VM 602 physio (biochem stuff)

Fatty acids

Fatty acids are primarily stored as triglycerides in adipose tissue, where they serve as the main long-term energy reserve.

Fatty acid catabolism

Fatty acid catabolism (β-oxidation) breaks fatty acids into acetyl CoA, which enters the TCA cycle or ketogenesis to generate ATP.

Fatty acid anabolism

Fatty acid anabolism builds new fatty acids from acetyl CoA and stores them as triglycerides, mainly when energy intake exceeds demand.

Bile role in fat absorption

Bile salts emulsify dietary fats into micelles, increasing surface area for pancreatic lipase to digest triglycerides into fatty acids and monoglycerides for absorption.

Insulin and glucagon effects on fat metabolism

High insulin stimulates fat anabolism by promoting triglyceride storage, while high glucagon activates fat catabolism, breaking down triglycerides to release fatty acids.

Insulin in fat storage

Insulin increases glucose uptake and activates lipoprotein lipase, encouraging fatty acid uptake by adipocytes and stimulating triglyceride synthesis for storage.

Lipoprotein lipase

Lipoprotein lipase, located on capillary walls, hydrolyzes triglycerides in chylomicrons and VLDL into free fatty acids, which are taken up by tissues for storage or energy.

Glucagon in fasting state

Glucagon stimulates lipolysis in adipose tissue, activating adipocyte lipase to release fatty acids and glycerol, which are used for energy production and gluconeogenesis.

Adipocyte lipase

Adipocyte lipase is an enzyme inside fat cells that breaks down stored triglycerides into free fatty acids and glycerol during fasting or energy demand.

Lipoprotein lipase vs adipocyte lipase

Lipoprotein lipase helps store fats by breaking down circulating triglycerides for uptake, while adipocyte lipase mobilizes stored triglycerides to release fatty acids during fasting.

Ketogenesis

Ketogenesis is the liver's process of converting acetyl CoA from fatty acid breakdown into ketone bodies, which can be used as an alternative fuel by the brain and muscles during fasting or low carbohydrate intake.

Acetyl CoA in metabolism

Acetyl CoA is a central metabolic intermediate that can enter the TCA cycle for energy, be used in ketogenesis during fasting, or serve as a building block for fatty acid and cholesterol synthesis when energy is abundant.

Essential amino acids

Essential amino acids cannot be synthesized by the body and must be obtained from the diet.

Non-essential amino acids

Non-essential amino acids can be synthesized internally.

Synthesis of non-essential amino acids

Non-essential amino acids are primarily synthesized from intermediates of glycolysis and the TCA cycle, often through transamination reactions.

Transamination

Transamination transfers an amino group from one amino acid to a keto acid, forming a new amino acid.

Deamination

Deamination removes an amino group from an amino acid, releasing ammonia and leaving behind a keto acid.

Glucogenic amino acids

Glucogenic amino acids are catabolized into intermediates that can form glucose.

Ketogenic amino acids

Ketogenic amino acids are broken down into acetyl CoA or acetoacetate, which form ketone bodies.

Final product of amino acid catabolism

The final product is ammonia, which is converted into urea for safe excretion, along with carbon skeletons that can enter energy pathways.

Inter-organ amino acid exchange

Amino acids circulate between tissues: muscle releases alanine and glutamine, the liver uses them for gluconeogenesis and urea synthesis, and the kidney helps excrete nitrogen.

Tissue inter-relationships in fed state

In the fed state, the liver stores glucose as glycogen and converts excess into fat, muscle takes up amino acids and glucose for protein and glycogen synthesis, and adipose stores triglycerides under insulin influence.

Tissue inter-relationships in fasted state

In the fasted state, the liver produces glucose via gluconeogenesis and ketone bodies from fatty acids, muscle releases amino acids for energy, and adipose tissue breaks down fat to supply free fatty acids and glycerol.

Importance of Proteins

Proteins are the most abundant and functionally diverse molecules in living systems.

Common Amino Acids in Mammals

20

Functional Groups of Amino Acids

An amino group (-NHI) and a carboxyl group (-COOH).

Amino Acids in Nature vs. Mammals

Over 300 exist in nature; only 20 are commonly used in mammalian proteins.

Reactivity of α-carboxyl and α-amino Groups

No, because they form peptide bonds.

Determining Protein Folding

The nature of the side chains (R groups).

Bond Linking Amino Acids

Covalent peptide bonds.

Polypeptide Chain Definition

A chain formed by linking multiple amino acids through peptide bonds.

Primary Structure of a Protein

The amino acid sequence of the polypeptide chain.

Determining Amino Acid Sequence

The gene (DNA).

Effect of Change in Amino Acid Sequence

It can affect the protein's structure and function.

Secondary Structure of Proteins

Regular, repeating local folding patterns (α-helices, β-sheets, β-turns).

Amino Acids per Turn in α-Helix

3

Stabilization of α-helices

Hydrogen bonds between carbonyl oxygens and amide hydrogens.

Example of α-helical Protein

Keratin (found in hair).

Stabilization of β-sheets

Hydrogen bonds between polypeptide backbones.

Stability of β-sheets

Antiparallel β-sheet.

Definition of β-turn

A structure that allows a polypeptide chain to change direction and fold.

Tertiary Structure of a Protein

The 3D folding of a single polypeptide chain.

