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CARBOHYDRATES

Carbohydrates are among the most abundant constituents of plants, animals, and microorganisms. Polymeric carbohydrates function as important food reserves and as structural components in cell walls. Animals and most microorganisms are dependent upon the carbohydrates produced by plants for their very existence. Carbohydrates are the first products formed in photosynthesis, and are the products from which plants synthesize their own food reserves and other chemical constituents. These materials then become the foodstuffs of other organisms. The main pathways of carbohydrate biosynthesis and degradation comprise an important component of primary metabolism that is essential for all organisms. Secondary metabolites are also ultimately derived from carbohydrate metabolism, and the relationships of the acetate, shikimate, mevalonate, and methylerythritol phosphate pathways to primary metabolism have already been indicated. Many of the medicinally important secondary metabolites described in the earlier chapters have been seen to contain clearly recognizable carbohydrate portions in their structures; for example, note the frequent occurrence of glycosides. In this chapter, some of the important natural materials which can be grouped together because they are composed entirely or predominantly of carbohydrate units are discussed. Because of their widespread use in medicinal preparations, some materials with no inherent biological activity, and which are clearly of primary metabolic status (e.g. sucrose, starch, alginic acid) are also included. The name carbohydrate was introduced because many of the compounds had the general formula Cx(H2O)y, and thus appeared to be hydrates of carbon. The terminology is now commonly used in a much broader sense to denote polyhydroxy aldehydes and ketones, and their derivatives. Sugars or saccharides are other terms used in a rather broad sense to cover carbohydrate materials. Though these words link directly to compounds with sweetening properties, application of the terms extends considerably beyond this. A monosaccharide is a
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carbohydrate usually in the range C3C9, whilst oligosaccharide covers small polymers comprised of 210 monosaccharide units. The term polysaccharide is used for larger polymers.

A. Monosaccharides Six-carbon sugars (hexoses) and five-carbon sugars (pentoses) are the most frequently encountered monosaccharide carbohydrate units in nature. Photosynthesis produces initially the three-carbon sugar 3phosphoglyceraldehyde, two molecules of which are used to synthesize the hexose glucose 6-phosphate by a sequence which effectively achieves the reverse of the glycolytic reactions. Alternatively, by the complex reactions of the Calvin cycle, 3-phosphoglyceraldehyde may be used in the construction of the pentoses ribose 5-phosphate, ribulose 5-phosphate, and xylulose 5-phosphate. Although these sequences need not be considered, they do incorporate a range of

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fundamental transformations which are used in the biochemical manipulation of monosaccharide structures, and which will be encountered here and elsewhere: Intramolecular transfer of a group (mutation), e.g. the isomerization of glucose 6-phosphate and glucose 1-phosphate, which is actually achieved via an intermediate diphosphate. Epimerization to change the stereochemistry at one of the chiral centres, e.g. the interconversion of ribulose 5-phosphate and xylulose 5-phosphate. Aldoseketose interconversions, e.g. glucose 6-phosphate to fructose 6phosphate, also proceed through a common enol intermediate. Transfer of C2 and C3 units in reactions catalysed by transketolase and transaldolase respectively modify the chain length of the sugar. Oxidation and reduction reactions, typically employing the NAD/NADP nucleotides, alter the oxidation state of the substrate. Transamination reactions on appropriate keto sugars allow the introduction of amino groups. B. Oligosaccharides The formation of oligosaccharides and polysaccharides is dependent on the generation of an activated sugar bound to a nucleoside diphosphate. The nucleoside diphosphate most often employed is UDP, but ADP and GDP are sometimes involved. A UDPsugar is formed by the reaction of a sugar 1phosphate with UTP, and then nucleophilic displacement of the UDP leaving group by a suitable nucleophile generates the new sugar derivative. This will be a glycoside if the nucleophile is a suitable aglycone molecule or an oligosaccharide if the nucleophile is another sugar molecule. This reaction, if mechanistically of SN2 type, should give an inversion of configuration at C-1 in the electrophile, generating a product with the -configuration in the case of UDPglucose as shown. Many of the linkages formed between glucose monomers actually have the -configuration, and it is believed that a double SN2 mechanism operates, via participation of a nucleophilic group on the enzyme.

