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Questions and Answers
Which complex of the electron transport chain is responsible for transferring electrons from NADH to coenzyme Q (UQ)?
What is a key difference in the electron transfer process between Complex 1 and Complex 2?
What does Complex 3 transfer electrons from and to during its function?
Which complex does NOT pump protons into the intermembrane space during electron transfer?
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What is the end product of the electron transfer process catalyzed by Complex 4?
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What is the primary function of reactive oxygen species (ROS) generated during the respiratory burst?
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Which enzyme is responsible for converting superoxide radicals into hydrogen peroxide and oxygen?
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Which antioxidant is primarily involved in degrading hydrogen peroxide into water and oxygen?
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What is the role of glutathione peroxidase in the glutathione-centered antioxidant system?
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Which radical is NOT produced during the reaction of O2- with nearby molecules in pathogen destruction?
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What conformation does the 𝛽1 subunit adopt when both ADP and Pi bind to their respective sites?
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Which condition inhibits oxidative phosphorylation in the mitochondrial matrix?
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How does phosphate (H2PO4-) enter the mitochondrial matrix?
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What process is initiated by the interaction of the 𝛶-shaft with 𝛽1?
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Which compound is reduced by NADH in the glycerol-phosphate shuttle?
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What is the primary function of Cyt c in the electron transport chain?
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How many protons are pumped out of the matrix into the intermembrane space during the transfer from Cyt c to O2?
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What role does ATP play in relation to cytochrome oxidase during electron transfer?
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What is the main purpose of the chemiosmotic coupling theory in relation to ATP synthesis?
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What occurs when the inner mitochondrial membrane is disrupted?
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How many protons are required for the synthesis of one molecule of ATP?
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What components make up the F1 unit of ATP synthase?
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Which of the following best describes the role of uncouplers like Dinitrophenol?
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What does the ‘18’ in the fatty acid notation ‘18:2𝜔-6’ represent?
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Which fatty acids are classified as essential fatty acids?
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What is the primary source of 𝜔-3 fatty acids?
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Which type of fatty acids promotes inflammation?
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How are triacylglycerols characterized?
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What process involves the hydrolysis of triacylglycerols to produce soap?
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Which phospholipid is known as lecithin?
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What role do phospholipids play in biological systems?
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What describes the structure of waxes?
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What is the healthy ratio of 𝜔-6 to 𝜔-3 fatty acids believed to influence inflammation?
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Which fatty acid is a precursor for arachidonic acid?
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What kind of emulsifying agent do soaps act as in water?
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Which of the following is a characteristic of saturated fatty acids?
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Which compound is found in the inner leaflet of membranes and also known as cephalin?
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What is the primary role of cardiolipin in the mitochondrial inner membrane?
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Which signaling molecules are derived from phosphatidylinositol-4,5-bisphosphate (PIP2)?
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Which statement accurately describes the function of phospholipases?
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Which of the following is true regarding phosphatidylethanolamine?
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Which type of phospholipase hydrolyzes the bond at C1 of the glycerol backbone?
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What role does cardiolipin play in mitochondria?
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Which of the following statements accurately describes phospholipase enzymatic actions?
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Which type of sphingolipid contains a monosaccharide as its head group?
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How do signaling molecules derived from phosphatidylinositol function in cellular processes?
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Which characteristic is unique to sulfatides among glyolipids?
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What is a primary function of phosphatidylethanolamine in biological membranes?
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What role does cardiolipin play in mitochondria?
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Which of the following signaling molecules can be derived from phosphatidylinositol?
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What is the primary action of phospholipase enzymes?
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Which type of sphingolipid is involved in nerve signal transmission?
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What is the composition of phosphatidylethanolamine?
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Which sphingolipid is known for being a component in the cell membranes of neurons?
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Which of the following is NOT a function of eicosanoids derived from omega-3 fatty acids?
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What characterizes the structure of sphingolipids?
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Which enzyme is involved in the dephosphorylation of phosphatidylinositol?
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Which property do phospholipids possess that makes them essential for cell membrane structures?
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What type of eicosanoids are derived from arachidonic acid?
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Which type of lipid modification occurs in sphingolipids to enhance their function?
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What is a key feature of phosphatidylglycerol within biological systems?
