The Building Blocks

The building blocks for secondary metabolites are derived from primary metabolism as indicated in Figure 2.1. This scheme outlines how metabolites from the fundamental processes of photosynthesis, glycolysis, and the Krebs cycle are tapped off from energy-generating processes to provide biosynthetic intermediates. The number of building blocks needed is surprisingly few, and as with any child's construction set a vast array of objects can be built up from a limited number of basic building blocks. By far the most important building blocks employed in the biosynthesis of secondary metabolites are derived from the intermediates acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid, and 1-deoxyxylulose 5-phosphate. These are utilized respectively in the acetate, shikimate, mevalonate, and deoxyxylulose phosphate pathways, which form the basis of succeeding chapters. Acetyl-CoA is formed by oxidative decarboxylation of the glycolytic pathway product pyruvic acid. It is also produced by the ^-oxidation of fatty acids, effectively reversing the process by which fatty acids are themselves synthesized from acetyl-CoA. Important secondary metabolites formed from the acetate pathway include phenols, prostaglandins, and macrolide antibiotics, together with various fatty acids and derivatives at the primary/secondary metabolism interface. Shikimic acid is produced from a combination of phos-phoenolpyruvate, a glycolytic pathway intermediate, and erythrose 4-phosphate from the pentose phosphate pathway. The reactions of the pentose phosphate cycle may be employed for the degradation of glucose, but they also feature in the synthesis of sugars by photosynthesis. The shikimate pathway leads to a variety of phenols, cinnamic acid derivatives, lignans, and alkaloids. Meval-onic acid is itself formed from three molecules of acetyl-CoA, but the mevalonate pathway channels acetate into a different series of compounds than does the acetate pathway. Deoxyxylulose phosphate arises from a combination of two glycolytic pathway intermediates, namely pyruvic acid and glyceraldehyde 3-phosphate. The mevalonate and deoxyxylulose phosphate pathways are together

CO2H

NH2 L-cysteine

OH D-glucose

^CO2H

glycine t nh2

L-serine

CO2H

NH2 L-valine

^CO2H

L-alanine

GLYCOLYSIS OH

OH glucose 6-P

glyceraldehyde 3-P

3-phosphoglyceric acid

phosphoenolpyruvate

HO2C^O pyruvic acid

Alanine Nh2 Nh2

PHOTOSYNTHESIS

COTh

L-phenylal ho y OH

OH Nv SHIKIMIC ACID

PHOTOSYNTHESIS

COTh

L-phenylal ho y OH

OH Nv SHIKIMIC ACID

CO2H

L-phenylalanine CO2H

L-tyrosine C

L-tryptophan

CO2H

O OH DEOXYXYLULOSE 5-P

I Mt

CO2H

CoAS.^O

NH2 L-leucine

ACETYL-CoA \

HO2C -OH MEVALONIC ACID

CO2H

^co2h ho2c^y'1

nh2 nh2

L-isoleucine L-aspartic acid

NH2 nh2

L-methionine L-lysine

ACETYL-CoA \

KREBS CYCLE

HO2C^C°2H_

ho2c^^co2h

O

O

oxaloacetic acid

2-oxoglutaric acid

h2n n

ho2c

,co2h

h2n n

^co2h h2n nh2

L-glutamic acid

co2h nh2

L-arginine nh2

L-ornithine

Figure 2.1

responsible for the biosynthesis of a vast array of terpenoid and steroid metabolites.

In addition to acetyl-CoA, shikimic acid, meval-onic acid, and deoxyxylulose phosphate, other building blocks based on amino acids are frequently employed in natural product synthesis. Peptides, proteins, alkaloids, and many antibiotics are derived from amino acids, and the origins of the most important amino acid components of these are briefly indicated in Figure 2.1. Intermediates from the glycolytic pathway and the Krebs cycle are used in constructing many of them, but the aromatic amino acids phenylalanine, tyrosine, and tryptophan are themselves products from the shikimate pathway. Ornithine, a non-protein amino acid, along with its homologue lysine, are important alkaloid precursors having their origins in Krebs cycle intermediates.

