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192 PROCEEDINGS OF THE CALIFORNIA ACADEMY OF SCIENCES Series 4, Volume 60, No. 10 to polyphenols through cross-coupling. There are also shikimic acid derivatives that have numerous hydroxyl groups. Fatty acids have acetyl-CoA as a starting point and through a complex series of reactions a linear chain is formed from a number of two-carbon subunits. The isoprenoid pathway again starts with acetyl-CoA, three units of which condense to form mevalonic acid, which gives rise to 5-carbon isoprene (2-methyl-1,3-butadiene) units. The isoprene units are linked up to form terpenes, steroids, carotenoids and similar compounds. The terpenes are classified according to the number of subunits in a way that sometimes confuses the beginner. A monoterpene consists of two isoprene units each with five carbon atoms. Therefore, the series goes: hemiterpenes (5 carbon atoms), monoterpenes (10), sesquiterpenes (15), diterpenes (20), sesterterpenes (25), triterpenes (30), etc. The amino acid pathway derives from various precursors in the Krebs cycle, the glycolytic and shikimic pathways, with some intermediate steps. These are nitrogenous compounds, and in general the nitrogenous secondary metabolites called alkaloids are derived from them. Amino acids also form peptides, which are sometimes cyclic ones, and a fair number of these are of interest from the point of view of chemical defense. The sacoglossan Elysia rufescens contains a peptide, Kahalalide F (Atlas 652), which has anti-tumoral properties and has been undergoing clinical tests (Hamann, Scheuer & Paul, 1994). Returning to Figure I, we see that the glycolysis pathway gives rise to acetyl-CoA, which, as we just said, forms polyketides and the mevalonic acid that begins the isoprenoid pathway. Primary metabolites within the glycolysis pathway give rise to several amino acids. 3-phosphoglyceric acid gives rise to the amino acid serine, which in turn is modified into two other amino acids, glycine and cysteine. Pyruvic acid, which is transformed into acetyl-CoA at the end of the glycolysis cycle, is also modified into three amino acids: valine, alanine, and leucine. Acetyl-CoA also enters into the Krebs cycle. Within the Krebs cycle there are two primary metabolites that are modified to form amino acids. Oxaloacetic acid is first transformed into aspartic acid, which in turn may be modified to form isoleucine, methionine and lysine. 2-oxoglutaric acid gives rise to three amino acids through a linear series of reactions: glutamic acid, then ornithine, then arginine. The other three primary amino acids (phenylalanine, tyrosine and tryptophan) are all cyclic. They are produced from shikimic acid, which is formed by the unification of phosphoenolpyruvic acid from the glycolysis pathway with erythrose-4-phosphate from the pentose phosphate cycle. The shikimic acid pathway does not occur in animals, so we have to derive these amino acids from our food. Making use of such simple starting materials, organisms are able to build up a vast variety of secondary compounds by combining subunits and variously modifying them by altering their composition and rearranging the parts. To understand how this is accomplished it will help to consider a series of examples. The particular examples have been chosen partly because they are relevant to what is said in later chapters. Let us begin with a fatty acid, stearic acid, CH 3(CH 2) 16COOH. It is a saturated fatty acid (the sort that one is admonished to eat less of) meaning that it has no double or triple bonds between the carbon atoms. Like other acetogenins it is synthesized from acetyl-CoA units. Two carbon atoms are added at each step, the details of which are too complex to concern us here. The reactions are facilitated by systems of enzymes called fatty acid synthases. The elongate stearic acid molecule that results can then be modified in various ways. For one thing, further two-carbon units can be added. Or the fatty acid can be desaturated, so that there are double or triple bonds between carbon atoms at various positions in the chain. Arachidic acid, CH 3(CH 2) 18COOH has the same number of carbon atoms as does arachidonic acid, with four double bonds, and eicosapentenoic acid with five double bonds. Eicosanoids and prostaglandins, which are formed from arachidonic and eicosapentenoic acid derivatives, are of considerable interest for the natural products chemistry of marine animals (see De Petrocellis & Di Marzo, 1994). Although originally found in human