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What compound is formed when sphinganine reacts with a long chain fatty acid?
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What is the role of sphingomyelin in the nervous system?
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Which compound is involved in the degradation of sphingomyelin?
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What type of sugar head group is present in cerebrosides?
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What occurs due to a defective sphingomyelinase?
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What is the primary consequence of macrophages accumulating LDL in the presence of high levels?
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What critical molecule's synthesis may be affected by statin therapy?
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Which organ plays a key role in regulating blood glucose levels?
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Which hormone stimulates appetite and is secreted by the stomach?
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What is the effect of the hormone peptide YY (PYY) secreted by the small intestine?
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Which mechanism is primarily responsible for the hardening and narrowing of heart arteries due to plaque buildup?
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What type of drugs lower blood cholesterol by inhibiting HMG-CoA reductase?
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What can happen as foam cells necrose in the plaques within blood vessels?
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What is the primary role of adipose tissue in the body?
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Which hormone is secreted by adipose tissue to promote satiety?
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During prolonged fasting, which substances primarily provide energy for muscles?
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What triggers insulin release from pancreatic β-cells after a meal?
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What is the main function of glucagon during fasting?
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How does the brain contribute to metabolic processes?
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What is the main effect of insulin on skeletal muscle?
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What efficiently maintains stable internal environments in the body?
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What is a consequence of defective 𝛽-glucosidase enzyme activity?
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Which enzyme is responsible for degrading galactocerebrosides?
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Which of the following is a result of cholesterol accumulation in the body?
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What is the primary site of cholesterol synthesis in the body?
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What role does Insig play in cholesterol homeostasis?
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What is the consequence of low cellular cholesterol levels on HMGR activity?
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Which of the following phases is NOT involved in cholesterol synthesis?
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What regulates the expression of the HMGR gene in response to cholesterol levels?
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What happens to SREBP2 when cholesterol levels are low?
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Which enzyme's activity is inhibited by glucagon and epinephrine via phosphorylation?
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What occurs to the brain's energy source after several weeks of fasting?
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Which hormone is responsible for stimulating food intake?
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What is a primary difference between Type 1 and Type 2 diabetes?
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What effect does leptin have on appetite regulation?
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What is the major symptom related to high blood glucose in diabetes?
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What is the role of the arcuate nucleus (ARC) in the hypothalamus?
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During prolonged fasting, what does the body primarily utilize for gluconeogenesis?
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What triggers frequent urination (polyuria) in diabetes?
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Which treatment option is primarily used for Type 1 diabetes?
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Why are humans increasingly predisposed to obesity in the modern world?
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Study Notes
Electron Transport Chain
- Four complexes are embedded in the inner mitochondrial membrane, facilitating electron transfer: Complex 1, Complex 2, Complex 3, and Complex 4.
- Complex 1 (NADH Dehydrogenase Complex) transfers electrons from NADH to coenzyme Q (UQ), pumping four protons (H+) from the matrix into the intermembrane space.
- Complex 2 (Succinate Dehydrogenase Complex) transfers electrons from FADH2 to UQ, but doesn't pump protons across the membrane.
- Complex 3 (Cytochrome bc1 Complex) transfers electrons from reduced UQ (UQH2) to cytochrome c (Cyt c), pumping four protons from the matrix into the intermembrane space.
- Complex 4 (Cytochrome Reductase) transfers four electrons from four Cyt c to oxygen (O2), forming water (H2O), and pumping another four protons from the matrix into the intermembrane space.
Oxidative Phosphorylation
- Oxidative phosphorylation utilizes the energy released from the electron transport chain for the synthesis of ATP from ADP.
- The electron transport chain pumps protons from the matrix into the intermembrane space, creating a proton motive force.
- The Chemiosmotic Coupling Theory explains how this proton motive force drives ATP formation.
Chemiosmotic Theory
- The movement of protons from the intermembrane space back into the matrix via ATP synthase drives ATP production.
- Evidence for the Chemiosmotic Theory includes:
- A decrease in pH within weakly buffered mitochondria during active respiration.
- Disruption of the inner mitochondrial membrane stops respiration.
- Uncouplers (like Dinitrophenol) collapse the proton gradient by carrying protons across the membrane.
