Biochemistry Lecture 22: Lipids - Spring 2024 PDF

Principles of Biochemistry SPRING 2024 Professor: Moncef LADJIMI [email protected] Office: C-169 As faculty of Weill Cornell Medical College in Qatar we are committed to providing transparency for any and all external relationships prior to giving an academic presentation. I, Moncef LADJ...

Principles of Biochemistry SPRING 2024 Professor: Moncef LADJIMI [email protected] Office: C-169 As faculty of Weill Cornell Medical College in Qatar we are committed to providing transparency for any and all external relationships prior to giving an academic presentation. I, Moncef LADJIMI DO NOT have a financial interest in commercial products or services. Lecture 22 Lipids: Structure and Function Additional material for this lecture may be found in: § Lehninger’s Biochemistry (8th ed), chapter 11: p. 341-361 LIPIDS Key topics: – Biological roles of lipids – Structure and properties of storage lipids – Structure and properties of membrane lipids – Structure and properties of signaling lipids BIOLOGICAL FUNCTIONS OF LIPIDS (1) Storage of energy – Reduced compounds: lots of available energy – Hydrophobic nature: good packing Insulation from environment – Low thermal conductivity – High heat capacity (can “absorb” heat) – Mechanical protection (can absorb shocks) Water repellant – Hydrophobic nature: keeps surface of the organism dry Prevents excessive wetting (birds) Prevents loss of water via evaporation BIOLOGICAL FUNCTIONS OF LIPIDS (2) Membrane structure – Main structure of cell membranes Cofactors for enzymes – Vitamin K: blood clot formation – Coenzyme Q: ATP synthesis in mitochondria Signaling molecules – Paracrine hormones (act locally) – Steroid hormones (act body-wide) – Growth factors – Vitamins A and D (hormone precursors) Pigments – Color of tomatoes, carrots, pumpkins, some birds Antioxidants – Vitamin E FATTY ACIDS ARE HYDROCARBON DERIVATIVES § Carboxylic acids with hydrocarbon chains C4 up to C36 § Even number of carbon atoms; commonly C12-C24 § Most natural fatty acids are un-branched § Fully saturated (saturated), or with one (monounsaturated) or more (polyunsaturated) double bonds in the alkyl chain § Double bonds: cis and usually not conjugated § degradation involves removal of 2-carbon unit at a time § Synthesis involves condensation of 2-carbon (acetate) units The saturated chain tends to adopt extended conformations The double bonds in natural unsaturated fatty acids are commonly in cis configuration, which kinks the chain C18 stearate C18 oleate (animal fat: waxy) (liquid: olive oil) TWO CONVENTIONS FOR NAMING FATTY ACIDS (a) Standard convention: assigns the number 1 to the carboxyl carbon (C-1), and α to the carbon next to it. The position of any double bond(s) is indicated by Δ followed by a superscript number indicating the lower-numbered carbon in the double bond. Examples: Palmitic acid, a C16 saturated fatty acid - 16:0 Palmitoleic acid, a C16 mono-unsaturated - 16:1(D9) Oleic acid, a C18 mono-unsaturated - 18:1(D9) (a) Alternative convention: For polyunsaturated fatty acids (PUFAs):, this convention numbers the carbons in the opposite direction, assigning the number 1 to the methyl carbon at the other end of the chain; this carbon is also designated ω (omega; the last letter in the Greek alphabet). The positions of the double bonds are indicated relative to the ω carbon. ω-3 fatty acids are essential nutrients. Humans need them but cannot synthesize them, including ALA, DHA, and EPA (although DHA and EPA can be synthesized from ALA) ALA Alpha Linolenic Acid; 18:3(D9,12,15) (ALA) (soybeans, flaxseeds, walnuts), Eicosa Pentanoic Acid; 20:5(D5,8,11,14,17) (EPA), (fish oil), Docosa Hexanoic Acid; 22:6(D4,7,10,13,16,19) (DHA) (fish oil), are essential Omega-3 fatty acid (although EPA and DHA can be made from ALA). SOLUBILITY AND MELTING POINT OF FATTY ACIDS Solubility: – decreases as the chain length increases Melting Point: – decreases as the chain length decreases – decreases as the number of double bonds