Interactions Stabilizing Tertiary Structure

Hydrogen bonds, ionic interactions, hydrophobic interactions, and disulfide bonds.

Protein Domain Definition

A stable, independently folding unit of a protein with possible distinct functions.

Quaternary Structure of Proteins

The assembly of two or more polypeptide subunits into a multimeric protein.

Example of Quaternary Protein

Hemoglobin (2 α-globin + 2 β-globin subunits).

Difference Between Tertiary and Quaternary Structure

Tertiary involves folding of a single chain; quaternary involves multiple folded chains.

Cause of Sickle Cell Disease

A point mutation in the β-globin gene that produces HbS, leading to RBC sickling.

Deoxygenated HbS in Sickle Cell Disease

It polymerizes, distorting RBCs into sickle shapes.

Symptoms of Sickle Cell Disease

Anemia, pain/swelling, jaundice, vision problems, or developmental delays.

Globular Proteins

Compact, soluble proteins with complex secondary structures; they perform metabolic functions.

Fibrous Proteins

Extended, insoluble proteins with simple secondary structures; they perform structural functions.

Collagen's Structure

Three polypeptide chains arranged as a left-handed helix.

Collagen

High glycine and proline content, with modified amino acids like hydroxyproline.

Vitamin C

Required for collagen synthesis.

Scurvy

Disease resulting from vitamin C deficiency.

Symptoms of scurvy

Weak connective tissue, bleeding gums, bruising, scaly skin, weakness, or fatigue.

Final folded shape of a protein

Determined by its amino acid sequence.

Molecular chaperones

Proteins that assist in correct protein folding.

Molecular chaperones binding

Bind to exposed hydrophobic patches of incompletely folded proteins.

Improperly folded proteins

Targeted for destruction.

Molten globule state

An intermediate state in protein folding.

Misfolded protein aggregates

Cause neurodegenerative diseases in the nervous system.

Alzheimer's disease

Molecular cause is amyloid-β peptide aggregation into plaques.

Huntington's disease

Caused by excessive CAG repeats in the HTT gene, producing toxic huntingtin protein.

Prion diseases

Caused by misfolded prion proteins (PrPII) that induce misfolding in normal prion proteins (PrPI).

Examples of prion diseases

Creutzfeldt-Jakob disease (CJD), mad cow disease, kuru, scrapie, chronic wasting disease.

Structural difference between PrPI and PrPII

PrPI is α-helix rich and protease-sensitive; PrPII is β-sheet rich, protease-resistant, and aggregates.

Stanley B. Prusiner

Discovered prions and won the Nobel Prize in 1997.

Hypoproteinemia

Low blood protein levels from malnutrition, malabsorption, nephrotic syndrome, or hepatic failure.

Hyperproteinemia

High blood protein levels from dehydration, chronic inflammation, viral infections, or blood cancers.

Acute phase proteins (APPs)

Plasma proteins whose levels change by at least 25% during inflammation or cancer.

Examples of positive APPs

CRP, MBP, α1-antitrypsin, SAA, plasminogen, ceruloplasmin, haptoglobin, AGP.

Examples of negative APPs

Albumin, transferrin, transthyretin, transcortin, retinol-binding protein.

Importance of APP measurements

Help in diagnosis and management of inflammatory diseases.

Enzymes

Biological catalysts that speed up chemical reactions in cells.

Most enzymes

Are proteins with tertiary or quaternary structure (except ribozymes).

Ribozymes

RNA molecules that can catalyze reactions by breaking or forming covalent bonds.

Importance of enzymes for life

Nearly all cellular chemical reactions require enzymes to occur fast enough to sustain life.

Keq > 1

The reaction is favorable, ∆G < 0.

Keq < 1

The reaction is unfavorable, ∆G > 0.

Free energy equation for chemical reactions

∆G = -RT ln Keq.

Enzymes and ∆G

Enzymes lower activation energy but do not alter overall ∆G.

Transition state (T*)

A high-energy intermediate between substrate and product.

Enzymes increase reaction speed

By lowering the activation energy required for the reaction.

Lock-and-Key Model

The enzyme active site has a rigid shape that fits one substrate specifically.

Induced Fit Model

Substrate binding causes a conformational change in the enzyme active site.

Substrate Concentration

Reaction velocity increases with substrate concentration until Vmax is reached (enzyme saturation).

Vmax

The maximum velocity of an enzyme-catalyzed reaction when all active sites are saturated.

Km

Michaelis constant; substrate concentration at which reaction velocity is half of Vmax.

Km Reflection

The enzyme's affinity for its substrate (lower Km = higher affinity).

Optimum Temperature

Between 35-40 °C for most human enzymes.

High Temperatures Effect

Enzymes denature and lose activity.

pH Effect on Enzymes

Each enzyme has a specific pH optimum for maximal activity.

Reversible Inhibition

Inhibition that can be reversed when the inhibitor is removed.

Competitive Inhibition

Inhibitor binds to the active site; Vmax unchanged, Km increased.

Competitive Inhibitor Drug

Statins (inhibit cholesterol synthesis).

Noncompetitive Inhibition

Inhibitor binds to a site other than active site; Vmax decreased, Km unchanged.

Noncompetitive Inhibitor Drug

MAO inhibitors.

Uncompetitive Inhibition

Inhibitor binds only to the enzyme-substrate complex; both Vmax and Km decrease.