- Ionophores (like Gramicidin A) create channels, allowing protons to pass through and disrupt the proton gradient.
ATP Synthase
- ATP synthase consists of two components: the F1 unit (ATP synthase) and the F0 unit (transmembrane channel).
- The F1 unit:
- Composed of five subunits: 3α, 3β, γ, δ, and ε.
- Subunits α and β form the catalytic core.
- The F0 unit:
- Composed of three subunits: a, 2b, and 12c.
- Creates a channel through the membrane for proton movement.
- The F0 unit converts the proton motive force into rotational force within the central shaft (γ and ε subunits), which powers the ATP synthase.
- The formation of one ATP molecule requires the movement of three protons through ATP synthase.
𝛽-Subunits
- The three β subunits of ATP synthase undergo conformational changes:
- Loose (L) conformation: ADP and Pi bind.
- Tight (T) conformation: ADP and Pi join to form ATP.
- Open (O) conformation: ATP is released into the matrix.
- The γ subunit interacts with the β subunits, triggering these conformational changes.
Transport Across the Mitochondrial Membrane
- ATP is synthesized in the mitochondrial matrix and exits through the ADP-ATP translocator.
- ADP enters the matrix through the same translocator.
- Inorganic phosphate (Pi) is transported into the matrix as H2PO4- via the phosphate translocase, which also transports a proton.
Regulation of Oxidative Phosphorylation
- High levels of ADP and Pi in the matrix activate oxidative phosphorylation.
- High levels of ATP in the matrix inhibit oxidative phosphorylation.
- The ADP-ATP translocator regulates mitochondrial ATP and ADP levels.
- The phosphate translocase regulates the H2PO4- concentration in the matrix.
Glycerol-Phosphate Shuttle
- The Glycerol-Phosphate Shuttle transports cytoplasmic NADH into the mitochondrial matrix.
- Cytoplasmic NADH reduces dihydroxyacetone phosphate (DHAP) to glycerol-3-phosphate.
- Glycerol-3-phosphate diffuses across the outer mitochondrial membrane and reduces FAD to FADH2.
- FADH2 enters the electron transport chain at Complex 2, contributing to ATP synthesis.
Respiratory Burst
- Macrophages and neutrophils produce large amounts of reactive oxygen species (ROS) to destroy pathogens.
- During phagocytosis, NADPH oxidase on phagolysosome membranes converts oxygen (O2) into superoxide (O2-), a reactive oxygen species.
- Superoxide reacts with other molecules to generate hydroxyl radical (OH), hypochlorite (OCl-), peroxynitrite (ONOO-), and nitrogen dioxide (NO2) radicals.
- These reactive species are toxic to pathogens, contributing to their destruction.
Antioxidants
- Living organisms have developed defense mechanisms against oxidative stress:
- Enzyme Systems:
- Superoxide Dismutase (SOD): Converts superoxide to hydrogen peroxide (H2O2) and oxygen (O2).
- Catalase: Degrades hydrogen peroxide to water (H2O) and oxygen (O2).
- Glutathione-centered System: Uses glutathione (GSH) to reduce hydrogen peroxide and organic hydroperoxides, protecting against oxidative damage.
- Thioredoxin-centered System: Functions similarly to the glutathione system for reducing hydrogen peroxide, reducing oxidative stress.
- Molecule Systems:
- Alpha-tocopherol (Vitamin E): Protects against lipid peroxidation.
- Beta-carotene (Vitamin A): Acts as an antioxidant, minimizing free radical damage.
- Ascorbic Acid (Vitamin C): An important antioxidant, scavenging free radicals and promoting immune function.
- Enzyme Systems:
Fatty Acid Nomenclature
- The ω Numbering System is used to describe fatty acid structure:
- The number before the colon indicates the number of carbon atoms in the molecule.
- The number after the colon indicates the number of double bonds.
- The number following the ω indicates the position of the first double bond, counting from the ω- end (methyl terminus) of the fatty acid chain.
Essential and Nonessential Fatty Acids
- Plants and bacteria synthesize all required fatty acids, but animals acquire most from dietary sources.
- Nonessential fatty acids can be synthesized by animals.
