Biochemistry - The Chemical Reactions of Living Cells, Volume 2 - D. Metzler 1980

Biosynthesis: How New Molecules Are Formed
Synthesis and Utilization of Oligosaccharides

Our common dietary sugar, sucrose, is synthesized in all green plants and exclusively in them, where it mainly serves as a transport form of sugar. Sucrose is formed both in METABOLISM/14.html">Chloroplasts and in other sites where starch accumulates, and it is highly soluble in Water. Since the semiacetal groups of its two constituent carbohydrate rings are blocked, it is chemically inert¹⁾. However, from a thermodynamic standpoint, sucrose is an active compound, as its glucosyl group transfer potential is 29.3 kJ∙mol^-1. Transporting sugar in the form of a disaccharide offers the evolutionary advantage for plants that a disaccharide creates lower osmotic pressure than the equivalent amount of sugar transported as a monosaccharide.

¹⁾ However, sucrose is extremely sensitive to acid-catalyzed Hydrolysis.

The Biosynthesis of sucrose [7] involves UDP-glucose and fructose-6-phosphate [equation (12-8)]:

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The metabolism of sucrose in animals begins with the hydrolysis of the disaccharide into fructose and glucose by the action of sucrase (invertase) [equation (12-9), reaction a]. This enzyme has also been found in Higher Plants and Fungi. The Cleavage of sucrose by sucrose phosphorylase [equation (12-9), reaction b], which occurs in certain Bacteria, leads to The formation of activated glucose-1-phosphate, which can then be directly utilized as a substrate in catabolic processes. The breakdown of sucrose to support biosynthetic processes proceeds according to reaction c in equation (12-9), during which UDP-Glucose is formed in a single step.

Among Disaccharides sharing largely the same properties as sucrose is trehalose ("mushroom sugar", see ch. 2, sec. B,2), which consists of two a-glucose residues linked by a 1→1 bond. Trehalose is chemically more inert than sucrose and, in particular, is highly resistant to acid hydrolysis. The biosynthetic pathway of trehalose [equation (12-10)] is entirely analogous to that of sucrose. Trehalose is found in fungi and also in many insects [8]. In insect hemolymph, this compound serves not only as a transport form of sugars but also acts as an antifreeze.

The principal milk carbohydrate, lactose, is formed by transferring a glycosyl residue from UDP-galactose directly to glucose [equation (12-11), reaction a]. A similar transfer of a galactosyl residue to N-acetylglucosamine [equation (12-11), reaction b] occurs in many animal Tissues. Here we encounter a remarkable example of regulatory enzyme modification. The transferase catalyzing reaction b [equation (12-11)], in the presence of a-lactalbumin, becomes lactose synthetase, i.e., The enzyme catalyzing reaction a of equation (12-11). Lactalbumin was discovered in milk long before its regulatory function was elucidated.

Many higher plants contain the trisaccharide raffinose and related Oligosaccharides. Raffinose is synthesized by transferring a galactosyl residue from UDP-galactose to the hydroxyl group at position 6 of the glucose ring of sucrose [equation (12-11), reaction c]. Another important reaction is The transfer of a galactosyl residue to myo-Inositol [equation (12-11), reaction d]. The resulting galactinol is widely distributed in the plant kingdom. Galactinol, in turn, serves as a specific donor of activated galactosyl residues. Thus, many plants contain stachyose and higher homologs formed by the successive addition of a-D-galactosyl residues to the 6-OH group of galactose in raffinose. Apparently, these sugars play The Role of antifreezes in plants.

One of the important reactions involving UDP-glucuronic acid is the formation of glucuronides (glucosiduronic acids). Glucuronides are excretory products eliminated in the urine; they are formed by replacing the UDP residue in UDP-glucuronic acid with compounds such as phenol or benzoic acid. In the case of phenol, phenyl glucuronide is synthesized, while in the case of benzoic acid (which is partially excreted as hippuric acid; see Supplement 9-A), an ester is formed via the same substitution reaction [equation (12-12)].

Among the interesting sugar derivatives found in nature are numerous Antibiotics, which frequently also contain amino groups (e.g., supplement 12-A; Fig. 12-10) [9, 10].

Supplement 12-A

Biosynthesis of Streptomycin

Streptomycin belongs to the family of aminoglycoside antibiotics widely used in medicine. Other members of this family include kanamycins, neomycins, and gentamicins. All of them are basic, water-soluble CARBOHYDRATES containing three or four unusual cyclic sugars. The primary precursor of streptomycin is D-glucose: all three streptomycin rings are formed from it. How 2-deoxy-2-methylamino-b-glucose is synthesized is still not entirely clear, but the synthetic Pathways of the other two rings—L-streptose and streptidine—have been fully characterized^b,c. The precursor of streptidine is a nucleoside diphosphate monosaccharide—an intermediate in the synthesis of L-rhamnose [equation (12-7)]. The carbon-carbon bond undergoes aldol cleavage between C-2 and C-3, as shown in the following scheme (step a):

Note that the open-ring compound is depicted as an enediol, which in the subsequent aldol reaction b recyclizes into a five-membered ring with a substituent at C-3. The L-streptosyl nucleoside diphosphate formed in this manner serves as the streptose donor in streptomycin synthesis.

Streptidine, a basic cyclic alcohol, is formed from myo-inositol [equation (12-3)], which in turn is derived from glucose-6-phosphate. The Introduction of guanidine groups occurs via The oxidation of the corresponding hydroxyls to carbonyl groups, followed by Transamination with specific amino group Donors. In the reaction depicted in the following equation, glutamine serves as the amino group donor during transamination, and a-ketoglutaramic acid is formed as the keto acid:

An amidine group from Arginine is subsequently attached to the amino group introduced into the ring, with the transfer occurring via nucleophilic substitution. However, this is preceded by phosphorylation at position 2; following the transfer of the amidine group and the Formation of the guanidine group, the phosphate group is cleaved off by the action of a phosphatase. Here again we encounter a phosphorylation-dephosphorylation reaction sequence (ch. 11, sec. B,3) that ensures the main process proceeds in the desired direction. The incorporation of the second guanidine group proceeds in an entirely analogous manner via oxidation at the third position followed by transamination (in this case, Alanine serves as the amino group donor), phosphorylation, and transfer of the amidine group from arginine. However, The final stage—the hydrolytic Cleavage of the phosphate group, which in this case is located at the C-6 position—is carried out only after the synthesis of streptomycin phosphate is completed, i.e., after The addition of the other two cyclic sugars. The latter occurs through transfer from nucleoside diphosphate precursors.

Streptomycin can be inactivated by the action of Enzymes whose synthesis depends on genetic resistance factors (ch. 15, sec. G,7). This category includes, in particular, enzymes that catalyze the Transfer of phosphate or adenylyl groups to streptomycin at the sites indicated by arrows on the structural formula. It follows that while dephosphorylation leads to the formation of the active antibiotic, phosphorylation of the other site results in the inactivation of the antibiotic.

^a Benveniste R., Davies J. Annu. Rev. Biochem., 42, 471—506 (1973).

^b Luckner M., Secondary Metabolism in Plants and Animals, pp. 78—80, Academic Press, New York, 1972.

^c Walker J. B., Skorvaga M., JBC, 248, 2441—2446 (1973).