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Transcript
SCH 511 Secondary Metabolites Derived from Acetate Acetyl CoA Dr. Derese Dr.Solomon Solomon Derese 1 LEARNING OBJECTIVES SCH 511 • Recognize the source, structure and function in biological systems of fatty acids • Identify the roles of acetyl coenzyme A and malonyl coenzyme A in biosynthesis of acetate derived secondary metabolites. • To understand how even-numbered, oddnumbered and branched fatty acids are biosynthesized • Describe how unsaturated fatty acids are produced from saturated fatty acids • Describe how fatty acids can undergo further modification. Dr. Solomon Derese 2 SCH 511 • To understand the role of essential fatty acids in animals. • Recognize the structure of natural products derived from the polyketide pathway. • Describe the primary process in which polyketides are biosynthesized. • Recognize the various cyclization pathways encountered in the formation of polyketides. • Describe how secondary processes give further structural diversification. Dr. Solomon Derese 3 CO2 + H2O Photosynthesis O SCoA PO O SCoA CO2 O OHOH CO 2 CO2 Acetyl coenzyme A Glucose HO HO Glycolysis O SCH 511 HO Pyruvate Phosphoenol pyruvate Fatty Acids & Polyketides Prostaglandins Polyacetylenes Aromatic compounds. Malonyl coenzyme A Dr. Solomon Derese 4 SCH 511 O S CoA Acetyl CoA n FAS O CH2 O O S O CoA Malonyl CoA PKS CoA O H3C H O S CH2 n-1 S CoA O or O O n-2 Saturated thioesters SCoA Polyketo thioesters Saturated fatty acids Aromatic compounds or other Polyketide derived metabolites Unsaturated fatty acids Prostaglandins Dr. Solomon Derese Polyacetylenes 5 SCH 511 Dr. Solomon Derese 6 Biosynthesis of Fatty Acids SCH 511 Acetyl CoA Malonyl CoA Fatty Acid Synthase Saturated thioesters Saturated fatty acids Dr. Solomon Derese 7 SCH 511 Fatty acids are alkanoic acids and the majority of naturally occurring fatty acids have straight-chains possessing an even number of carbon atoms. Fatty acids are usually encountered in nature as their ester derivatives and these ester derivatives are collectively known as lipids, a term which recognizes their insolubility in water. Dr. Solomon Derese 8 SCH 511 Naturally occurring fatty acids (Lipids) are almost entirely straight chain aliphatic carboxylic acids. The broadest definition includes all chain lengths, but most natural fatty acids are C4 to C22, with C18 being the most common. The most abundant fatty acids, the saturated fatty acids have the general formula (example octadecanoic acid (n=7)): CH3CH2-(CH2CH2)n-CH2CO2H a ω Dr. Solomon Derese 9 Occurrence and function of fatty acids SCH 511 Fatty acids, esterified to glycerol, are the main constituents of oils and fats. Storage fats (seed oils and animal adipose tissue) consist chiefly (98%) of triglycerides. Triglyceride Dr. Solomon Derese 10 SCH 511 Animal fats contain a high proportion of glycerides of saturated fatty acids and tend to be solids, whilst those from plants and fish contain predominantly unsaturated fatty acid esters and tend to be liquids. Saturated fatty acid Dr. Solomon Derese Cis unsaturated fatty acid 11 SCH 511 The biological function fatty acids are: I. Storage of metabolic fuel, II. Protective coatings on skin, fur, feathers, leaves, etc III. Cell membrane component Dr. Solomon Derese 12 SCH 511 I. Storage of metabolic fuel Glycerides act as an energy store in biological systems; they can be broken down into their fatty acid constituents which can subsequently undergoes a process termed as b-oxidation. In b-oxidation, the fatty acid is broken down, two carbon atoms at a time, into acetyl coenzyme A units to provide energy. Triglycerides are a highly concentrated store of energy (9 kcal/g). Dr. Solomon Derese 13 SCH 511 b-Oxidation of fatty acids Dr. Solomon Derese 14 SCH 511 II. Protective coatings on skin, fur, feathers, leaves Dr. Solomon Derese 15 SCH 511 III. Cell membrane component Fatty acids are also the major component of the cell membrane. A cell is composed of nucleic acids, proteins, and other biochemicals surrounded by a membrane. Dr. Solomon Derese 16 SCH 511 The membranes completely enclose their