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Biochemistry Week4, Fatty acid, Farnesylation of Proteins, Example of…

- - - - Tissues
      - Organelles 細胞器
      - Organisms(Can Adjust the Membrane Composition)
        
        At higher temperatures, cells need more long, saturated fatty acids; At lower temperatures, cells need more unsaturated fatty acids.
        
        More fluid membranes require shorter and more unsaturated fatty acids.
        
        Melting temperature decreases as double bonds are added.
        
        Melting temperature increases with length of saturated fatty acids.
        
        Membrane fluidity is determined mainly by:
        
        The fatty acid composition
        
        Melting point
    - - Abundance and type to sterols varies
      - Lack of sterols in prokaryotes
      - Cholesterol predominant 顯著的in the plasma membrane,virtually absent in mitochondria
      - Galactolipids 半乳糖abundant in plant chloroplasts but almost absent in animals.
      - Type of phospholipid varies
  - - - Channels ,gates,pumps
        
        Nutrients(maltoporin)
        
        Ions(K-channel)
        
        Neurotransmitters(serotonin reuptake protein)
      - Enzymmes
        
        Lipid biosynthesis(some acyltransferases)
        
        ATP synthesis(F0F1 ATPPase/ATP syngthase)
      - Receptors: detecting signals from outside
        
        Neurotrasmitters(acetylcholine receptor)
        
        Hormones(insulin receptor)
        
        Pheromones(taste and smell receptors)
        
        Light(opsin視蛋白)
    - - Amphitrophic 兩性的
        and GPI-linked proteins
        
        Can be conditionally attached to the membrane by covalent interaction with lipids or carbohydrates attached to lipids.
        
        Biological regulation results in attachment to,or cleavage from,lipids.
        
        Removement
        
        Protein-glycan
        
        Biological regulation
      - Integral membrane proteins 穿透性膜蛋白
        
        Span the entire membrane
        
        Have asymmetry 不對稱 like the membrane-different domains in different compartments
        
        Tightly associated with membrane-Hydrophobic stretches in the protein interact with the hydrophobic regions of the membrane.
        
        Removed by detergents that disrupt the membrane.
        
        Purified integral membrane proteins still have phospholipids associated with them
        
        Have Selectively Placed Nonpolar Amino Acids Within the Membrane
        
        Can Also Contain β-Sheets
        
        Can be monotopic(穿一層) and polytopic(穿兩層)
        
        Amino Acids in Membrane Proteins Cluster in Distinct Regions氨基酸分佈的特異性
        (Have Selectively Placed Nonpolar
        Amino Acids Within the Membrane)
        
        Transmembranes egments are predominantly hydrophobic.
        
        Tyr and Trp cluster at nonpolar/polar interface.
        
        Charged amino acids are only found in aqueous domains
        
        Caveolin小窩蛋白
        
        are the principal components of caveolae
        
        involved in receptor-independent endocytosis
        
        may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules
      - Peripheral(non-GPI linked)
        membrane proteins 周邊膜蛋白
        
        Removed by disrupting ionic interactions either with high salt or change in pH 高離子濃度水溶液或高pH值(此方法可保持脂質雙層的完整)
        
        Relatively loosely associated with membrane
        
        Associate with the polar head groups of membranes,所形成非共價作用力
        
        Purified peripheral membrane proteins are no longer associated with any lipids.
      - Lipid-linked Membrane Proteins
        
        Outer
        
        Inter
        
        N-Myristoyl group on among-terminal Gly
        
        Farnesyl(or geranylgeranyl)group on carbonyl-terminal Cys
        
        Pal toys group on nternal Cys(or Ser)
  - - - Two leaflets have different lipid compositions.
      - The outer leaflet is often more positively charged.
      - Phosphatidylserine outside has a special meaning:
        
        platelets: activates blood clotting
        
        other cells: marks the cell for destruction
    - - Lateral Diffusion 側向擴散
        
        Individual lipids undergo fast lateral diffusion within the leaflet.
      - Study of Membrane Dynamics: FRAP
        
        From the rate of return of lipids, the diffusion coefficient of a lipid in the leaflet can be determined.
        
