted to Lactate via Lactate Dehydrogenase.
  • Yields only 2 ATP (compared to ~36 ATP in aerobic respiration).

Pyruvate Dehydrogenase Complex

  • Converts Pyruvate to Acetyl-CoA and CO2 (an irreversible, one-way reaction).

Enzyme Actions: Kinases & Phosphatases

  • Kinases: Transfer phosphate groups to hydroxyl (-OH) groups.
  • Phosphatases: Remove phosphate groups.

Hexokinase vs. Glucokinase

  • Hexokinase: Binds glucose tightly, has low Km and Vmax, found in all tissues, active at low glucose levels.
  • Glucokinase: (Implied contrast) Higher Km and Vmax, primarily in liver and pancreatic beta cells, active at high glucose levels.

Gluconeogenesis: Glucose Synthesis

The process of synthesizing glucose from non-carbohydrate precursors, bypassing irreversible glycolytic steps:

  1. Pyruvate → Phosphoenolpyruvate (PEP) via Pyruvate Carboxylase.
  2. Fructose-1,6-bisphosphate → Fructose-6-phosphate via Fructose-1,6-bisphosphatase.
  3. Glucose-6-phosphate → Glucose via Glucose-6-phosphatase.

Pentose Phosphate Pathway (PPP)

  • Produces Ribose-5-phosphate (for nucleotide synthesis) and NADPH.
  • NADPH is used in anabolic reactions; NADP+ is involved in catabolic reactions.

Reactive Oxygen Species (ROS)

Four common ROS:

  • Superoxide
  • Hydroxyl radical
  • Hydrogen Peroxide: Reduced by the antioxidant Glutathione.
  • Nitric Oxide: NADPH-dependent enzymes contribute to its synthesis.

Cytochrome P450 System

  • Neutralizes toxins in xenobiotics (foreign compounds).

Glycolytic Pathway Entry for Other Sugars

  • Galactose: Enters as Galactose-1-phosphate.
  • Fructose: Enters directly as Fructose-6-phosphate OR Fructose-1-phosphate splits into Glyceraldehyde + Dihydroxyacetone Phosphate (DHAP).

Sorbitol Pathway

  • Glucose —(Aldose Reductase)—→ Sorbitol.
  • Hyperglycemia (high blood glucose) leads to increased sorbitol levels.

Mitochondrial Functions

The Mitochondria are central to many metabolic processes:

  • Acetyl-CoA production
  • TCA Cycle (Krebs Cycle)
  • Electron Transport Chain (ETC)
  • ATP Synthesis (via F1/F0 ATPase)
  • Fatty Acid Breakdown (β-oxidation)
  • Urea Cycle (partially)

Mitochondrial DNA

  • Contains approximately 16,000 base pairs.
  • Encodes 37 genes for protein synthesis and components of the Electron Transport System (respiration).

Redox States of Coenzymes

  • NADH & FADH2: Reduced forms (electron-rich).
  • NAD+ & FAD: Oxidized forms (electron-poor).

Gibbs Free Energy (ΔG)

  • Represents energy available for work.
  • Negative ΔG (-G): Indicates an energetically favorable (spontaneous) reaction where the final state has lower free energy than the starting state.

Substrate Shuttles

  • Move electrons across the mitochondrial membrane when reduced cofactors (like NADH) cannot pass directly.
  • Example: Dihydroxyacetone Phosphate (DHAP) / Glycerol-3-Phosphate (G3P) shuttle transfers electrons from cytosolic NADH to mitochondrial FAD.

Metabolic Deficiencies & Mutations

  • Glucose-6-Phosphatase Deficiency: Leads to Von Gierke disease, characterized by glycogen buildup.
  • Inherited Adenosine Deaminase (ADA) Deficiency: Causes Severe Combined Immunodeficiency (SCID).

Fatty Acid Metabolism & Glycogen Storage

  • Glycogen: Primary glucose storage in animals.
  • UDP-Glucose: A glucose carrier molecule for glycogen synthesis.
  • Glycogen Bonds: Linear chains have alpha-1,4 glycosidic bonds; Branches have alpha-1,6 glycosidic bonds.

Glycogen Synthesis & Breakdown

  • Adding Glucose to Glycogen:
    1. Glycogenin initiates the chain.
    2. Glycogen Synthase extends the chain.
  • Removing Glucose from Glycogen: Glycogen Phosphorylase.

Glycoprotein Linkages

  • O-linked Glycoprotein Amino Acid: Serine (or Threonine).

Glycogenolysis Regulation

  • Protein Kinase A (PKA) activates Phosphorylase Kinase, which in turn activates Glycogen Phosphorylase, leading to glycogen breakdown.

Fatty Acid Synthesis

  • First Step: Acetyl-CoA + CO2 → Malonyl-CoA (a 2-carbon unit addition).