increases Saturated fatty acids C12-C24: waxy at room temperature Unsaturated fatty acids: oily liquids Saturated fatty acids pack in a fairly orderly way: – extensive favorable interactions (àhigh melting point) Unsaturated cis fatty acid pack less orderly due to the kink –less-extensive favorable interactions (àlow melting point) PROPERTIES OF SOME NATURAL FATTY ACIDS § Determined by length and degree of unsaturation § Longer chain, fewer double bonds: lower water solubility § Saturated fatty acids C12C24: waxy at room temperature § Unsaturated fatty acids: oily liquids § Melting temp: lower for unsaturated fatty acids FA MP (oC) 18:0 69.6 18:1(D9) 13.4 18:2 (D9,12) IP3 + DAG) § PLA2 releases a fatty acid from the C-2 position of glycerol; the C-2 fatty acid that is released is often arachidonic acid [used for synthesis of eicosanoids] JC10: LYSOSOMAL STORAGE DISEASES DEFECTS IN THE TURNOVER OF MEMBRANE LIPIDS LEAD TO A NUMBER OF DISEASES Pathways for the breakdown of GM1, globoside, and sphingomyelin to ceramide. A defect in the enzyme hydrolyzing a particular step is indicated by V; the disease that results from accumulation of the partial breakdown product is noted. LIPIDS NOT CONTAINING FATTY ACIDS STEROLS § Sterols: STEROLS AND CHOLESTEROL § Steroid nucleus - 4 fused rings, almost planar, relatively rigid § Made from isoprene units § Amphipathic (polar: OH at C-3, non-polar hydrocarbon side-chain at C-17) § Hydroxyl group (polar head) at C-3 in the A-ring § Various nonpolar side chains at C-17 § Synthesized from acetyl CoA via 5-carbon isoprene units § Cholesterol: major sterol in animals §Structural lipid; component of membranes Acetyl CoA H2C H3C Cholesterol: The C-3 hydroxyl group (pink in both representations) is the polar head group. H C CH2 Isoprene units For storage and transport of the sterol, this hydroxyl group condenses with a fatty acid to form a sterol ester. PHYSIOLOGICAL ROLE OF STEROLS Cholesterol and related sterols are present in the membranes of most eukaryotic cells – Modulate fluidity and permeability – Thicken the plasma membrane – Most bacteria lack sterols 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 (LDL) tends to deposit and clog arteries Many hormones are derivatives of sterols BILE ACIDS ARE POLAR DERIVATIVES OF CHOLESTEROL §Produced in the liver and stored in the gallbaldder § Act as detergents in the intestine, emulsifying dietary fats and making them more accessible to lipases Cholic acid (made in the liver) One of cholic acid derivatives Emulsification of fat by Bile From Understanding Nutrition, 14th edition STEROID HORMONES Steroids are oxidized derivatives of sterols Steroids have the sterol nucleus, but lack the alkyl chain found in cholesterol More polar than cholesterol Steroid hormones are synthesized from cholesterol in gonads and adrenal glands They are carried through the body in the bloodstream, usually attached to carrier proteins Many of the steroid hormones are male and female sex hormones STEROID HORMONES CARRY MESSAGES BETWEEN TISSUES § Oxidized derivatives of sterols lacking the alkyl side-chain § Male & female sex hormones: testosterone, estradiol § Corticosteroids (cortisol) Steroids derived from cholesterol. - Testosterone, the male sex hormone, is produced in the testes. - Estradiol, one of the female sex hormones, is produced in the ovaries and placenta. - Cortisol and aldosterone are hormones synthesized in the cortex of the adrenal gland; they regulate glucose metabolism and salt excretion, respectively. - Prednisone and prednisolone are synthetic steroids used as antiinflammatory agents. - Brassinolide is a growth regulator found in vascular plants. BIOLOGICALLY ACTIVE LIPIDS (signals, cofactors and pigments) BIOLOGICALLY ACTIVE LIPIDS Present in much smaller amounts than storage or structural lipids Play vital roles as signaling molecules between nearby cells (paracrine hormones) Lipid soluble vitamins (A, D, E, and K) EICOSANOIDS (SIGNALING LIPIDS) ARE DERIVATIVES OF ARACHIDONIC ACID § Eicosanoids: