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GLYCAN STRUCTURES, CLUES TO THE ORIGIN OF SACCHARIDES
Jun Hirabayashi
Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University
Sagamiko, Kanagawa 199-0195, Japan
Tel: 0426-85-3741 Fax: 0426-85-3742 E-mail: [email protected]
(Received 1 August 2001, Accepted 11 September 2001)
Abstract
Glycans are carbohydrate chains that are considered to be one of the most essential bio-informative macromolecules as
well as nucleic acids and proteins. Although biological significance and actual states of glycans are not yet fully
understood, they certainly play fundamental roles in various recognition phenomena, such as microbe-parasite
infections, cell proliferation and differentiation, fertilization, apoptosis, cancer metastasis, etc. Distinct from nucleic
acids, glycans are expressed on cell surfaces and in extracellular matrices as various forms of glycoconjugates. They are
indispensable to cover vital cells and to protect against physical and biochemical attacks. Distinct from proteins,
glycans are indirect products of so-called glycogenes, i.e., genes that encode glycosyltransfearses, glycosidases and
sugar nucleotide transporters involved in glycan biosynthesis. Since individual steps of these processes are not complete,
a series of glycans are produced simultaneously as a consequence of collaboration of glycogenes. Here, a"multi genes-
multi glycans" principle is applied for glycan biosynthesis instead of the "one gene-one enzyme" principle for nucleic
acids and proteins.. As another unique feature of glycans, they have a number of linkage and branching isomers.
Nevertheless, sugar units, e.g., glucose (C6H12O6), are extremely simple in their compositions, reflecting formal name,
"carbohydrates", which mean "C + H2O". In addition, only carbohydrates lack nitrogen, whereas amino acids and
nucleotides contain this atom. On the other hand, saccharides have chirality like amino acids. Naturally occurring
saccharides are basically defined as "D-enantiomers", while L-fucose, L-rhamnose and some other L-sugars are actually
biosynthesized from either D-mannose or D-glucose. Important notation is that only few component saccharides, i.e.,
D-glucose, D-mannose and D-galactose are utilized in nature among possible 16 aldohexoses. This observation implies
that the first living organisms could make use of a relatively small number of simple saccharides that had been
sufficiently available on the prebiotic earth. In this article, the author reviews structural and metabolic features of
naturally occurring saccharides and classic glycochemistries. Hence, he presents a possible scenario on the origin of
saccharides consisting of i) formose reaction to generate the smallest (C3) sugars, ii) aldol condensation between
glyceraldehyde (GA) and dihydroxyacetone (DHA) to yield few ketohexoses, and iii) Lobry de Bruyn rearrangement to
convert fructose into glucose. The scenario clearly explains how and why only a few elementary saccharides were born
and selected. On the other hand, galactose is categorized into "late-comer" saccharides together with many other
"bricolage" saccharides, such as ribose, sialic acid and more unusual deoxy- and dideoxyaldohexoses. In the end, the
author refers to the essence of "glycome project", which is an emerging field of glycobiology along with the concept of
post-genome science.
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Fig. 1. Structures of naturally occurring saccharides. For simplicity,all of the structures are drawn as β-anomers.
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Fig. 2. Basic pathways proposed for formose reaction [2]. In thepresence of an appropriate base catalyst, formaldehyde undergoesself-condensation reaction, yielding a series of saccharides. Amongthese, generation of C5 and C6 saccharides is estimated to be theresult of aldol condensation between C2 and C3, and between C3and C3 saccharides, respectively.
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Fig. 3. Friendly relationship between water and saccharide. Watermolecules tend to form a favored "tridymite" structure, which ismaintained by the presence of equatorial hydroxyl groups such asβ-glucose.
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Fig. 4. Various forms of D-glucose. By way of the intermediatelinear (aldehyde) form, D-glucose is convertible into either α/β-furanoses (left) or α/β−pyranoses (right).
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Fig. 5. Variation of glucose polymers. By the presence of variablelinkage patterns, i.e., α1-4/6, β1-3/4/6, different types of naturallyoccurring glucose polymers (glucans) are generated, of whichbiological functions are distinct. For example, α1-4 glucan(amylose) is soluble and an essential energy source, while β1-4glucan (cellulose) forms a mechanically stable insoluble fiberhardly digested by most organisms.
