Enzyme Regulation and Clinical Relevance

Allosteric Regulation: Allosteric enzymes have sites where molecules (effectors) bind. These binding events cause conformational changes in the enzyme, either activating or inhibiting its activity. These enzymes do not follow Michaelis-Menten kinetics.
Covalent Modification: Some enzymes are regulated by reversible covalent modifications, such as phosphorylation or dephosphorylation.
Feedback Inhibition: In some metabolic pathways, the end product of a reaction can inhibit an enzyme earlier in the pathway. This helps to control the flow of metabolites.
Proteolytic Cleavage: Certain enzymes are synthesized as inactive precursors (zymogens) and become activated by cleavage. This process is exemplified by digestive enzymes like trypsin.

Measuring enzyme levels in the blood can be a diagnostic tool for diseases.
Elevated levels of creatine kinase (CK) can indicate muscle damage, including heart attacks.
Enzymes like lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) are used to diagnose liver and tissue damage.

Free Energy (G): Represents the energy available to do work in a system.
ΔG (Change in Free Energy): Determines the spontaneity of a biochemical reaction.
- Exergonic: Reactions with a negative ΔG (ΔG < 0) release energy and are spontaneous.
- Endergonic: Reactions with a positive ΔG (ΔG > 0) require energy input to proceed and are non-spontaneous.

Enthalpy (H): The total heat content of a system.
- Exothermic: Reactions with negative ΔH release heat.
- Endothermic: Reactions with positive ΔH absorb heat.
Entropy (S): The disorder or randomness of a system. Systems naturally tend to move towards higher entropy. An increase in entropy favors the spontaneity of a reaction.

ΔG⁰': The standard free energy change, measured under specific conditions (1 M concentration of reactants/products, pH 7, 25°C, and 1 atm pressure). It provides a reference point for comparing energy changes.
In cells, actual conditions can vary, so the actual free energy change (ΔG) is influenced by reactant and product concentrations.

Adenosine triphosphate (ATP): The primary energy carrier in the cell. It stores energy in its high-energy phosphoanhydride bonds.
Hydrolysis: The breakdown of ATP to ADP (adenosine diphosphate) or AMP (adenosine monophosphate) releases energy, which drives numerous biological reactions. ATP hydrolysis has a large negative ΔG⁰' (-30.5 kJ/mol), making it a potent energy source.
Regeneration: ATP is regenerated through processes like oxidative phosphorylation and glycolysis.

Endergonic reactions can proceed by coupling them to exergonic reactions.
For example, biosynthetic pathways requiring energy are often coupled to ATP hydrolysis to drive them forward.

Oxidation-Reduction (Redox) Reactions: Involve the transfer of electrons.
- Oxidation: Loss of electrons.
- Reduction: Gain of electrons.
- Fundamental to processes like cellular respiration, where electrons are transferred from nutrients to oxygen, producing ATP.
Ligation Reactions: Use ATP to form bonds between molecules.
- Example: Synthesis of oxaloacetate from pyruvate and carbon dioxide requires energy from ATP hydrolysis.
Isomerization Reactions: Involve the rearrangement of atoms within a molecule.
- Example: In glycolysis, glucose-6-phosphate is converted to fructose-6-phosphate.
Group Transfer Reactions: Transfer of a chemical group from one molecule to another.

Digestion and Absorption of Dietary Lipids:
- Mouth: Lingual lipase begins triglyceride digestion.
- Stomach: Gastric lipase continues digestion, but its role is limited.
- Small Intestine: Bile acids emulsify dietary fats. Pancreatic lipase, along with bile salts, hydrolyzes triglycerides into monoglycerides and free fatty acids.
- Absorption:
  - Micelle formation: Digested lipids form micelles with bile salts.
  - Enterocyte uptake: Monoglycerides and free fatty acids are taken up by enterocytes.
  - Chylomicron formation: Triglycerides are packaged into chylomicrons, entering the lymphatic system and eventually the bloodstream.

Chylomicrons: Transport dietary triglycerides and other lipids from the intestine to peripheral tissues.
Lipoprotein Lipase (LPL): Hydrolyzes triglycerides in chylomicrons, releasing free fatty acids and glycerol for uptake by tissues.
VLDL (Very Low-Density Lipoprotein): Transports endogenous triglycerides from the liver to peripheral tissues.
IDL (Intermediate-Density Lipoprotein): Formed from VLDL after triglyceride removal. Can be converted into LDL or taken up by the liver.
LDL (Low-Density Lipoprotein): Transports cholesterol to peripheral tissues. Often referred to as "bad cholesterol" due to its role in atherosclerosis.
LDL Receptors: Peripheral tissues take up LDL through receptor-mediated endocytosis.

Neurotransmitters and Hormones:
- Catecholamines (Dopamine, Norepinephrine, and Epinephrine): Synthesized from tyrosine.
  - Dopamine regulates mood, cognition, and motor control.
  - Norepinephrine functions in attention and arousal.
  - Epinephrine (adrenaline) prepares the body for "fight-or-flight" situations.
- Serotonin and Melatonin: Synthesized from tryptophan.
  - Serotonin is important for mood and sleep regulation.
  - Melatonin regulates the sleep-wake cycle.
- Histamine: Derived from histidine. Crucial mediator of immune responses, gastric acid secretion, and acts as a neurotransmitter.
Creatine: Synthesized from glycine, arginine, and methionine. Essential in muscle tissue, storing and providing energy.
Melanin: Synthesized from tyrosine. Responsible for skin, hair, and eye color. A deficiency in tyrosinase activity leads to albinism.

Glutathione: Major antioxidant that protects cells from reactive oxygen species (ROS). Essential for detoxifying harmful compounds in the liver.
Nitric Oxide (NO): Synthesized from arginine. A signaling molecule involved in vasodilation, neurotransmission, and immune defense.
Heme and Nucleotide Synthesis:
- Heme Synthesis: Vital as an oxygen-carrying molecule in hemoglobin and myoglobin. The pathway starts in the mitochondria and continues partly in the cytoplasm. Disruptions lead to porphyrias.
- Nucleotide Bases: Several amino acids (aspartate, glutamine, glycine) contribute nitrogen and carbon atoms to purine and pyrimidine base synthesis, forming DNA and RNA.

Phenylketonuria (PKU): Deficiency in phenylalanine hydroxylase, leading to phenylalanine buildup and decreased synthesis of tyrosine-derived compounds.
Albinism: Primarily due to tyrosinase deficiency, resulting in an inability to produce melanin.