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Linkages are usually represented by a shorthand version which indicates the atoms bonded and the configuration at the appropriate centre(s). Thus, maltose, a hydrolysis product from starch, contains two glucoses linked 14, whilst lactose, the main sugar component of cows milk, has galactose linked 14 to glucose. In the systematic names, the ring size (pyranose or furanose) is also indicated. Sucrose (sugar) is composed of glucose and fructose, but these are both linked through their anomeric centres, so the shorthand representation becomes 12. This means that both the hemiacetal structures are prevented from opening, and in contrast to maltose and lactose, there can be no open-chain form in equilibrium with the cyclic form. Therefore, sucrose does not display any of the properties usually associated with the masked carbonyl group, e.g. it is not a reducing sugar. Sucrose is known to be formed predominantly by a slightly modified form of the sequence shown in Figure 8.16, in that UDPglucose is attacked by fructose 6-phosphate and that the first-formed product is sucrose 6Fphosphate (F indicating the numbering refers to the fructose ring). Hydrolysis of the phosphate then generates sucrose. C. Polysaccharides Polysaccharides fulfil two main functions in living organisms: as food reserves and as structural elements. Plants accumulate starch as their main food reserve, a material that is composed entirely of glucopyranose units, but in two types of molecule. Amylose is a linear polymer containing some 10002000 glucopyranose units linked 14. Amylopectin is a much larger molecule than amylose (the number of glucose residues varies widely, but may be as high as 106) and is a branched-chain molecule. In addition to 14 linkages, amylopectin has branches at about every 20 units through 16 linkages. These branches continue with 14 linkages, but then may have subsidiary branching, giving a tree-like structure. The mammalian carbohydrate storage molecule is glycogen, which is analogous to amylopectin in structure, but is larger and contains more frequent branching, about every 10 residues. The branching in amylopectin and glycogen is
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achieved by the enzymic removal of a portion of the 14 linked straight chain consisting of several glucose residues, then transferring this short chain to a suitable 6-hydroxyl group. A less common storage polysaccharide found in certain plants of the Compositae/Asteraceae and Campanulaceae is inulin, which is a relatively small polymer of fructofuranose, linked through 21 bonds. Cellulose is reputedly the most abundant organic material on earth, being the main constituent in plant cell walls. It is composed of glucopyranose units linked 14 in a linear chain. Alternate residues are rotated in the structure (Figure 8.19), allowing hydrogen bonding between adjacent molecules and construction of the strong fibres characteristic of cellulose, e.g. as in cotton. The structure of chitin is rather similar to cellulose, though it is composed of amino sugar residues, N-acetylglucosamine linked 14. Chitin is a major constituent in the shells of crustaceans, e.g. crabs and lobsters, and insect skeletons, and, as withcellulose, its strength again depends on hydrogen bonding between adjacent molecules, producing rigid sheets. Chemical deacetylation of chitin provides chitosan, a valuable industrial material used for water purification because of its chelating properties and in wound-healing preparations. The mammalian blood anticoagulant heparin is also a carbohydrate polymer containing glucosamine derivatives, but these alternate with uronic acid residues. Polymers of this kind are known as mucopolysaccharides or glycosaminoglycans. Heparin consists of two repeating disaccharide units, in which the amino functions and some of the hydroxyls are sulfated, producing a heterogeneous polymer. The carboxyls and sulfates together make heparin a strongly acidic water-soluble material. Heparan sulfate is structurally related to heparin, but the chains are longer and more heterogeneous. Heparin is secreted only by mast cells, whereas heparan sulfate is more widely distributed and found in different cell types and tissues. Bacterial carbohydrate acetylglucosamine cell walls are contain composed peptidoglycan of alternating structures 14 (also in which NNchains linked called

and

O-lactyl-N-acetylglucosamine

acetylmuramic acid) residues. These chains are cross-linked via short peptide
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structures of variable composition and complexity according to species. The biological activities of the -lactam antibiotics, e.g. penicillins and cephalosporins and of the last-resort antibiotic vancomycin, stem from an inhibition of the crosslinking mechanism during the biosynthesis of the bacterial cell wall, and relate to this terminal d-Alad-Ala sequence during biosynthesis. The subdivision of bacteria into Gram-positive or Gram-negative reflects the ability of the peptidoglycan cell wall to take up Grams dye stain. In Gram-negative organisms, an additional lipopolysaccharide cell membrane surrounding the peptidoglycan prevents attack of the dye. D. Aminosugars and Aminoglycosides Amino sugars are readily produced from keto sugars by transamination processes, in many cases UDPsugars or TDPsugars are involved in the conversions. Glucosamine or N-acetylglucosamine has featured in several of the polysaccharide structures described, though the major route to glucosamine for these compounds tends to be via a more complicated process involving conversion of fructose 6-phosphate into glucosamine 6-phosphatebya transaminaseisomerase enzyme. Other less common aminosugars will be encountered in the aminoglycoside antibiotics. In addition, there are some further structures where the newly introduced amino group subsequently becomes part of a heterocyclic ring system, generating compounds termed variously iminocyclitols, azasugars, or iminosugars. These arise by using the amino group as a nucleophile to generate an aminohemiacetal linkage. This, of course, is simply the initial addition step in the formation of an imine (see page 19). Should the anomeric hydroxyl then be removed in subsequent modifications, such as imine formation, the product will be a polyhydroxy-piperidine or -pyrrolidine. Any confusion with ornithine/lysine-derived alkaloids (see pages 311, 326) should be dispelled by the characteristic sugar-like polyhydroxy substitution. The piperidine structures deoxynojirimycin and deoxymannojirimycin (Figure 8.23) from Streptomyces subrutilis are good examples.

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The aminoglycosides form an important group of antibiotic agents are immediately recognizable as modified carbohydrate molecules. Typically, they have two or three uncommon sugars, mainly aminosugars, attached through glycoside linkages to an aminocyclitol, i.e. an amino-substituted cyclohexane system, which also has carbohydrate origins. The first of these agents to be discovered was streptomycin from Streptomyces griseus, whose structure contains the aminocyclitol streptamine, though both amino groups in streptamine are bound as guanidino substituents, making streptidine. Other medicinally useful aminoglycoside antibiotics are based on the aminocyclitol 2-deoxystreptamine e.g. gentamicin C1. The other component parts of streptomycin, namely l-streptose and 2deoxy-2-methylamino-l-glucose (N-methyl-l-glucosamine), are also derived from d-glucose 6-phosphate, though the detailed features of these pathways will not be considered further. These materials are linked to streptidine through stepwise glycosylation reactions via appropriate nucleoside sugars; the less common nucleosides deoxythymidine and cytidine feature in these reactions. Oxidation of the primary alcohol at C-3 to a formyl group and hydrolysis of the phosphate at C6 are late modifications in the pathway.

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