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Fig. 6. Image of the hierarchy presumed for three componentsaccharides, glucose, mannose and galactose. Glucose (mostly inthe form GlcNAc) is most fundamental, and mannose is second toit. On the other hand, galactose is distinct from these saccharides inboth chemical and biological aspects (see text). Sialic acids and L-fucose are rather optional, but actually play critical roles asmodifiers of galactose.
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Fig. 7. Linear forms and C1 chair forms of 8 possible D-aldohexoses. Naturally occurring glucose, mannose and galactoseare shown in bold face. In each linear form, OH group(s) epimericrelative to glucose are shown with solid box(es). In each chair form,axial OH-group(s) are shown in red for emphasis, and hydrogenatom(s) which cause thermodynamically unfavored 1, 3-diaxialinteractions are shown in bold bars (H is not shown). It is obviousthat the numbers of such interactions are minimal for glucose (0),mannose (1) and galactose (1). For simplicity, all of the pyranosestructures are drawn as C1 conformers of β-anomers.
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Fig. 8. Biosynthetic pathways of protein N-glycosylation(asparagine-linked saccharides) in yeast (upper) and mammal(lower). Both organisms utilize the same starting material, i.e.,Glc3Man9GlcNAc2-dolicol, but after the removal of outer Glc3Mthey take completely different pathways. As a result, in yeast,"high-mannose type" structures lacking galactose are constructed,whereas in mammal the common Man9GlcNAc2 precursoroligosaccharide undergoes "processing" and subsequent transfer ofGlcNAc and galactose to convert the oligosaccharides into mature"complex-type" structures.
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Fig. 9. Structures of galactose-containing glycotope.Representative blood group antigens are shown. Data fromref. [19].
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Fig. 10. Two alternative biosynthetic pathways for epimerization.(A) This type of epimerization proceeds via a common linearenediol 6-phosphate intermediate, from which both ketose(fructose) and aldoses (glucose and mannose) are generated. Thereaction essentially the same as Lobry de Bruyn-Alberda vanEckenstein rearrangement [17]. (B) This type of epimerizationproceeds via the 4-keto-intermediate of nucleotide-sugars. For theformation of the 4-keto-intermediate, NAD+ is utilized, and uponits reduction with NADH 4-epimerization is achieved. Such 4-keto-intermediates are variously utilized not only for epimerization of 4-OH but that of 3-OH and 5-CH2OH, as well as for the formation ofdeoxysaccharides, such as L- fucose, L-rhamnose, and variousdideoxyaldohexoses listed in Table 3.
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Fig. 11. Lobry de Bruyn-Alberda van Eckenstein rearrangement.According to Wolform (1928), he obtained glucose (63.5%),mannose (2.5%) and fructose (31%) as a result of reaction ofglucose in saturated lime water at 35; for a week [11].
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Fig. 12. Aldol condensation between DHA and GA as reverseglycolysis. Fischer et al [1] demonstrated that only fructose andsorbose having trans-configurations as regards 3-OH and 4-OH aregenerated as a result of aldol condensation between DHA and GA.Importantly, fructose can be converted into stable aldohexoses,glucose or mannose by Lobry de Bruyn rearrangement, whereassorbose cannot yield such stable aldohexoses. If any, gulose oridose, neither of them naturally occurr.
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Fig. 13. Summary of proposed scenario on the origin of saccharides.The figure is constructed originally on the basis of the previouspaper [19]. As a result of chemical evolution on the prebiotic earth,formose reaction generated small saccharides including GA andDHA, which subsequently undergo aldol condensation yielding fewketohexoses. Among the products, only fructose could be convertedinto the most stable aldohexose glucose and also mannose, and thus,these saccharides formed the first triplet. As the first metabolicpathways were developed by the first living organisms, glucose andmannose were maximally utilized, and a number of "bricolage"saccharides were produced that included galactose as a"recognition" saccharide (glycotope) and ribose as a framesaccharide in nucleic acids. In this context, galactose should beregarded as "late-comer" saccharide relative to glucose andmannose, both classified into the same aldohexose group.
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