- Essential fatty acids cannot be synthesized by animals and must be obtained from the diet:
- Linoleic acid (omega-6 fatty acid): Precursor for many derivatives including arachidonic acid.
- Alpha-linolenic acid (omega-3 fatty acid): Precursor for EPA and DHA.
Omega-6 Fatty Acids
- Linoleic acid (18:2ω-6) is a key precursor for:
- Gamma-linolenic acid (18:3ω-6)
- Arachidonic acid (20:4ω-6)
- Docosapentaenoic acid (22:5ω-6)
- Food sources include: Vegetable oils (sunflower, soybean), eggs, poultry.
Omega-3 Fatty Acids
- Alpha-linolenic acid (18:3ω-3) is a precursor for:
- Eicosapentaenoic Acid (EPA) (20:5ω-3)
- Docosahexaenoic Acid (DHA) (22:6ω-3)
- Sources include:
- Flaxseeds, soybean oils, walnuts
- EPA and DHA are found in fish (salmon, tuna, sardines) and fish oils.
- Health benefits of omega-3 fatty acids:
- Promote cardiovascular health.
- Lower blood triacylglycerol levels.
- Lower blood pressure.
- Decrease platelet aggregation.
Eicosanoids
- Eicosanoids are hormone-like molecules derived from omega-6 and omega-3 fatty acids.
- Types include:
- Prostaglandins
- Thromboxanes
- Leukotrienes
- They regulate:
- Smooth muscle contraction
- Blood flow
- Inflammation
- Pain perception
- Omega-6 derived eicosanoids promote inflammation.
- Omega-3 derived eicosanoids have anti-inflammatory properties.
- The ratio of omega-6 to omega-3 fatty acids in the diet influences the production of inflammatory and anti-inflammatory eicosanoids.
Triacylglycerols
- Triacylglycerols (Triglycerides) are esters of glycerol with three fatty acids.
- They are neutral fats, meaning they have no charge.
- They contain fatty acids of varying lengths and have a mixture of saturated and unsaturated fatty acids.
- Monoacylglycerols and diacylglycerols are intermediates in triacylglycerol metabolism.
Properties of Triacylglycerols
- Triacylglycerols can be fats or oils based on their fatty acid composition:
- Fats are solid at room temperature and have a high proportion of saturated fatty acids.
- Oils are liquid at room temperature and have a high proportion of unsaturated fatty acids.
- Saponification is a process that produces soap:
- Heating oil with KOH or NaOH hydrolyzes triacylglycerols to glycerol and potassium or sodium salts of fatty acids (soap).
- The soap forms micelles in water due to its amphipathic nature.
- Soap acts as an emulsifying agent, dispersing grease and oil droplets in micelles.
Wax Esters
- Waxes are complex mixtures of nonpolar lipids that are essential for protective coatings in plants and animals.
- Waxes contain long-chain fatty acids esterified with long-chain alcohols.
Phospholipids
- Phospholipids are amphipathic molecules with a polar head group (phosphate and charged groups) and hydrophobic fatty acid tails.
- Phospholipids play a vital role in cell membranes, forming ordered structures like monolayers, micelles, and bilayer vesicles.
Types of Phospholipids
- Phospholipids are classified into two categories:
- Phosphoglycerides: Contain glycerol, two fatty acids, a phosphate, and an alcohol.
- Sphingolipids: Contain a sphingosine backbone, a fatty acid, and a phosphate group linked to variable head group.
Phosphoglycerides
- The simplest phosphoglyceride is phosphatidic acid, which contains glycerol-3-phosphate and two fatty acids.
- Phosphatidylcholine (PC) (Lecithin) is a major component of biological membranes, functioning as a surfactant.
- Phosphatidylserine (PS) is a key component of biological membranes and acts as a signal for macrophages to engulf cells.
- Phosphatidylglycerol is present in the lungs and amniotic fluid, playing a crucial role as a surfactant and indicating fetal lung maturity.
Phosphatidylethanolamine and Diphosphatidylglycerol
- Both Phosphatidylethanolamine and Diphosphatidylglycerol have relatively smaller polar head groups and are often found in the inner leaflet of cellular membranes.
- Phosphatidylethanolamine is also called cephalin.