contents, and so cells have a defined inside and outside. A typical membrane-forming lipid is phosphatidyl choline. Hydrophobic Dr. Solomon Derese Hydrophilic 17 SCH 511 Dr. Solomon Derese 18 SCH 511 The ubiquity of many of the common fatty acids and the vital roles they play, puts them into the class of primary metabolites. It is only the more unusual or uncommon fatty acids that can be considered as true secondary metabolites. Dr. Solomon Derese 19 SCH 511 Naturally occurring fatty acids share a common biosynthesis. The chain is built from two carbon units, and cis double bonds are inserted by desaturase enzymes at specific positions relative to the carboxyl group. Dr. Solomon Derese 20 SCH 511 This results in even-chain-length fatty acids with a characteristic pattern of methylene interrupted cis double bonds. A typical example of a fatty acid is linoleic acid. O H O Methylene separated by cis-double bonds Linoleic acid A large number of fatty acids varying in chain length and unsaturation result from this pathway. Dr. Solomon Derese 21 SCH 511 Fatty acids with trans or non-methyleneinterrupted unsaturation also occur naturally. Examples O O H Vaccenic acid (18:1) (11t)) O O Dr. Solomon Derese Rumenic acid (18:2 (9t, 11c)) H 22 SCH 511 Nomenclature of fatty acids Systematic names for fatty acids are too cumbersome for general use, and shorter alternatives are widely used. Two numbers separated by a colon give, respectively, the chain length and number of double bonds: octadecenoic acid with 18 carbons and 1 double bond is therefore 18:1. Dr. Solomon Derese 23 SCH 511 The position of double bonds is indicated in a number of ways: explicitly, defining the position and configuration; or locating double bonds relative to the methyl or carboxyl ends of the chain. Double-bond position relative to the methyl end is shown as n-x or x, where x is the number of carbons from the methyl end. The n-system is now preferred, but both are widely used. The position of the first double bond from the methyl end is designated x. Dr. Solomon Derese 24 SCH 511 Example Linoleic acid O 18 1 O H 9 12 9Z,12Z-Octadecadienoic acid 18:2 (9c, 12c) 18:2 n-6 Dr. Solomon Derese 18:2 ∆9,12 18:2 ω6 25 SCH 511 The terms cis and trans, abbreviated c and t, are used widely for double-bond geometry; as with only two substituents, there is no ambiguity that requires the systematic E/Z convention. Acetylinic bond (abbreviated as “a”) Crepenynic acid 12 18 1 9 cis double bond abbreviated as “c” 18 : 2 (9c , 12a) [18 carbons: 2 points of unsaturation (cis double bond at position 9, acetylinic bond at the 12-position) Dr. Solomon Derese 26 SCH 511 Biosynthesis of Fatty Acids O S Acetyl CoA CoA O n H O O S CoA Malonyl CoA O H3C CH2 CH2 n-1 S CoA Saturated thioesters Dr. Solomon Derese Saturated fatty acids 27 SCH 511 Sources of Acetyl CoA A. b-Oxidation of fatty acids Acetyl CoA is formed in the cell by degredation of fatty acids (b-oxidation). Fatty acids esters are energy stores which during metabolism yield acetyl CoA and energy. Dr. Solomon Derese 28 SCH 511 b-Oxidation Dr. Solomon Derese 29 SCH 511 a b Dr. Solomon Derese 30 SCH 511 b Dr. Solomon Derese 31 SCH 511 b Dr. Solomon Derese 32 SCH 511 B. Decarboxylation of pyruvic acid which is obtained via glycolysis of glucose also yields acetyl CoA. O O C6 H12O6 Glucose H O Pyruvic acid CoASH NAD S CoA O Acetyl coenzyme A Dr. Solomon Derese 33 SCH 511 Synthesis of Malonyl CoA The formation of Malonyl coenzyme A takes place in two steps: Step I:Carboxylation of biotin (involving ATP) O O HO ATP O HO OP Coupling to ATP ‘hydrolysis’ provides energy to drive carboxylation process. Dr. Solomon Derese 34 SCH 511 O HO OP O HN NH H H OH S Biotin (Cofactor) O O O NH N HO H H OH S N'-Carboxybiotin Dr. Solomon Derese O 35 SCH 511 Step II: Transfer of the carboxyl group to Acetyl CoA to form Malonyl CoA OH O Keto-enol tautomerization CoA CoA S S O HO Acetyl CoA N O NH H H OH S N'-Carboxybiotin O O O CoA S OH Malonyl-CoA Dr. Solomon Derese 36 SCH 511 Synthesis of Malonyl CoA Acetyl-CoA carboxylase O HCO3 ATP CoA O O CoA S Acetyl CoA Dr. Solomon Derese BIOTIN S OH Malonyl CoA 37