CIMINO & GHISELIN: CHEMICAL DEFENSE AND EVOLUTION OF GASTROPODS 193 prostate secretion, eicosanoids are widely distributed in animal tissues. They often have a signaling function. Some opisthobranchs synthesize them and use them defensively. Others defend themselves with eicosanoids derived from food. Acetylenic fatty acids, i. e., ones with triple bonds between at least two of their carbon atoms, are another important class of biologically active molecules. Not uncommon defensive metabolites in marine sponges and algae, they occasionally occur in the opisthobranchs that feed upon them. Head-to-tail condensation of acetate subunits can also produce polyketides characterized by their oxo-groups. These readily undergo cyclization, as we shall see, but in some cases the oxogroups are readily made out in larger molecules. The biosynthesis of polyketides, which is effected by systems of enzymes called polyketide synthases, is very similar to that of fatty acids (Staunton & Weissman, 2001). Polyketides that are not biosynthesized from acetyl-CoA are most unusual, but for that very reason they need to be discussed here. Certain bacteria, opisthobranchs and fungi have been thought to synthesize polypropionates, which are polyketides that consist of propionic acid units made from propionyl-CoA. In the fungi, it turns out that the molecules in question are not made that way after all (Pedras, Soledade & Chumala, 2005). They are polyketides formed from acetate and then methylated, with the methyl groups derived from the amino acid methionine. The fungi did not incorporate propionate into the metabolites in question. The original evidence for the opisthobranch molecules being polypropionates had been some experiments in which it was shown that propionate labeled with a reactive isotope was indeed incorporated into the molecules (Ireland & Scheuer, 1979; Di Marzo, Vardaro, De Petrocellis, Villani, Minei & Cimino, 1991; Vardaro, Di Marzo, Marin & Cimino, 1992; Cimino, Fontana, Cutignano & Gavagnin, 2004). The possibility had not been excluded, however, that the propionate was degraded into acetate, then condensed into a polyacetate, and finally methylated, as in the fungi. Therefore some experiments using propionate labeled appropriately with 13C were carried out, providing compelling evidence that the propionate units are incorporated intact (Cutignano, Fontana & Cimino, 2009). Propionate biosynthesis in opisthobranchs is therefore like that of bacteria. In a few cases to be mentioned later, there is evidence for opisthobranchs using butyrl-CoA in the biosynthesis of secondary metabolites. Alkaloids may be roughly characterized as nitrogenous compounds derived from amino acids (Christophersen, 1985a). For example, tryptamine (from tryptophan) combines with pyruvic acid to form 1-methyl-β-carboline. However, alkaloids are often synthesized from other precursors such as isoprenoid compounds (Roddick, 1980) and purines (Misra, Luthra, Sing & Kumar, 1999). Leete (1983) discusses the problem of how the term “alkaloid” should be defined, given that any definition tends to exclude some of them. Pelletier’s definition “a cyclic organic compound containing nitrogen in a negative oxidation state which is of limited distribution among living organisms” is the one that Leete prefers, but he notes that it excludes, for example, such acyclic compounds as spermine. In terms of formal logic, it would seem that the term “alkaloid” is a cluster concept or a term that is disjunctively defined. The alkaloids that do not have the defining properties shared by all of the “typical” ones are included in the class by allowing for exceptions and alternatives. Alkaloids are very common in terrestrial plants, and include such familiar products as strychnine, caffeine, and nicotine. In marine environments they are largely produced by bacteria, often ones that live within the bodies of various animals, such as sponges. The alkaloids of marine organisms often contain halogen atoms, usually chlorine or bromine. The famous “purple of Tyre,” a dye that has been extracted from marine mollusks since antiquity, is a dibromo derivative of indigo (Christophersen, 1983). As is common knowledge, proteins are polymers made up of amino acid subunits. Although proteins are synthesized by the ribosomes, using DNA as a template, many of the shorter amino
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