Lipid Classification
- Lipids are a diverse group of naturally occurring molecules that are soluble in organic solvents.
- They are a major component of cell membranes and serve as energy storage.
- Lipid classification is based on their structure and function.
-
Fatty Acids: Amphipathic molecules with a long hydrocarbon chain
- The length of the hydrocarbon chain varies.
- Saturated fatty acids have no double bonds between carbon atoms.
- Unsaturated fatty acids have one or more double bonds.
- The location of double bonds in unsaturated fatty acids is important for their biological activity.
-
𝜔 Number System: Used to describe the position of the first double bond starting from the methyl end of the fatty acid.
- Example: Linoleic acid (18:2𝜔-6) is an 𝜔-6 fatty acid.
- 18 indicates the number of carbons in the fatty acid.
- 2 indicates the number of double bonds.
- 𝜔-6 indicates the position of the first double bond from the 𝜔 carbon.
- Example: Linoleic acid (18:2𝜔-6) is an 𝜔-6 fatty acid.
-
𝜔 Number System: Used to describe the position of the first double bond starting from the methyl end of the fatty acid.
- Fatty acids are important for structure and function within membranes.
-
Triacylglycerols (Triglycerides): Ester of glycerol with three fatty acids.
- Neutral fats, with no charge.
- Contain varying length fatty acids with a mixture of saturated and unsaturated fatty acids.
- Solid (fats) at room temperature (high saturated fatty acid content)
- Liquid (oils) at room temperature (high unsaturated fatty acid content)
-
Saponification: The process that produces soap.
- Hydrolyzes triacylglycerol to glycerol and salts of fatty acids.
- Soap forms micelles in water, acting as an emulsifying agent to help disperse fat droplets.
-
Waxes: Complex, nonpolar mixtures of long-chain fatty acids and long-chain alcohols.
- Found as protective coatings on plants and animals.
-
Phospholipids: Amphipathic molecules with a polar head group (phosphate and charged groups) and nonpolar fatty acid tails.
- Essential for cell membranes, forming lipid monolayers, micelles, and bilayer vesicles.
- Two main types:
-
Phosphoglycerides: contain glycerol, two fatty acids, a phosphate, and an alcohol.
- Important phosphoglycerides:
- Phosphatidylcholine (Lecithin): Major component of biological membranes, a surfactant.
- Phosphatidylserine (PS): Important for biological membranes, signaling for macrophages to engulf cells.
- Phosphatidylglycerol: Present in the lungs and amniotic fluid, functions as a surfactant.
- Phosphatidylethanolamine (Cephalin): Found in the inner leaflet of membranes, stabilizing membrane curvature.
- Diphosphatidylglycerol (Cardiolipin): Found in the mitochondrial inner membrane, helping to stabilize the electron transport chain.
- Phospholipases: Hydrolyse the ester bonds in phosphoglycerides. - PLA1: Hydrolyzes the ester bond at C1 of glycerol. - PLA2: Hydrolyzes the ester bond at C2 of glycerol. - PLB: Hydrolyzes both C1 and C2 ester bonds. - PLC: Hydrolyzes the phosphodiester bond between glycerol and phosphate. - PLD: Hydrolyzes the phosphodiester bond between phosphate and fatty acid (i.e. R3).
- Acyltransferases: Add fatty acids to phosphoglycerides.
- Important phosphoglycerides:
-
Sphingolipids: Contain sphingosine, a fatty acid, and a head group.
- Ceramide: Fatty acid amide derivative of sphingosine, the core for sphingomyelin and glycolipids.
- Sphingomyelin: Involved in nerve cell insulation and rapid nerve impulse transmission.
- Glycolipids: Contain an oligosaccharide attached to ceramide. - Found on the extracellular side of eukaryotic membranes. - Functions: Maintain membrane stability, facilitate cell-cell interactions, and act as receptors for viruses and pathogens. - Important classes of glycolipids: - Cerebrosides - Sulfatides - Gangliosides
-
Phosphoglycerides: contain glycerol, two fatty acids, a phosphate, and an alcohol.
-
Isoprenoids: Contain repeating isoprene units.
- Terpenes: Two isoprene units joining to form monoterpenes (used in perfumes).
- Tetraterpenes (Carotenoids): Four isoprene units joined together, pigments.
