Chapter 18: Metabolic Pathways and ATP Production

Key Concepts:
- Bonding of phosphate in nucleotides
- Hydrolysis of disaccharides, esters, and amides
- Redox reactions of organic molecules

Describe how ATP stores and releases energy for metabolism.
Identify the digestion products of carbohydrates, triacylglycerols, and proteins.
Describe the functions of coenzymes NAD$^+$, FAD, and CoA.
Describe broadly the conversion of glucose to pyruvate in glycolysis.
Contrast how pyruvate is consumed under aerobic and anaerobic conditions.
Identify the stages of glycolysis that absorb and release energy.

Metabolism: A set of chemical reactions that provide energy and nutrients necessary for cell growth. These reactions are tightly regulated to maintain homeostasis and respond to cellular needs.
Catabolism:
- Definition: Breaking down complex molecules to release energy stored as ATP.
- Three-stage process: Includes hydrolysis of macromolecules, glycolysis, and aerobic/anaerobic respiration.
Anabolism:
- Definition: Building up complex molecules using smaller molecules and energy input in the form of ATP.
Adenosine Triphosphate (ATP):
- Main energy currency in cells, which stores energy and releases it through hydrolysis. The energy is primarily stored in the high-energy phosphate bonds between the second and third phosphate groups.
- Hydrolysis reaction: \text{ATP} + \text{H}2\text{O} \rightarrow \text{ADP} + \text{P}i + \text{energy}

Energy in ATP:
- ATP can release energy upon hydrolysis between the second and third phosphate groups:
- Energy released: -7.3 \text{ kcal/mole} \; (31 \text{ kJ/mole})
- Used in catabolic reactions (energy-releasing).
Energy Usage:
- Anabolic reactions require energy (energy stored in ATP): Hydrolysis used to convert ADP back into ATP.

Carbohydrates:
- Hydrolyzed to form monosaccharides such as glucose, galactose, and fructose.
- Initiated by enzymes like amylase (mouth, small intestine) and completed by disaccharidases (intestinal lining).
- Monosaccharides are transported to the liver for conversion into glucose.
Lipids:
- Partially hydrolyzed into lipoproteins.
- Digestion primarily by lipases in the small intestine, forming monoglycerides and free fatty acids, which are then re-esterified into triacylglycerols and packaged into chylomicrons (a type of lipoprotein).
- Lipoproteins are then hydrolyzed into glycerol and fatty acids at the cellular level.
Proteins:
- Denatured and partially hydrolyzed into polypeptides.
- Begins with pepsin in the stomach and continues with proteases (e.g., trypsin, chymotrypsin) in the small intestine, ultimately producing individual amino acids or small peptides.
- Polypeptides further hydrolyzed into amino acids.

Oxidation: Loss of hydrogen atoms (or loss of electrons)
Reduction: Gain of hydrogen atoms (or gain of electrons)
Coenzymes: Organic molecules that assist enzymes, frequently by transporting H$^+$ and e$^-$ in redox reactions.

NAD$^+$ (Nicotinamide Adenine Dinucleotide):
- Role: Involvement in making C=O double bonds.
- Oxidized form: NAD$^+$
- Reduced form: NADH
- Reaction: \text{NAD}^+ + 2\text{H}^+ + 2\text{e}^- \rightarrow \text{NADH} + \text{H}^+
FAD (Flavin Adenine Dinucleotide):
- Role: Involvement in constructing C=C double bonds.
- Oxidized form: FAD
- Reduced form: FADH$_2$
- Reaction: \text{FAD} + 2\text{H}^+ + 2\text{e}^- \rightarrow \text{FADH}_2
CoA (Coenzyme A):
- Role: Prepares acyl groups for reactions with enzymes.
- Involved in the synthesis of acetyl CoA from fatty acids.

