BMS 131 Lecture 10: Lipid Chemistry 2 - Fall 2024 PDF

BMS 131 Lecture No: 10 Title: Lipid chemistry 2 Instructor Name: Dr Wael Elayat Medicine and Surgery Program Fall 2024 Intended Learning Outcomes (ILOs) By the end of this lecture, each student should be able to: 1- 1- E...

BMS 131 Lecture No: 10 Title: Lipid chemistry 2 Instructor Name: Dr Wael Elayat Medicine and Surgery Program Fall 2024 Intended Learning Outcomes (ILOs) By the end of this lecture, each student should be able to: 1- 1- Enumerate significance of phospholipid 2-Define cholesterol and its importance. 3-Define lipoproteins 4- Enumerate different types of lipoproteins and their functions 5- Demonstrate relation ship between different types of lipoproteins and atherosclerosis Functions of phospholipids Structural component of membranes (2) Enter in lipoprotein structure, which help in lipid transport in body-Transport of TG from liver to body, any defect lead to fatty liver (3) Solubilize cholesterol in bile, any defect lead to cholesterol stones (4) Special function of phospholipids 3 Special function of phospholipids Dipalmityl Phosphatidyl choline = Cephalins: Dipalmityl lecithin= Lung surfactant 4  Cephalins They are mixture of phosphatidyl serine, and phosphatidyl ethanolamine They are also present in liver and brain. They play a role in blood coagulation and clot lysis. Antibodies against acidic phospholipids cause recurrent thrombosis and recurrent fetal loss (antiphospholipids syndrome) 5  Examples Alcohols Fatty acids Steroids Glycerol in TAG Vitamin A and D and phosphoglycerides 6 A-Steroids Are the compounds that have steroid nucleus. Steroid nucleus is composed of 4 rings identified by A-B-C- D, and formed of 19 carbons i-Cholesterol Is the major steroid in animal tissue i- CHOLESTEROL-BIOLOGICAL IMPORTANT COMPONDS BILE ACIDS CHOLESTEROL STEROID VITAMIN D HORMONES 9  i-Cholesterol Steroid nucleus with an 8 hydrocarbon side chain at C-17 (Is 27 C steroid). C D It also has a double A B bond between C5 &C6. It contains an OH group attached to C3 Structure of Cholesterol  May be esterified with unsaturated fatty acid (cholesterol ester). Cholesterol ester is the storage form inside the cell Blood cholesterol is either in free form(1/3) or in ester form (2/3). Lipoproteins Lipids are insoluble in water. However they must be transported from the tissue of origin to tissues in which they will be stored or consumed. They are carried in blood plasma from one tissue to another by plasma lipoproteins.  Structure of Lipoproteins Lipoproteins have a central hydrophobic core of: -Triacylglycerols (TAG) -Cholesterol esters. The outer layer contains the more polar components -Phospholipids -Free cholesterol -Proteins (apoprotein: A,B, C & E). Classification of Plasma Lipoproteins : Four major groups of plasma lipoproteins can be separated by electrophoresis and ultracentrifugation (chylomicrons , VLDL, LDL, HDL). Chylomicrons : Chylomicrons are assembled in the intestinal mucosal cell and secreted into the lymphatic system. Chylomicrons transport dietary triacylglycerols and cholesterol ( exogenous lipids ) to the rest of the body. The predominant lipid in nascent chylomicrons is dietary triacylglycerol (90%) whereas the protein component includes apo B48. responsible for post-alimentary lipemia. It acquires apo C and apo E from circulating HDL. VLDL:  VLDL are the major carriers of endogenous triacylglycerols.  VLDL are produced by liver cells from lipid and apoprotein B100.  It acquires apo C and apo E from circulating HDL.  VLDL is converted to a relatively smaller  size particle IDL or VLDL remnant.  The fate of IDL is either : a-Conversion to LDL by acquiring cholesterol from plasma. b-Direct uptake by liver. LDL:  LDL formed from VLDL  small particles rich in cholesterol and containing apo B100.  LDL transports cholesterol from liver to peripheral tissues.  LDL concentration in blood is related to incidence of cardiovascular diseases.  The LDL receptor is located in specialized region in the cell membrane specialized for endocytosis called coated pits. . HDL:  HDL is the main transport form of cholesterol from peripheral tissues to liver ( reverse cholesterol transport ) to be excreted through bile.  