- Steroids: Derivatives of triterpenes with four fused rings (e.g., cholesterol).
-
Fatty Acids: Amphipathic molecules with a long hydrocarbon chain
Essential Fatty Acids
- Essential fatty acids (EFAs) are fatty acids that cannot be synthesized by the body and need to be obtained from the diet.
-
Omega-6 Fatty Acids:
-
Linoleic Acid (18:2𝜔-6): Precursor to numerous derivatives, including:
- 𝛶-linolenic acid (18:3𝜔-6)
- Arachidonic acid (20:4𝜔-6)
- Docosapentanenoic (22:5𝜔-6) (DPA)
- Food sources: Vegetable oils (sunflower and soybean), eggs, poultry
-
Linoleic Acid (18:2𝜔-6): Precursor to numerous derivatives, including:
-
Omega-3 Fatty Acids:
-
𝛼-linolenic acid (18:3𝜔-3): Precursor to:
- Eicosapentaenoic Acid (20:5𝜔-3) (EPA)
- Docosahexaenoic Acid (22:6𝜔-3) (DHA)
- Sources: Flaxseeds, soybean oil, walnuts, fish (salmon, tuna, sardines), and fish oils.
- Health Benefits: Enhance cardiovascular health, lower blood triacylglycerol levels, reduce blood pressure, and decrease platelet aggregation.
-
𝛼-linolenic acid (18:3𝜔-3): Precursor to:
-
Eicosanoids: Hormone-like molecules derived from 𝜔-6 and 𝜔-3 fatty acids.
-
Prostaglandins, Thromboxanes, and Leukotrienes: Influence smooth muscle contraction, blood regulation, inflammation, and pain perception.
- 𝜔-6 derived eicosanoids promote inflammation.
- 𝜔-3 derived eicosanoids have an anti-inflammatory effect.
-
Prostaglandins, Thromboxanes, and Leukotrienes: Influence smooth muscle contraction, blood regulation, inflammation, and pain perception.
Sphingolipid Synthesis
- Sphingosine is synthesized from palmitoyl-CoA and serine to form sphinganine.
- Ceramide is formed when sphinganine reacts with a long-chain fatty acid.
- Sphingomyelin is synthesized from ceramide and either phosphatidylcholine or phosphatidylethanolamine.
- Galactocerebroside is formed when ceramide reacts with UDP-galactose.
- Glucocerebroside is formed when ceramide reacts with UDP-glucose.
Sphingomyelin Metabolism
- Sphingomyelin is a phospholipid that insulates nerves and facilitates rapid nerve impulse transmission.
- Sphingomyelinase degrades sphingomyelin.
- Niemann-Pick Syndrome is caused by a deficiency in sphingomyelinase, leading to an accumulation of sphingomyelin.
Cerebroside Metabolism
- Cerebrosides are sphingolipids with a monosaccharide head group.
- Glucocerebroside is found in non-neuronal tissues and is degraded by β-glucosidase.
- Gaucher's disease is caused by a deficiency in β-glucosidase, leading to an accumulation of glucocerebrosides.
- Galactocerebroside is found in brain cell membranes and is degraded by β-galactosidase.
- Krabbe's disease is caused by a deficiency in β-galactosidase, leading to an accumulation of galactocerebrosides.
- Sulfatides are sulfated galactocerebrosides degraded by Arylsulfatase A.
- Alzheimer's and Parkinson's diseases can be linked to the accumulation of sulfatide due to a deficiency in Arylsulfatase A.
Ganglioside Metabolism
- Gangliosides are sphingolipids containing oligosaccharide groups with one or more sialic acid residues.
- GM2 gangliosides are degraded by β-Hexosaminidase.
- Tay-Sachs disease is caused by a deficiency in β-hexosaminidase A, leading to an accumulation of GM2 gangliosides.
Cholesterol Synthesis
- Cholesterol is synthesized from isoprenoids and is a precursor for bile salts and steroid hormones.
- Cholesterol is obtained from the diet and synthesized de novo.
- Most cholesterol synthesis takes place in the liver.
- Dietary cholesterol inhibits cholesterol synthesis and LDL receptor synthesis.