        Rates of lateral diffusion are high (up to 1 μm/sec)
        — A lipid can circumnavigate an E.coli cell in one second.
        
        Fluorescence 螢光性recovery after photobleaching 光致褪色(FRAP) allows us to monitor lateral lipid diffusion by monitoring the rate of fluorescence return.
        
        Steps
        
        Step2: photobleaching
        
        Step3: measure recovery
        
        Step1: label outside of cell
      - Transverse Diffusion
        
        Spontaneous flips from one leaflet to another are rare because the charged head group must transverse the hydrophobic tail region of the membrane.
      - Flippases 翻轉酶
        (Special enzymes catalyze transverse diffusion.)
        
        Floppase
        
        Moves phospholipids from cytotoxic to outer leaflet,need ATP
        
        Scramblase
        
        Moves lipids in either direction,toward equilibrium,no need ATP
        
        Flippase
        
        Moves PE and PS from outer to cytotoxic leaflet,need ATP
    - - Heating causes phase transition from the gel to fluid.
      - Under physiological conditions, membranes are more fluid-like than gel-like.
        — must be fluid for proper function
      - Depending on their composition and the temperature, the lipid bilayer can be in:
        
        liquid-ordered state (i.e., “gel phase”): individual molecules do not move around
        
        liquid-disordered state (i.e., “fluid phase”): individual molecules can move around
  - - - Fusion can be spontaneous or protein mediated.
      - Can fuse with each other itch out exposure of lipids to aqueous solvent.
    - - Endocytosis
        胞吐作用
        
        Phagocytosis 吞噬作用
        
        Pinocytosis 胞飲作用
      - Exocytosis 胞吐作用
      - Viral infection
      - Fusion of sperm and egg
      - Fusion of endosome and lysosome
      - Budding os vesicles from Golgi complex
      - Fusion of small vacuoles(plants)
      - Separation of two plasma membranes at cell division.
  - - - Hydrophilic head groups interact with water on both sides of the bilayer. Hydrophobic fatty acid tails are packed inside.
      - Forms when lipids with polar head groups and more than one lipid tail
        are in aqueous solution.(phospholipids and sphingolipids)
      - Consists of two leaflets of lipid monolayers,units are cylindrical
    - - The central aqueous cavity can enclose dissolved molecules.
      - They are useful artificial carriers of molecules (ex.drugs)
      - Synthetic vesicle membranes can be made in vitro and can contain artificially inserted proteins.
      - Vesicles fuse readily with cell membranes or with each other.
      - Small bilayers will spontaneously seal into spherical vesicles in a concentration-dependent manner.
    - - Aggregation of individual lipids into micelles is concentration dependent.濃度依賴
      - Micelles are composed of a few dozen to a few thousand lipid molecules,units are wedge-shaped.
      - Forms in the solution of amphipathic molecules that have larger, more polar head than tail
        
        fatty acids
        
        sodium dodecyl sulfate
- - - - Derivatives as Signaling Lipids
      - Enzymatic oxidation of arachidonic acid yields:
        
        prostaglandins 前列腺素類-inflammation and fever
        
        thromboxanes 血栓素-formation of blood clots
        
        leukotrienes-smooth muscle contraction in lungs
    - - is Derived from β-carotene
      - Involved in visual pigment
      - Precursor 先驅 for other hormones involved in signaling
    - - Is Synthesized from Cholesterol
      - Regulates Calcium Metabolism
    - - Warfarin (和Vitamin K拮抗)
      - Ubiquinone
      - Plastoquinone
      - Dolichol
- - - - Glycerophospholipids
        
        General Structure
        
        Glycerol backbone 甘油骨架
        
        Saturated fatty acid 飽和脂肪酸
        
        Head-group substituent 磷酸根頭部：
        
        is charged at physiological pH.
        
        The highly polar phosphate group may be further esterified by an alcohol; such substituent groups are called the head groups.
        
        Unsaturated fatty acid 不飽和脂肪酸：are commonly found connected to C2 of glycerol-3-phosphate.
        
        sn (stereospecific numbering) system:
        The numbering follows the one of Fischer's projections,need assign 1 position to group occupying the proS position of a prochiral center.Orient molecule C1 at top.
        