Beta-Oxidation of Fatty Acids

  • Occurs in the mitochondria.
  • Results in Acetyl-CoA, NADH, and FADH2.

Ketone Bodies

Three ketone bodies produced during fatty acid breakdown:

  • Acetone
  • Acetoacetate
  • 3-Hydroxybutyrate

Glycosaminoglycans (GAGs)

Two examples of GAGs:

  • Hyaluronic Acid
  • Chondroitin Sulfate

Hormonal Regulation & Metabolic Disorders

Insulin & Beta Cells

  • Insulin Hexamers: Stored in storage granules within pancreatic beta cells.
  • Released from beta cells when blood glucose levels are high.
  • High glucose levels lead to glucose entry into beta cells via low-affinity GLUT2 transporters.

Hypoglycemia Response

  • Rise in Human Growth Hormone (mobilizes fatty acids for energy).
  • Rise in Cortisol (raises blood glucose).

Adipokines: Appetite Control

Mediators that control appetite:

  • Leptin: Satiety/fullness hormone.
  • Ghrelin: Hunger hormone.

High BMI & Lipid Profile

  • Associated with high cholesterol, high Triglycerides (TAGs), and decreased HDL (High-Density Lipoprotein).

Ethanol Metabolism & Glucose

  • Ethanol metabolism in the liver produces NADH.
  • This shifts Pyruvate to Lactate and Oxaloacetate to Malate.
  • Results in reduced liver capacity to produce glucose (gluconeogenesis).

Type 1 Diabetes Management

  • Glucagon is administered to Type 1 Diabetics after insulin to prevent hypoglycemia.
  • Glucagon stimulates the breakdown of glycogen into glucose.

Nitrogen & Protein Metabolism

Protein Turnover

  • Approximately 400 grams of protein are turned over per day.

Proteasome System

  • The proteasome is a cellular machinery responsible for degrading ubiquitinated proteins (cellular garbage disposal for proteins).

Nitrogenous Waste Products

  • Aquatic Organisms: Ammonia (highly toxic, requires much water).
  • Mammals/Amphibians: Urea (less toxic, water-soluble).
  • Birds/Insects/Reptiles: Uric Acid (least toxic, insoluble, conserves water).

Factors Influencing Nitrogen Waste

  • Water availability
  • Waste toxicity
  • Metabolic cost of synthesis

Nucleotide Synthesis Example

  • UMP (Uridine Monophosphate) is a precursor for UTP (Uridine Triphosphate) and CTP (Cytidine Triphosphate).

Lysosomal Targeting

  • Mannose-6-Phosphate is a signal for proteins destined for lysosomes.

Feedback Inhibition Example

  • ALAS1 (Aminolevulinate Synthase 1) is inhibited by Heme.

Transaminase (Aminotransferase) Enzymes

  • Catalyze the transfer of an amino group from an amino acid to a keto acid, forming a new amino acid and a new keto acid.
  • Vitamin B6 (Pyridoxal Phosphate) is a key cofactor.
  • Examples: Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) are involved in amino acid interconversion.

Glutamate Dehydrogenase Enzyme

  • Can remove or add ammonia as an amino group to/from glutamate.
  • NAD+ is typically involved in catabolic reactions; NADH in anabolic reactions.

Urea Cycle

  • Converts two nitrogen atoms into urea, which is excreted in urine.
  • Occurs in both mitochondria and cytoplasm.
  • Initiated by the enzyme Carbamoyl Phosphate Synthetase I.

Nitrogen Flow in Metabolism

  • Alpha-ketoglutarate —(transaminases transfer amino groups)—→ Glutamate —→ Glutamine.

Blood Urea Nitrogen (BUN) Levels

  • High BUN: May indicate kidney disease or heart disease (e.g., high blood pressure can affect urea reabsorption).
  • Low BUN: May indicate liver disease.

Ammonia Scavenging

  • Phenylbutyrate helps clear ammonia from the blood in patients with urea cycle failure.

Gout

  • A condition caused by the accumulation of uric acid crystals.

Ribonucleotide Reductase

  • Converts ribonucleotide diphosphates (e.g., GDP, ADP) to deoxyribonucleoside diphosphates (precursors for DNA synthesis).

Alpha-Keto Acids & Amino Acid Interconversion

  • Alanine → Pyruvate
  • Aspartate → Oxaloacetate
  • Glutamate → Alpha-ketoglutarate

Amino Acid Metabolism Disorders

  • Phenylketonuria (PKU): Due to Phenylalanine Hydroxylase deficiency.
  • Alkaptonuria (Black Urine Disease): Due to Homogentisate 1,2-dioxygenase deficiency.
  • Albinism: Often due to Tyrosinase deficiency.