- Insufficient dietary cholesterol intake stimulates LDL receptor and HMG-CoA reductase (HMGR) synthesis.
Cholesterol Synthesis Phases
- Phase 1: Acetyl-CoA is converted to HMG-CoA.
- Phase 2: HMG-CoA is converted to squalene.
- Phase 3: Squalene is converted to cholesterol.
Cholesterol Homeostasis
- Cholesterol is crucial for biological functions, but excessive amounts can be toxic.
- Blood cholesterol levels are regulated through the intricate control of bile acid synthesis and cholesterol synthesis.
- HMG-CoA reductase (HMGR) is a key enzyme for regulating cholesterol biosynthesis.
Regulation of Cholesterol Biosynthesis
- Covalent modification: phosphorylation/dephosphorylation of HMGR regulates its activity.
- Glucagon and epinephrine inhibit HMGR activity by activating phosphoprotein phosphatase (PRO).
- Insulin activates HMGR activity by inhibiting cAMP production.
- Genomic modification: Steroid regulation of gene expression alters HMGR levels.
Covalent Regulation of HMGR
- HMGR activity is regulated by phosphorylation or dephosphorylation.
- Glucagon and epinephrine inhibit HMGR activity by activating PRO.
- Insulin activates HMGR activity by inhibiting cAMP production.
Genomic Regulation of Cholesterol Biosynthesis
- Sterol-regulatory-element-binding protein-2 (SREBP2) is a membrane protein in the ER that regulates cholesterol homeostasis.
- SREBP2 regulates LDL receptor expression and NADPH synthesis.
- When cholesterol levels are low, the transcription factor domain of SREBP2 is released.
Functional Units of SREBP2
- SREBP2 has a transcription factor domain (TFD), a sterol-sensing domain (SSD), and a binding site for Insulin-induced gene (Insig).
- Insig is a retention protein that keeps SREBP2 in the ER.
Sterol-Mediated Gene Expression
- High cholesterol levels keep Insig bound to SSD, retaining SREBP2 in the ER.
- Low cholesterol levels release Insig from SSD.
- The SREBP/SCAP complex is transferred from the ER to the Golgi complex.
- Two proteases cleave SREBP2 in the Golgi, releasing the active TFD.
- TFD moves to the nucleus and binds to sterol regulatory elements (SRE) of sterol-related genes, stimulating mRNA synthesis.
Sterol Regulation of HMGR Gene Expression
- Low cellular cholesterol stimulates:
- Cholesterol biosynthesis (e.g., HMGR) expression.
- LDL receptor gene expression.
- NADPH synthesizing genes: glucose-6-phosphate dehydrogenase (G-6-PD), 6-phosphogluconate dehydrogenase, malic enzyme.
Atherosclerosis
- Atherosclerosis is the hardening and narrowing of arteries due to plaque buildup.
- Macrophages have LDL receptors that bind and oxidize LDL.
- High LDL levels lead to macrophage accumulation of LDL, transforming them into foam cells.
- Foam cells stick to blood vessel walls and promote plaque formation.
- As foam cells necrose, cholesterol crystals form in the plaques.
- Atheromas (plaques) can block blood flow and rupture veins.
High Cholesterol and Drug Therapy
- High total cholesterol (VLDL, LDL, and HDL) combined with high LDL is strongly associated with cardiovascular disease.
- Statins are drugs that lower blood cholesterol by inhibiting HMGR.
- Statins are usually taken in the evening because most cholesterol synthesis occurs at night.
- Statin therapy may be accompanied by CoQ supplements because statins can interfere with ubiquinone (UQ) synthesis.
Organ Sparing Metabolic Workload in Feeding-Fasting Cycle
- Gastrointestinal (GI) tract: mixes, digests, absorbs, and propels food.
- Liver: crucial for nutrient metabolism, regulates blood glucose, and detoxifies.
- Muscle: skeletal and cardiac muscle consume a large portion of energy.
- Adipose tissue: stores energy as triglycerides.
- Brain: directs most metabolic processes.
- Kidney: maintains internal body environments.
Role of Gastrointestinal Tract
- The stomach secretes ghrelin, a hormone that stimulates appetite.
- The small intestine secretes peptide YY (PYY), a hormone that inhibits appetite.
