Desaturation reactions

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

Fatty acyl CoA may be elongated and desaturated (to a limited extent in humans) using enzymes associated with the smooth endoplasmic reticulum (SER). Cytochrome is involved in the desaturation reactions. These enzymes carmot introduce double bonds past position 9 in the fetty add. 

Some characteristics of the enzymes that catalyse desaturation reactions are as follows ... 

Although these are termed essential fatty acids, they are, in fact, precursors for the major polyunsaturated fatty acids that have essential roles in the body but are present only in small amounts in the diet. Linoleic acid is converted, via elongation and desaturation reactions, to dihomo-y-linolenic (20 3n-6) and then to arachidonic (20 4n-6) acid. a-Linolenic is converted to eicosapentaenoic (20 5n-3) and then docosahexae-noic (22 6n-3). The pathways for formation of these latter fatty acids, from their dietary precursors, are presented in Figures 11.11 and 11.12. Full details of one pathway are provided, as an example, in Appendix 11.4. For comparison of the two pathways, they are presented side by side in Figure 11.13. 

Figure 20.3 Essential fatty acids in the diet, production of physiological essential acids and their roles in the cell cycle. Essential fatty adds in the diet are mainly linoleic and a-linolenic but they are converted by desaturation and elongation reactions to the essential acids that are used in phospholipid formation and synthesis of eicosanoids. (For details of the elongation and desaturation reactions and eicosanoid formation, see Chapter 11.).

A series of desaturation reactions convert phytoene to i -carotene and then to lycopene, the important red pigment in tomatoes. In pepper, lycopene undergoes a cyclization reaction on both ends by lycopene P-cyclase, thus producing P-carotene (Fig. 8.2) [25]. Beta-carotene is then converted to -cryptoxanthin, zeaxanthin. 

Biosynthesis and Metabolism.—Pathways and Reactions. Two reviews of carotenoid biosynthesis discuss, respectively, the early steps and the later reactions." The former paper deals with the mechanism of formation of phytoene and the series of desaturation reactions by which phytoene is converted into lycopene, and also describes in detail the biosynthesis of bacterial C30 carotenoids. The second paper" presents details of the mechanism and stereochemistry of cyclization and the other reactions that involve the carotenoid C-1 —C-2 double bond and the later modifications, especially the introduction of oxygen functions. 

A desaturation reaction forming a double bond between C-2 and C-3 of the C-ring is involved in the formation of both flavones and flavonols, and the respective substrates involved, (25)-flavanones and (2R,3R)-DHFs, differ only in the presence or absence of the 3-hydroxyl (Figure 3.2). 

Methyl-1 //-pyrrole gives93 a very similar product mix Over cobalt(III) fluoride at 140 C to 1-methylpyrrolidine,92 suggesting that the latter is converted to the former by some sort of desaturation reaction. Fluorination over potassium tetrafluorocobaltate(III) at 220 C gives a similar result.93... 

On the other hand, in the fatty acid desaturation reaction, molecular oxygen is not incorporated into the final product. Nevertheless, monooxygenation is believed... 

Enzymes present in the ER are responsible for desaturating fatlyj j acids (that is, adding cis double bonds). Termed mixed-function oxidases, the desaturation reactions require NADPH and 02. A van-l ety of polyunsaturated fatty acids (PUFA) can be made through addi-l tional desaturation combined with elongation. [Note Humans laal the ability to introduce double bonds between carbon 9 and the col... 

Scheme 2.2 Examples of reactions catalyzed by and RNA by the protein AlkB [54] (R = sugar al

In Eq. (3) [S]o and [S]f are starting and ending substrate concentrations. S approaches [S] when substrate consumption is minimal, and S is substituted for [S] to correct for excess substrate consumption. In these analyses, however, substrate inhibition can be a problem if the product has a similar affinity to the substrate. Fortunately, most P450 oxidations produce products that are less hydrophobic than the substrates, resulting in lower affinities to the enzymes. There are exceptions, including desaturation reactions that produce alkenes from alkanes (10) and carbonyl compounds from alcohols. These products have hydrophobicities that are similar or increased relative to their substrates. 

