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8.5: N-glycosidic Bonds

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    We have just seen that when a second alcohol attacks a hemiacetal or hemiketal, the result is an acetal or ketal, with the glycosidic bonds in carbohydrates providing a biochemical example. But if a hemiacetal is attacked not by a second alcohol but by an amine, what results is a kind of ‘mixed acetal’ in which the anomeric carbon is bonded to one oxygen and one nitrogen.

    Bond line drawing of a mixed acetal.

    This arrangement is referred to by biochemists as an N-glycosidic bond. You may recognize these as the bonds in nucleosides and nucleotides that link the G, C, A, T, or U base to the sugar.

    N-glyosidic bond is between the nitrogenous base and the sugar.

    The formation of \(N\)-glycosidic bonds in ribonucleotides is closely analogous to the formation of glycosidic bonds in carbohydrates – again, it is an \(S_N1\)-like process with an activated water leaving group. Typically, the hemiacetal is activated by diphosphorylation, as illustrated in step A of the general mechanism below.

    Mechanism for formation of an \(N\)-glycosidic bond:

    clipboard_e0c4ae433e14fdddf39dce2c331bf281e.png

    The starting point for the biosynthesis of purine (G and A) ribonucleotides is a five-carbon sugar called ribose-5-phosphate, which in solution takes the form of a cyclic hemiacetal. The critical \(N\)-glycosidic bond is established through substitution of \(NH_3\) for \(OH\) at the anomeric carbon of the ribose. The anomeric \(OH\) group is first activated (step A below) to form an activated intermediate called phosphoribosylpyrophosphate (PRPP). The inorganic pyrophosphate then leaves to generate a resonance-stabilized carbocation (step 1) which is attacked by a nucleophilic ammonia in step 2 to establish the \(N\)-glycosidic bond.

    Ribose-5-phosphate reacts with ATP to produce AMP and PRPP. PRPP loses PPi and is attacked by NH3 to get purine ribonucleotides.

    With the \(N\)-glycosidic bond in place, the rest of the purine base is assembled piece by piece by other biosynthetic enzymes.

    (The mechanism above should look familiar - we saw step A in chapter 9 as an example of alcohol diphosphorylation , and steps 1 and 2 in chapter 8 as an example of a biochemical \(S_N1\) reaction).

    Establishment of the \(N\)-glycosidic bond in biosynthesis of the pyrimidine ribonucleotides and (U, C and T) also begins with PRPP, but here the ring structure of the nucleotide base part of the biomolecule has already been 'pre-fabricated' in the form of orotate:

    PRPP reacts with orotate to produce PPI and pyrimidine ribonucleotides.

    Exercise 10.5.1

    We have just seen an illustration of the formation of an N-glycosidic bond in a biosynthetic pathway. In the catabolic (degradative) direction, an N-glycosidic bond must be broken, in a process which is analogous to the hydrolysis of a glycosidic bond (illustrated earlier). In the catabolism of guanosine nucleoside, the N-glycosidic bond is broken by inorganic phosphate (not water!) apparently in a concerted (SN2-like) displacement reaction (Biochemistry 2011, 50, 9158). Predict the products of this reaction, and draw a likely mechanism.

    Guanosine reacts with Pi.

    Exercise 10.5.2

    Glycoproteins are proteins that are linked, by glycosidic or N-glycosidic bonds, to sugars or carbohydrates through an asparagine, serine, or threonine side chain on the protein. As in other glycosylation and N-glycosylation reactions, the hemiacetal of the sugar must be activated prior to glycosidic bond formation. Below is the structure of the activated sugar hemiacetal substrate in an asparagine glycosylation reaction.

    Bond line drawings of an activated sugar and an asparagine side chain.

    Draw the product of the asparagine glycosylation reaction, assuming inversion of configuration of the anomeric carbon.


    This page titled 8.5: N-glycosidic Bonds is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Tim Soderberg.

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