- Pancreatic β-cells secrete insulin, a hormone that stimulates glucose uptake by muscle.
- Pancreatic α-cells secrete glucagon, a hormone that stimulates catabolism.
Role of Liver and Muscle
- The liver plays a key role in nutrient metabolism, regulating blood glucose levels.
- Muscle consumes a large portion of the body's energy and uses fatty acids in the fasting state.
- Insulin activates glucose absorption into skeletal and cardiac muscle through GLUT4 translocation.
Role of Adipose Tissue, Brain, and Kidney
- Adipose tissue stores energy as triglycerides and secretes leptin, which promotes satiety (inhibits appetite).
- The brain directs most metabolic processes, and the hypothalamus plays a critical role in energy balance.
- The kidney maintains internal body environments.
Feeding-Fasting Cycle
- Mammals consume food intermittently due to the mechanism for storing and mobilizing energy.
- Hormone regulation and substrate concentrations control metabolism.
- Postprandial state: after a meal, nutrient levels are high.
- Post-absorptive state: overnight fasting, nutrient levels are low.
Feeding Phase
- Nutrients are absorbed from the intestine and transported to the liver.
- Glucose movement from the intestine to the liver stimulates insulin release from β-cells.
- Insulin triggers glucose uptake, glycogen synthesis, fat synthesis and storage, and protein synthesis.
- Lipids are transported as chylomicrons to muscle and adipose tissue.
- Chylomicron remnants deliver phospholipids, cholesterol, and remaining triglycerides to the liver.
Fasting Phase
- Decreased blood glucose and insulin levels induce glucagon release from α-cells.
- Glucagon stimulates glycogenolysis and gluconeogenesis in the liver, preventing hypoglycemia.
- Fatty acid mobilization maintains blood glucose during prolonged fasting.
- Muscles use fatty acids to conserve glucose for the brain and red blood cells.
- During starvation, fatty acids from adipose tissue and ketone bodies from the liver are mobilized.
- Gluconeogenesis is essential after 7 hours of fasting, as glycogen is depleted.
- Amino acids from muscle protein are used for gluconeogenesis.
- After several weeks of fasting, the brain adapts to using ketone bodies as an energy source.
Feeding Behavior
- Feeding behavior is regulated by hormone and neuronal signals, as well as sensory input from the environment.
- The arcuate nucleus (ARC) in the hypothalamus plays a key role in regulating appetite.
- The ARC contains two types of neurons:
- Agouti-related protein (AgRP) and neuropeptide Y (NPY) neurons: stimulate appetite.
- Pro-opiomelanocortin (POMC) neurons: inhibit appetite.
Ghrelin and Food Intake
- Ghrelin, a stomach hormone, stimulates food intake by activating AgRP/NPY neurons.
Leptin and Food Intake
- Leptin, insulin, and PYY inhibit AgRP/NPY neurons, reducing food intake.
- Leptin activates POMC neurons, further inhibiting appetite.
Diabetes Mellitus
- Diabetes mellitus is a metabolic disease with two main types: type 1 and type 2.
- Both types of diabetes are marked by the inability of cells to acquire glucose from the blood, leading to hyperglycemia.
Type 1 Diabetes
- Known as juvenile diabetes or insulin-dependent diabetes.
- An autoimmune disease where the β-cells of the pancreas are destroyed.
- Characterized by inadequate insulin production.
- Symptoms include thirst, frequent urination (polyuria), and ketosis.
- Treatment involves insulin injection or infusion.
Type 2 Diabetes
- Known as insulin-independent diabetes.
- Caused by insulin resistance in target cells.
- Treatment includes diet, exercise, and sometimes insulin therapy.
Symptoms of Diabetes
- Dysfunctional fuel metabolism is a defining feature.
- Major symptoms include hyperglycemia, glucosuria, and dyslipidemia.
- Hyperglycemia is high blood glucose, a symptom of both type 1 and type 2 diabetes.
- Glycosuria is the presence of glucose in urine, causing osmotic diuresis and polyuria, leading to excessive thirst.
- Dyslipidemia is abnormal blood lipid and lipoprotein levels.
Obesity
- The reasons for the predisposition to obesity in the modern world are complex and multifactorial.
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