        Examples
        
        Phosphatidylcholine 卵磷脂
        
        is the major component of most eukaryotic cell membranes. Many prokaryotes, including E. coli, cannot synthesize this lipid; their membranes do not contain phosphatidylcholine.
        
        Ether lipids
        
        Plasmalogen 縮酸磷脂
        
        Vinyl ether analog of phosphatidylethanolamine 磷脂醯乙醇胺
        
        Common in vertebrate heart tissue
        
        Also found in some protozoa and anaerobic bacteria
        
        Function is not well understood
        
        Platelets-Activating Factor (PAF)
        血小板活化因子
        
        Aliphatic ether analog of phosphatidylcholine 磷脂醯膽鹼
        
        Acetic acid has esterified position C2
        
        First signaling lipid to be identified
        
        Stimulates aggregation of blood platelets
        
        Plays role in mediation of inflammation
      - Sphingolipids 神經磷脂
        
        Structure
        
        Sphingosine(it means the backbone is not glycerol,instead,is a long-chain amino alcohol sphingosine.)
        
        Fatty acid: is joined to sphingosine via an aside linkage,rather than an ester linkage as usually seen in lipids.
        
        Head-group substituent: is connected to sphingosine by a glycosidic or phosphodiester linkage.
        
        The sugar-containing glycosphingolipids are found largely in the outer face of plasma membranes.
        
        Example: Sphingomyelin 鞘磷脂
        
        Structure
        
        Ceramide 神經醯胺 (sphingosine+amino-liked fatty acid)
        
        Phosphocholine 磷酸膽鹼 attached to the alcohol
        
        is abundant in myelin sheath that surrounds some nerve cells in animals.
        
        Comparison with Phosphatidylcholine磷脂醯膽鹼
        
        Glycosphingolipids 鞘糖酯
        
        The blood groups 血型 are determined in part by the type of sugars located on the head groups in glycosphingolipids.
        
        The structure of sugar is determined by an expression of specific glycosyltransferases.糖基轉移酶
        
        Individuals with no active glycosyltransferase will have the O antigen.
        
        Individuals with a glycosyltransferase that transfers an N-acetylgalactosamine group have A blood group.
        
        Individuals with a glycosyltransferase that transfers a galactose 半乳糖 group have B blood group.
      - Degraded in the Lysosome
        
        Phospholipids are degraded by
        phospholipases A−D.(Each phospholipase cleaves a specific bond.)
        
        Gangliosides 神經節糖酯 are degraded via a
        series of enzymatic cleavages.(Failure to correctly degrade
        gangliosides results in lysosomal storage disorders.”)
    - - Sphingolipids
      - Galactolipid 半乳糖脂(suifolipids)
  - - - Structure
        
        hydroxyl group (polar head) in the A-ring
        
        various nonpolar side chains
        
        steroid nucleus: four fused rings
        
        The tetracycle structure of sterols is almost planar平面的.
      - Physiological Role
        
        Cholesterol and related sterols are present in the
        membranes of most eukaryotic cells.
        
        modulate fluidity and permeability
        
        thicken the plasma membrane
        
        no sterols in most bacteria
        
        Mammals obtain cholesterol from food or synthesize it de novo in the liver.
        
        Cholesterol, bound to proteins, is transported to tissues via blood vessels.
        (Cholesterol in low-density lipoproteins 脂蛋白 tends to deposit and clog arteries.)
        
        Many hormones are derivatives of sterols.
        
        Steroids hormones 類固醇
        
        They are more polar than cholesterol.
        
        are synthesized from cholesterol in gonads 生殖器and adrenal glands.腎上腺
        
        Steroids have the sterol nucleus
        but lack the alkyl chain found in cholesterol.
        
        are carried through the body in the bloodstream,
        usually attached to carrier proteins.
        
        Steroids are oxidized derivatives of sterols.
        
        Many of the steroid hormones are male and female sex hormones.
- - - - Ａdvantage
        
        Fatty acids carry less water per gram because they are nonpolar.
        
        Fats are for long-term (months) energy needs, good storage, and slow delivery.
        
        Fatty acids carry more energy per carbon because they are more reduced.