Paracrine hormones - act near the site of hormone synthesis § Carry messages to nearby cells § mediate inflammation, vasoconstriction and platelet aggregation § Enzymatic oxidation of arachidonic acid yields 3 classes of derivatives: §Prostaglandins, thromboxanes, leukotrienes § Non-steroidal anti-inflammatory drugs (NSAIDs; aspirin, ibuprofen) block cyclooxygenase (COX)-mediated conversion of arachidonate to prostaglandins and thromboxanes Nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin and ibuprofen block the formation of prostaglandins and thromboxanes from arachidonate by inhibiting the enzyme cyclooxygenase (prostaglandin H2 synthase). Arachidonic acid (20:4(D5,8,11,14)) and its derivatives - eicosanoids VITAMIN D (CHOLECALCIFEROL) REGULATES CALCIUM UPTAKE PLAYS A ROLE IN IMMUNITY Fat soluble hormone precursor modulates the innate and adaptive immune response Active hormone Vitamin D3 production and metabolism. Cholecalciferol (vitamin D3) is produced in the skin by UV irradiation of 7-dehydrocholesterol, which breaks the bond shaded light red. In the liver, a hydroxyl group is added at C-25; in the kidney, a second hydroxylation at C-1 produces the active hormone, 1α,25-dihydroxyvitamin D3. This hormone regulates the metabolism of Ca2+ in kidney, intestine, and bone. Deficiency leads to poor bone mineralization: rickets in children and oteomalacia in adults. Overdose à Hypercalcemia à anorexia, nausea, polyuria, weakness, DERIVATIVES OF VITAMIN A (RETINOL) PLAY A ROLE IN VISUAL TRANSDUCTION AND IN GENE EXPRESSION Fat soluble Precursor for other hormones involved in signaling Vitamin A1 and its precursor and derivatives β-Carotene is the precursor of vitamin A1. Isoprene structural units are set off by dashed red lines). Cleavage of β-carotene yields two molecules of vitamin A1 (retinol) (b). Oxidation at C-15 converts retinol to the aldehyde, retinal (c), Further oxidation produces retinoic acid (d), a hormone that regulates gene expression. Retinal combines with the protein opsin to form rhodopsin, a visual pigment widespread in nature. Deficiency leads to blindness hyperkeratosis and anemia... Overdose à liver dysfunction and osteoporosis.. In the dark, retinal of rhodopsin is in the 11-cis form (c). When a rhodopsin molecule is excited by visible light, the 11-cis-retinal undergoes a series of photochemical reactions that convert it to all-trans-retinal (e), forcing a change in the shape of the entire rhodopsin molecule. This transformation in the rod cell of the vertebrate retina sends an electrical signal to the brain that is the basis of visual transduction. VITAMIN E (a-TOCOPHEROL), VITAMIN K AND OTHER LIPID QUINONES ARE ANTIOXIDANTS Fat soluble Diverse roles Vitamin E removes free radicals. Protection against nonenzymatic oxidation of macromolecules Vitamin K1 (phylloquinone) is involed in carboxyglutamate formation involved in the activation of blood-clotting factors. Isoprenoids derivatives: Units derived from isoprene are set off by dashed red lines. In most mammalian tissues, Ubiquinone (also called coenzyme Q) has 10 isoprene units. Dolichols of animals have 17 to 21 isoprene units (85 to 105 carbon atoms), ANOTHER ROLE FOR LIPIDS: LIPID-MODIFIED PROTEINS Addition of lipid groups by: - Myristoylation - Palmytoylation - Prenylation - Farnesylation - etc. EXAMPLES § Oncoproteins §Ras: modified by thioether-linked farnesyl (~3 isoprene units) and thioester-linked C16:0 §Src: modified by amide-linked C14:0 POLYKETIDES ARE BIOLOGICALLY ACTIVE LIPIDS WITH MEDICINAL USES SUMMARY lipids are a structurally and functionally diverse class of molecules that are poorly soluble in water triacylglycerols are the main storage lipids phospholipids are the main constituents of membranes sphingolipids play roles in cell recognition cholesterol is both a membrane lipid and the precursor for steroid hormones some lipids carry signals from cell to cell and from tissue to tissue Remember to prepare for next lecture: Lehninger’s Biochemistry (8th ed), §chapter 17: p. 601-621