Definition: The breakdown of glucose in the cytosol to produce energy (ATP).
Glycolysis is divided into two phases:
- Energy-investment phase (Steps 1-5): Glucose is phosphorylated twice and then cleaved into two 3-carbon molecules of glyceraldehyde-3-phosphate (G3P), consuming 2 ATP molecules.
- Energy-payoff phase (Steps 6-10): The two G3P molecules are converted to pyruvate, generating 4 ATP (via substrate-level phosphorylation) and 2 NADH molecules.
Net Gain: 4 ATP produced - 2 ATP consumed = 2 ATP net gain.
Overall reaction:
\text{Glucose} \rightarrow 2\text{Pyruvate} + 4\text{ATP} + 2\text{NADH}

Aerobic Conditions:
- Pyruvate is oxidized in the mitochondria to produce CO$_2$ and acetyl-CoA.
- This conversion, catalyzed by the pyruvate dehydrogenase complex, links glycolysis to the citric acid cycle by forming acetyl-CoA.
Anaerobic Conditions:
- Pyruvate is reduced in the cytosol to produce lactate or ethanol.
- This reduction regenerates NAD$^+$ from NADH, allowing glycolysis to continue producing ATP in the absence of oxygen.

Maximal oxidation yields maximal energy output.
Also known as the Krebs cycle, it is a central metabolic pathway located in the mitochondrial matrix. It processes acetyl-CoA, producing ATP (or GTP), NADH, and FADH$_2$ through a series of redox reactions and decarboxylations.
Breakdown of acetyl-CoA into CO$_2$ releases energy:
- Steps 1-4: Incorporate acetyl-CoA and release 2 molecules of CO$_2$ via enzyme-catalyzed reactions.
Overall reaction for Citric Acid Cycle:
\text{Acetyl-CoA} + 3\text{NAD}^+ + \text{FAD} + \text{GDP} + \text{P}i + 2\text{H}2\text{O} \rightarrow \text{HS-CoA} + 3\text{NADH} + 3\text{H}^+ + \text{FADH}2 + \text{GTP} + 2\text{CO}2

Energy Production from Glucose:
- Glycolysis, oxidation of pyruvate, and the citric acid cycle yield:
- 10 NADH
- 2 FADH$_2$
Electron Transport:
- Transfer of H$^+$ and e$^-$ from NADH and FADH$_2$ to produce water.
- Reactions:
- \text{NADH} + \text{H}^+ \rightarrow \text{NAD}^+ + 2\text{H}^+ + 2\text{e}^-
- \text{FADH}_2 \rightarrow \text{FAD} + 2\text{H}^+ + 2\text{e}^-
- 4\text{H}^+ + 4\text{e}^- + \text{O}2 \rightarrow 2\text{H}2\text{O} + \text{energy}
Oxidative Phosphorylation:
- The synthesis of ATP from electron transport energy:
- This process involves the electron transport chain (ETC), where electrons from NADH and FADH$_2$ are passed through a series of protein complexes. The energy released drives the pumping of H$^{+}$ ions from the mitochondrial matrix into the intermembrane space, creating a proton gradient (proton motive force). ATP synthase then uses the energy from this gradient (chemiosmosis) to produce ATP.
- Reaction:
  \text{ADP} + \text{P}_i + \text{energy} \rightarrow \text{ATP}
- Oxidation outputs:
- NADH oxidation: \sim 2.5 \text{ ATP}
- FADH$_2$ oxidation: \sim 1.5 \text{ ATP}
- Total: Complete oxidation of one glucose yields \sim 32 \text{ ATP}

Fatty Acids:
- Oxidation via Beta Oxidation yielding acetyl-CoA.
- Steps include:
  - Step 1: Energy input to form fatty acyl-CoA, transport to mitochondria.
  - Step 2: Repeated cleavage of 2-carbon units to form acetyl-CoA.
Amino Acids:
- Undergo Transamination and Oxidative Deamination in the liver.
- By-products (e.g., pyruvate & NADH) feed into the citric acid cycle. The carbon skeletons of amino acids can be converted into intermediates of glycolysis or the citric acid cycle, or into acetyl-CoA.
- Ammonium is detoxified via urea formation.