3- Carbohydrate Metabolism: Oxidative Phosphorylation, Gluconeogenesis, Glycogen Metabolism & Pentose Phosphate Pathway

Final stage of cellular respiration.
OXPHOS = Electron Transport Chain (ETC) + ATP synthesis
Occurs continuously in tissues with mitochondria.
Produces the majority of ATP.
Full oxidation of energy-rich molecules (glucose, fatty acids) into ATP, $CO2$ , and $H2O$ .
- Glucose → Aerobic glycolysis.
- Fatty acids → Beta-oxidation.

Passes electrons from NADH and FADH2 to protein complexes and mobile electron carriers (CoQ and cytochrome C).
Inhibitors of these protein complexes are lethal.
Electrons combine with $O2$ and $H^+$ to form $H2O$ (metabolic water).
Major consumer of oxygen in mammalian cells.
4 transmembrane enzymatic complexes + 2 mobile electron carriers (CoQ, cytochrome C).
ETC is a mitochondrial proton ( $H^+$ ) pump.
Electron-transporting groups contain iron, sulfur, copper (all proteins except CoQ).
Electrons transferred from electron donor to electron receptor.
- Oxidation → electrons removed.
- Reduction → electrons gained.

ETC pumps $H^+$ from the matrix across the inner mitochondrial membrane at complexes I, III, and IV, creating an electrochemical gradient.
ATP synthase is a multi-subunit enzyme.
$H^+$ flow through the proton channel, rotating the enzyme, which allows ATP synthesis from ADP and Pi (phosphorylation of ADP to ATP).

Inhibitors block the ETC at various sites:
- Complex I → barbiturate, insecticide (rotenone).
- Complex II → malonate, carboxin and TTFA (an Fe-chelating agent).
- Complex III → dimercaprol, antimycin.
- Complex IV → hydrogen sulfide ( $H_2S$ ), carbon monoxide (CO), and cyanide.
Uncouplers dissociate oxidation (ETC) from phosphorylation (ATP synthase).
- NADH and FADH2 are oxidized, producing heat without ATP generation.
- Useful for generating heat during hibernation, postnatal period, and in cold-adapted animals.

Depending on the cell type you will see GTP instead of ATP
NADH ➔ 3 ATP
FADH2 ➔ 2 ATP
1 GTP = 1 ATP
Full oxidation of glucose → from glycolysis to oxidative phosphorylation (Oxphos)

Glycogenesis: glucose stored as glycogen when blood glucose is high.
- Main stores: liver (up to 10% of liver weight) and skeletal muscle (up to 1% of muscle weight).
Glycogenolysis: glycogen mobilized from glycogen stores when blood glucose is low (fasting, exercise).
- Muscle glycogenolysis provides glucose for itself.
- Liver glycogenolysis provides glucose for the body.
Glycogen: Large, branched polysaccharide made of α-glucose units.

Glycogen is a polysaccharide made exclusively of α-D-glucose.
Glycogen synthesis occurs in the cell cytosol; each molecule contains around 60,000 glucose residues and is highly hydrophilic.

Insulin (anabolic):
- Stimulates glycogenesis.
- Inhibits glycogenolysis.
Glucagon (and epinephrine) (catabolic):
- Stimulates glycogenolysis.
- Inhibits glycogenesis.

Production of glucose from non-sugar molecules.
- Supplies plasma glucose between meals.
- During prolonged fasting, when hepatic glycogen stores are depleted (~24h).
- Continual process in strict carnivores (cats) and ruminants.
- Hormone controlled: stimulated by glucagon and epinephrine, inhibited by insulin.
Substrates:
- Lactate.
- Pyruvate.
- Glycerol from TAG (triacylglycerol = glycerol + 3 fatty acids).
- Glucogenic amino acids.

Lactate  pyruvate.
Glycerol  glycerol phosphate/3-phosphoglycerate.
Glucogenic amino acids  TCA cycle  Oxaloacetate (OAA).
- Alanine, Arginine, Asparagine, Aspartate, Cysteine, Glutamate, Glutamine, Glycine, Proline, Serine, Histidine, Methionine, Threonine, Valine.

Lactate produced by anaerobic glycolysis (exercising muscle, cells without mitochondria, i.e., RBC) is transported to the liver and converted to glucose (gluconeogenesis).
- Prevents lactic acidosis during anaerobic conditions in the muscle.
- Important source of substrate for gluconeogenesis.
- Helps maintain blood glucose levels and provides an alternative energy source during increased metabolic demand.

Must maintain plasma glucose homeostasis for the brain.
1. Liver glycogen becomes glucose.
2. Adipose lipids become free fatty acids and glycerol that enter the blood.
3. Muscle glycogen can be used for energy. Muscles also use fatty acids and break down their proteins to amino acids that enter the blood.
4. Brain can use only glucose and ketones for energy.

Synonyms: hexose pathway, hexose monophosphate shunt (HMS).
An alternate cytoplasmic route for the metabolism of Glucose 6-phosphate (first step of glycolysis).
Two main functions:
1. Generation of NADPH for reductive biosynthesis of lipids (fatty acids, cholesterol, steroids).
2. Provision of ribose residues for nucleotide and nucleic acid biosynthesis (ATP, $NAD^+$ , FAD, RNA, and DNA).

Occurs in the cell cytosol; no ATP is consumed or generated.
High activity in:
- Liver and adipose tissue: biosynthesis of fatty acids from acetyl-CoA.
- Endocrine tissues: synthesis of cholesterol and steroid hormones.
- Lactating mammary gland: production of milk fats and proteins.
- Mature erythrocyte, lens, and cornea: glutathione production (oxidative damage protection).

An important source of electrons (reducing/oxidizing agent) contributing to cellular redox homeostasis.
Reducing cytochrome P450 (drug metabolism in liver).
Synthesis of Nitric Oxide (NO).
Lipogenesis: Synthesis of steroids and fatty acids.
Respiratory burst in phagocytic cells (NADPH-oxidase).
- relaxes smooth muscle, neurotransmitter, bactericidal activity

Phagocytosis: receptor-mediated ingestion (via endocytosis) of microorganisms, foreign particles, and cell debris (i.e., WBC neutrophils).
- Important cell defense mechanism.
NADPH is involved in the production of Oxygen-containing reactive species (ROS) such as $H2O2$ .
Occurs inside special lysosomes (phagolysosome) → NADPH activates enzymes that produce ROS → destroy microorganisms.