Of special significance is the appreciation that secondary metabolites can be synthesized by combining several building blocks of the same type, or by using a mixture of different building blocks. This expands structural diversity, and consequently makes subdivisions based entirely on biosynthetic pathways rather more difficult. A typical natural product might be produced by combining elements from the acetate, shikimate, and deoxyxylulose phosphate pathways. Many secondary metabolites also contain one or more sugar units in their structure, either simple primary metabolites such as glucose or ribose, or alternatively substantially modified and unusual sugars. To appreciate how a natural product is elaborated, it is of value to be able to dissect its structure into the basic building blocks from which it is made up, and to propose how these are mechanistically joined together. With a little experience and practice, this becomes a relatively simple process, and it allows the molecule to be rationalized, thus exposing logical relationships between apparently quite different structures. In this way, similarities become much more meaningful than differences, and an understanding of biosynthetic pathways allows rational connecting links to be established. This forms the basic approach in this book.

Relatively few building blocks are routinely employed, and the following list, though not comprehensive, includes those most frequently encountered in producing the carbon and nitrogen skeleton of a natural product. As we shall see, oxygen atoms can be introduced and removed by a variety of processes, and so are not considered in the initial analysis, except as a pointer to an acetate (see page 62) or shikimate (see page 123) origin. The structural features of these building blocks are shown in Figure 2.2.

• C1: The simplest of the building blocks is composed of a single carbon atom, usually in the form of a methyl group, and most frequently it is attached to oxygen or nitrogen, but occasionally to carbon. It is derived from the S -methyl of L-methionine. The methylenedioxy group (OCH2O) is also an example of a C1 unit.

• C2: A two-carbon unit may be supplied by acetyl-CoA. This could be a simple acetyl group, as in an ester, but more frequently it forms part of a long alkyl chain (as in a fatty acid) or may be part of an aromatic system (e.g. phenols). Of particular relevance is that in the latter examples, acetyl-CoA is first converted into the more reactive malonyl-CoA before its incorporation.

• C5: The branched-chain C5 'isoprene' unit is a feature of compounds formed from mevalonate or deoxyxylulose phosphate. Mevalonate itself is the product from three acetyl-CoA molecules, but only five of mevalonate' s six carbons are used, the carboxyl group being lost. The alternative precursor deoxyxylulose phosphate, a straight-chain sugar derivative, undergoes a skeletal rearrangement to form the branched-chain isoprene unit.

• C6C3: This refers to a phenylpropyl unit and is obtained from the carbon skeleton of either L-phenylalanine or L-tyrosine, two of the shikimate-derived aromatic amino acids. This, of course, requires loss of the amino group. The C3 side-chain may be saturated or unsaturated, and may be oxygenated. Sometimes the side-chain is cleaved, removing one or two carbons. Thus, C6C2 and C6C1 units represent modified shortened forms of the C6C3 system.

• C6C2N: Again, this building block is formed from either L-phenylalanine or L-tyrosine, L-tyrosine being by far the more common. In the elaboration of this unit, the carboxyl carbon of the amino acid is removed.

• indole.C2N: The third of the aromatic amino acids is L-tryptophan. This indole-containing system can undergo decarboxylation in a similar way to L-phenylalanine and L-tyrosine so providing the remainder of the skeleton as an indole.C2N unit.

• C4N: The C4N unit is usually found as a hetero-cyclic pyrrolidine system and is produced from the non-protein amino acid L-ornithine. In marked contrast to the C6C2N and indole.C2N units described above, ornithine supplies not its a-amino nitrogen, but the S-amino nitrogen. The carboxylic acid function and the a-amino nitrogen are both lost.

• C5N: This is produced in exactly the same way as the C4N unit, but using L-lysine as precursor. The e-amino nitrogen is retained, and the unit tends to be found as a piperidine ring system.

These eight building blocks will form the basis of many of the natural product structures discussed in the following chapters. Simple examples of how compounds can be visualized as a combination of building blocks are shown in Figure 2.3. At this stage, it is inappropriate to justify why a particular combination of units is used, but this aspect should become clear as the pathways are described.

The building blocks

CO2H

L-Met

SCoA

CO2H

SCoA

acetyl-CoA malonyl-CoA

SCoA

acetyl-CoA OH

HO2C

HO y mevalonic acid

O OH

deoxyxylulose phosphate

L-Phe ctr

CO2H NH2

OH OH methylerythritol phosphate

C6C3

L-Tyr xs isoprene unit

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