Mycelianamide.—Full details on the fate of the C-3 protons of tyrosine on incorporation into mycelianamide (157)149 have been published.103 In the course of mycelianamide formation the side-chain of tyrosine becomes unsaturated and this reaction involves loss of the 3 -pro-S proton. It is to be noted that in a similar reaction in the conversion of tryptophan into cryptoechinulin A the corresponding 3-pro-S proton is again lost.150 If the L-configuration in the amino-acid is assumed then the desaturation reactions occur with formal cis stereochemistry, as in the case of benzodiazepine biosynthesis (see above).107... 

A variety of unsaturated fatty acids can be formed from oleate by a combination of elongation and desaturation reactions. For example, oleate can be elongated to a 20 1 cis-A fatty acid. Alternatively, a second double bond can be inserted to yield an 18 2 cis-A, A fatty acid. Similarly, palmitate (16 0) can be oxidized to palmitoleate (16 1 cis-A ), which can then be elongated to cA-vaccenate (18 1 cis-A H). 

A -Desaturase, A -desaturase, and A -desaturase catalyze the fatty acid desaturation reactions in mammals. When A -desaturase acts on an omega-6 fatty acid, it remains an omega-6 fatty acid. When A -desaturase acts on an omega-3 fatty acid, it remains an omega-3 fatty acid. The desaturases received their names according to where their site of action is relative to the COOH-carbon. 

The steps of prenylation and dehydrogenation which follow (94) in the biosynthesis of these neoechinulins is unknown but from knowledge of echinulin biosynthesis (Scheme 6) introduction of the side chain at C-2 may be the next step. Prenylation of the benzene unit seems, by inspection of structures (97) through (101), to depend on C-8—C-9 unsaturation rather than the structure of the dioxo-piperazine ring. The stereochemistry of the desaturation reaction has been explored with L-tryptophan (85) samples stereospecifically labelled with tritium at... 

Palmitate, the product released by the fatty acid synthase complex, is converted to a series of other fatty acyl CoAs by elongation and desaturation reactions. 

A. Arachidonic acid is produced from linoleic acid (an essential fatty acid) by a series of elongation and desaturation reactions. Arachidonic acid is stored in membrane phospholipids, released, and oxidized by a cyclooxygenase (which is inhibited by aspirin) in the first step in the synthesis of prostaglandins, prostacyclins, and thromboxanes. Leukotrienes require a lipoxygenase, rather than a cyclooxygenase, for their synthesis from arachidonic acid. 

Fig. (4). Instead, the alternative A8-route begins with the elongation of Ci8 to C20, followed by two desaturations. Fig. (4). There also exists another unusual pathway to produce DHA which has been characterised in mammals and fish, called the Sprecher s pathway, this route is characterized by a lack of desaturation reaction at A4-position, but successive A5 and A6-desaturations of ALA (a-linolenic acid, 18 3 ) generating a C24 intermediate which is finally shortened by peroxisomal -oxidation forming DHA, Fig. (4).

Fulco, A.J. The biosynthesis of unsaturated fatty acids by bacilli. I. Temperature induction of the desaturation reaction. J Biol Chem, 244 (1969) 889-895. 

The physiological function of cytochrome is still uncertain, although several possibilities have been suggested. It has been implicated in fatty acid desaturation reactions in the endoplasmic reticulum of liver (II5) and in some hydroxylase reactions both in the reticulum 120) and mitochondria 121,122). It may participate in the reduction of methemo-globin in erythrocytes 109) since ferrocytochrome is readily oxidized by methemoglobin as well as ferricytochrome c. The half-life of cytochrome hi in rat liver microsomes is reported to be 45 hr 123). 

The biosynthesis of carotenoids in plants has been reviewed extensively in recent years and is only briefly described here (Britton, 1988 Bartley and Scolnik, 1994 Sandmann, 1994). The committed step to carotenoid synthesis is the formation of the first compound phytoene by the head-to-head condensation of two molecules of GGDP by phytoene synthase. Phytoene is subjected to a series of four sequential desaturation reactions, by two separate enzymes to yield lycopene, which has eleven conjugated double bonds. Lycopene is then cyclized to /3-carotene by two /3-cyclizations or to a-carotene... 

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