The level of HDL in serum is inversely related to incidence of myocardial infarction.  HDL are secreted from liver as discoidal nascent particles that contain relatively little cholesterol, phospholipids and apoproteins ( A ,C & E ).  Intended learning Outcomes (ILOs): Studying this topic should enable you to: Recognize the concept of metabolic pathways and the metabolic map. Identify types & characters of metabolic pathways- anabolic and catabolic. Understand the basis of metabolic regulation and integration. Identify the role of signaling pathways in regulation and integration of metabolism.  Metabolism 1- In a cell, biochemical reactions are organized into multistep sequence called pathways. 2- In pathways, The product of one reaction act as the substrate of the subsequent reaction. A 1 B 2 C 3 D 4 E 3. The sum of all biochemical reactions occurring in a cell, in a tissue or the body are called metabolism. 4- Different metabolic pathways can intersect, forming integrated network of chemical reactions called Metabolic map. Metabolism is the sum of all BIOCHEMICAL REACTIONS that occur in living organisms to maintain life. Importance Of Metabolism 1- ATP production (Catabolic) 2- Synthesis Of Complex Molecules (Anabolic)  Types of metabolic processes 1- Catabolic 2- Anabolic 3- Amphibolic  1- Catabolic Definition: break down of complex molecules into few simple molecules. Importance: ATP production (Exergonic). Nature of catabolic reactions: 1- Usually energy producing (Exergonic). 2. Usually oxidative requiring hydrogen carriers e.g. NAD 3- Convergent process: That is to say wide variety of molecules convert into few common end products. Stages of Catabolic Pathways 2- Anabolic Definition: Combination of small molecules (a.as) to form complex molecules (protein). Importance: Synthesis Of Complex Molecules. Nature: 1- Usually energy consuming (endergonic). 2- Mostly reductive (Utilize electron donor NADPH). 3- Divergent process: Few biosynthetic precursors form a wide variety of complex products.  Comparison of Catabolic and Anabolic Pathways Anabolic Catabolic  Simple to complex  Complex to simple molecules molecules  Endergonic  Exergonic  Involves reductions  Involves oxidations  Requires NAD+  Requires NADPH  Convergent process  Divergent process 3- Amphibolic The Pathway that has a dual function ( both Anabolic & Catabolic) e.g. TCA How are the metabolic pathway regulated? By regulating Enzymes catalyzing the rate determining step of the pathway (Irreversible reactions) How are the metabolic pathway regulated? I. Enzymatic activity. II. Compartmentation. III. Energy state & substrate availability  I. Regulation of Enzymatic activity Altering the enzyme quantity Changing enzyme activity long term Short term I. Allosteric (Feed-back inhibition or activation)  Synthesis  Synthesis Usually Gene induction Reactants are activators & Gene repression Products are inhibitors II.Covalent modification Under hormonal (Phosphorylation & control dephosphorylation) Kinases & Phosphatases Under hormonal control  Covalent modification In well fed state: In fasting state; insulin glucagon & Epinephrine Dephosphorylation Phosphorylation By ++phosphatase By ++cAMP dependant kinases II. Compartmentation Mitochondrial Cytosol Matrix Glycolysis TCA HMP Electron Transport chain. Pathway. FA Oxidation FA synthesis Interplay of both Compartments Gluconeogenesis  Signal transduction This is the process by which extracellular signals can be transduced (converted ) into intracellular chemical changes. These signals ( chemical messengers) include: Hormones, neurotransmitters, growth factors,.etc  Steps of Signal transduction Via second messenger Primary messenger 1.Recognition of signal: by specific receptors on target cells 2.Transduction; change of external signal into intracellular message (formation of second messenger) 3.Effects: Regulation of cell metabolism Adenylate Cyclase Signaling Pathway by Glucagon This system is formed of : PKA=cAMP dependant Protein kinase Phosphorylation of cellular proteins That stimulate or inhibit some enzymes.  This system is formed of : 1. Stimulus: Tendency to hypoglycemia (decrease of blood glucose level). 2. Release of glucagon hormone from pancreas. 