A 34-year-old homosexual man has recently been diagnosed with HIV (human immunodeficiency virus) infection. His CD4+ T-cell count has dramatically decreased, and he has a high viral load. He has been referred to an infectious disease clinic where he has been prescribed with a nucleoside analog. The nucleoside analogs inhibit DNA synthesis. Which of the following chemical groups essentially required for DNA polymerization is absent in the nucleoside analogs?
A. 5′ Phosphate
B. 3′ Hydroxyl
C. 2′ Methyl
E. 5′ Hydroxyl.
The correct answer is- B-3′ Hydroxyl.
Nucleosides are derivatives of purines and pyrimidines that have a sugar linked to ring nitrogen of a heterocycle called heterocyclic “base”. The sugar is linked to the heterocyclic base via a β -N-glycosidic bond, almost always to N-1 of a pyrimidine or to N-9 of a purine (Figure-1).
Mononucleotides are nucleosides with a phosphoryl group esterified to a hydroxyl group of the sugar (Figure-1).The 3′- and 5′-nucleotides are nucleosides with a phosphoryl group on the 3′- or 5′-hydroxyl group of the sugar, respectively.
Figure-1 -The structure of a -5′- Nucleotide. The numerals with a prime (e.g., 2′ or 3′) distinguish atoms of the sugar from those of the heterocyclic base.
The sugar in ribonucleotides is D-ribose, and in deoxyribonucleoside it is 2-deoxy-D-ribose (Figure-2).
Figure-2- An OH group is present at 2′ position in a ribonucleotide, whereas only H is present in a deoxyribonucleotide (deoxy means oxygen has been removed from the OH group).
Since most nucleotides are 5′-, the prefix “5′-” is usually omitted while naming them. Additional phosphoryl groups linked by acid anhydride bonds to the phosphoryl group of a mononucleotide form nucleoside diphosphate and triphosphates. The 5′-phosphoryl group of a mononucleotide can esterify a second —OH group, forming a phosphodiester (Figure-3). Most commonly, this second —OH group is the 3′-OH of the pentose of a second nucleotide. Phosphodiester bonds link the 3′- and 5′-carbons of adjacent monomers in a polynucleotide such as RNA or DNA.
Figure-3- 3′-5′ Phosphodiester linkage is an anhydrous linkage that joins nucleotides together in a polymer.
Synthetic analogs of purines, pyrimidines, nucleosides, and nucleotides altered in either the heterocyclic ring or the sugar moiety (Figure-4) have numerous applications in clinical medicine . Their toxic effects reflect either inhibition of enzymes essential for nucleic acid synthesis or their incorporation into nucleic acids with resulting disruption of base-pairing.
Figure-4- Nucleoside analogs are modified either at the level of heterocyclic bases or at the 3’OH group. The OH group is replaced by any other chemical group that prevents further polymerization process.
Nucleoside analogs in the treatment of HIV infection
Nucleoside analogues, which constitute the most effective family of antiretroviral drugs, operate by mimicking nucleic acids normally incorporated into viral DNA. They interfere with reverse transcriptase and thus prevent infection.
Figure-5- Structure of Zidovudine (AZT). AZT lacks 3′-OH group, hence prevents DNA polymerization.
Nucleoside analogues can be placed in two groups, those replacing thymidine, such as AZT(Figure-5) and d4T(Stavudine (2′,3′-dideoxythymidine) active against HIV, which protect activated T cells from infection, and non-thymidine analogues such as Dideoxyinosine (ddI) and 3TC(Lamivudine-2′,3′-dideoxy-3′-thiacytidine), which protect resting T cells. The mechanism of action of AZT is explained in Figure-6, that shows the mechanism of inhibition of viral DNA polymerization.
Figure-6- Mechanism of action of AZT. AZT is first phosphorylated by the host enzyme system to form a nucloside triphosphate since the nucleotides enter the polymerization process in the triphosphate form. After incorporation, the polymerization process gets inhibited due to lack of 3’OH group which is needed for forming 3′-5’phosphodiester linkage.
Nucleotide analogues have the same action but are based around a different sugar.
As regards other options
5′ phosphate- Phosphate is not present in a nucleoside.
Similarly 2′ Methyl is also not there in a nucleoside
3′-Phosphate can be there in a nucleotide but phosphate at none of the places 3′ or 5′ is present in a nucleoside.
5’Hydroxyl is not modified, the linkage is 3′-5’phosphodiester, the 3’OH group of existing nucleotide forms a linkage with 5’Phosphate of incoming nucleotide, and hence the modification of 3′ OH group can inhibit further polymerization of a polynucleotide such as DNA or RNA.
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