Metabolic

Carbohydrate Metabolic Pathways

Glycolysis: Glucose breakdown to pyruvate, yielding a bit of ATP and NADH
Gluconeogenesis: Making glucose from non-carb sources when glucose is low
Glycogenesis: Storing excess glucose as glycogen
Glycogenolysis: Breaking down glycogen to release glucose when needed
Pentose Phosphate Pathway: Produces NADPH (for building stuff) and ribose-5-phosphate (for DNA/RNA)

Purpose: The central pathway to break down glucose into pyruvate, generating ATP and NADH in the process
Location: Cytoplasm of all cells
Overview:
- Investment Phase (Energy Requiring):
  - Glucose is phosphorylated twice, consuming 2 ATP
  - Glucose is converted to fructose-1,6-bisphosphate
- Payoff Phase (Energy Releasing):
  - Fructose-1,6-bisphosphate is split into two 3-carbon molecules
  - These molecules are converted to pyruvate, generating 4 ATP and 2 NADH
- Net Yield: 2 ATP, 2 NADH, and 2 pyruvate molecules per glucose molecule
Regulation:
- Key Regulatory Enzymes:
  - Hexokinase/Glucokinase: Inhibited by glucose-6-phosphate (product inhibition). Glucokinase (in the liver) has a higher Km for glucose and is not inhibited by glucose-6-phosphate, allowing the liver to continue taking up glucose even when cellular glucose levels are high
  - Phosphofructokinase-1 (PFK-1): The most important regulatory enzyme
    - Activated by AMP, ADP, and fructose-2,6-bisphosphate
    - Inhibited by ATP and citrate
  - Pyruvate Kinase:
    - Activated by fructose-1,6-bisphosphate (feedforward activation)
    - Inhibited by ATP and alanine
Fate of Pyruvate:
- Aerobic Conditions: Pyruvate is converted to acetyl-CoA, which enters the citric acid cycle
- Anaerobic Conditions: Pyruvate is converted to lactate (lactic acid fermentation) to regenerate NAD+ for glycolysis to continue

Purpose: To synthesize glucose from non-carbohydrate precursors, primarily in the liver and kidneys
Location: Primarily in the liver and kidneys
Overview:
- Reversal of glycolysis with some bypass reactions to overcome irreversible steps
- Precursors: Pyruvate, lactate, glycerol, and glucogenic amino acids
- Key Bypass Reactions:
  - Pyruvate to Phosphoenolpyruvate (PEP):
    - Pyruvate carboxylase converts pyruvate to oxaloacetate (in mitochondria)
    - PEP carboxykinase converts oxaloacetate to PEP (in cytoplasm)
  - Fructose-1,6-bisphosphate to Fructose-6-phosphate:
    - Fructose-1,6-bisphosphatase catalyzes this reaction
  - Glucose-6-phosphate to Glucose:
    - Glucose-6-phosphatase catalyzes this reaction (primarily in the liver and kidneys)
- Energy Cost: Gluconeogenesis is energy-intensive, requiring 6 ATP equivalents per glucose molecule
Regulation:
- Key Regulatory Enzymes:
  - Pyruvate Carboxylase: Activated by acetyl-CoA
  - Fructose-1,6-bisphosphatase:
    - Inhibited by AMP and fructose-2,6-bisphosphate
  - Glucose-6-phosphatase: Regulated by substrate availability (glucose-6-phosphate)
- Hormonal Regulation:
  - Insulin: Inhibits gluconeogenesis
  - Glucagon: Stimulates gluconeogenesis
  - Cortisol: Stimulates gluconeogenesis

Purpose: To synthesize glycogen from glucose for storage, primarily in the liver and muscles
Location: Cytoplasm of liver and muscle cells
Overview:
- Glucose is converted to glucose-6-phosphate
- Glucose-6-phosphate is converted to glucose-1-phosphate
- Glucose-1-phosphate is activated by UTP to form UDP-glucose
- UDP-glucose is added to a growing glycogen chain by glycogen synthase
- Branching enzyme creates α-1,6-glycosidic branches
Regulation:
- Key Regulatory Enzyme:
  - Glycogen Synthase:
    - Activated by glucose-6-phosphate and insulin
    - Inhibited by glucagon and epinephrine (via phosphorylation)

Purpose: To break down glycogen into glucose for energy, primarily in the liver and muscles
Location: Cytoplasm of liver and muscle cells
Overview:
- Glycogen phosphorylase cleaves α-1,4-glycosidic bonds, releasing glucose-1-phosphate
- Debranching enzyme removes α-1,6-glycosidic branches
- Glucose-1-phosphate is converted to glucose-6-phosphate
- In the liver, glucose-6-phosphatase converts glucose-6-phosphate to glucose, which is released into the bloodstream. (Muscle lacks glucose-6-phosphatase, so glucose-6-phosphate enters glycolysis)
Regulation:
- Key Regulatory Enzyme:
  - Glycogen Phosphorylase:
    - Activated by AMP, epinephrine, and glucagon (via phosphorylation)
    - Inhibited by ATP, glucose-6-phosphate, and insulin

Nomenclature: Pentose Phosphate Pathway (PPP) or Hexose Monophosphate Shunt (HMP Shunt)
Purpose:
- Production of NADPH: Important for reducing power in anabolic reactions, detoxification of reactive oxygen species, and synthesis of fatty acids and steroids
- Production of Ribose-5-phosphate: A precursor for nucleotide biosynthesis
Location: Cytoplasm of various cells, particularly those involved in lipid synthesis (e.g., liver, adipose tissue, adrenal cortex)
Overview:
- Oxidative Phase:
  - Glucose-6-phosphate is converted to ribulose-5-phosphate, producing NADPH
  - This phase is irreversible
- Non-Oxidative Phase:
  - Ribulose-5-phosphate is converted to various sugar phosphates (e.g., ribose-5-phosphate, fructose-6-phosphate, glyceraldehyde-3-phosphate)
  - This phase is reversible and allows the pathway to adapt to the cell’s needs
Regulation:
- Key Regulatory Enzyme:
  - Glucose-6-phosphate dehydrogenase (G6PD):
    - Inhibited by NADPH (product inhibition)

Understanding these pathways is crucial because:

Diabetes Mellitus: Disruptions in glucose metabolism are central to the pathophysiology of diabetes
Metabolic Disorders: Genetic defects in enzymes of these pathways can lead to various metabolic disorders (e.g., glycogen storage diseases, G6PD deficiency)
Nutritional Status: These pathways are highly responsive to dietary intake and hormonal signals, reflecting the body’s adaptation to different nutritional states

Glycolysis: The breakdown of glucose to pyruvate, yielding ATP and NADH. It’s the foundation of cellular energy production
Gluconeogenesis: The synthesis of glucose from non-carbohydrate precursors. This is vital for maintaining blood glucose levels during fasting or starvation
Glycogenesis: The process of converting glucose into glycogen for storage in the liver and muscles
Glycogenolysis: The breakdown of glycogen to release glucose, providing a quick source of energy
Insulin: A hormone that promotes glucose uptake, glycogenesis, and glycolysis, effectively lowering blood glucose
Glucagon: A hormone that stimulates glycogenolysis and gluconeogenesis, raising blood glucose levels
ATP (Adenosine Triphosphate): The primary energy currency of the cell. Many of these pathways are geared toward producing or consuming ATP
NADPH (Nicotinamide Adenine Dinucleotide Phosphate): A crucial reducing agent in anabolic reactions, like fatty acid and steroid synthesis. It’s a key product of the pentose phosphate pathway