3. Binding and activation of cell-surface receptors, e.g., glucagon receptors on hepatocytes (glucagon-receptor complex). 4. Activation of G-proteins: Trimeric membrane proteins coupled to the receptor. 5. Activation of adenylyl cyclase: Membrane bound enzyme that converts ATP into cAMP. 6. Formation of the second messenger: cAMP. 7. Activation of protein kinase A (PKA): A kinase that phosphorylates target proteins upon its activation by cAMP (i.e., cAMP- dependent protein kinase). 8. Effects: Intracellular action of glucagon on Glycogen metabolism Glucagon effects on Glycogen Synthase and Glycogen Phosphorylase Enzyme phosphorylation P P Glycogen synthase Glycogen phosphorylase (Inactive form) (Active form) Inhibition of Stimulation of glycogenesis glycogenolysis Increase of blood glucose level back to normal. Termination of signal 1- Dephosphorylation of target proteins by Phosphatases. 2- Inactivation of PKA (via degradation of cAMP by Phosphodiesterase that convert cAMP into 5- AMP. 1Phosphodiesterase Termination of signal 3- Inactivation of G-protein and unbinding of glucagon from its receptor. Intended Learning Outcomes (ILOs) By the end of this lecture, each student should be able to: 1- Identify different chemichal composition of cell membrane 2- Recognize structure function relationship of different component of membrane 3- Explain on biochemical basis symptoms of cystic fibrosis Biological membrane chemistry Membranes are important biological structures, which are indispensable for life. Membranes give cells their individuality by separating them from their surroundings.They are highly selective and semi permeable containing specific gates, pumps, and channels. Membranes control the flow of information between cells and their environment since they contain specific receptor molecules in the form of glycoproteins. Macromolecules found in the cell membrane Lipids Phospholipid bilayer Glycolipid Cholesterol Proteins Peripheral proteins Integral proteins Carbohydrates Oligosaccharides on glycoproteins and glycolipids Chemical composition of membrane lipid 1- Lipid component (A) Phospholipids are the major class of membrane lipids. Fatty acid tails are hydrophobic and Phosphate group heads are hydrophilic and arranged as a bilayer. 1- lecithin (phosphatidyl choline) 2-Cephalins (phosphatidyl serine, phosphatidyl ethanolamine) 3-Phosphatidyl inositol 4- Cardiolipin 5- Plasmalogen 6- Sphingolipids (sphingomyelin) also form membrane structures, especially that of the brain cells and nerve cells. (B) Glycolipids (C) Cholesterol:Cholesterol lies within the bilayer with its OH group (polar head) facing the aqueous interface. It modulates membrane fluidity 2-Proteins seem to be floating in a sea of lipids. There are two groups: A- Peripheral proteins - They are present on either side of the bilayer associated with the polar head groups of membrane lipids and proteins. - Peripheral proteins can be removed without disrupting the membrane. B- Integral proteins - They are amphipathic proteins, deeply embedded in the bilayerand attached to membrane lipids. - Only detergents and organic solvents that leads to membrane disruption remove them. 3- Membrane Carbohydrates Carbohydrates are exclusively on the external surface. Carbohydrates are covalently linked to proteins or lipids (glycoproteins &glycolipids). They are responsible to inhibit random cell proliferation. Cancer cells lose this property due to changes in their glycolipids. It may also act as antigen in case of ABO blood group. Inside outside asymmetry of the cell membrane 1)- Asymmetry in Phospholipid distribution: - Phosphatidyl choline----- in the outer leaflet - Phosphatidyl serine & ethanolmine-------in the inner leaflet The presence of Phosphatidyl serine in the cell surface -------------- Apoptosis (cell death) (2)- Cholesterol is present in large quantities in outside more than inside. (3)- Irregular protein distribution (remember the integral and peripheral protein). (4)- External location of Carbohydrates. Membrane related disorders; Cystic fibrosis Hereditarynon functional chloride channel in the epithelial cells of both GIT and respiratory tracts. Thick mucus with Obstruction of GIT and respiratory tract Increased chance of bacterial infection