Answer- Case study- HIV infection- A 33 -year-old, homosexual man..

Case details

A 33 -year-old, homosexual man is recently diagnosed with human immuno deficiency virus (HIV) infection. His CD4+T- cell count is dramatically decreased, and he has a high HIV viral load. He is referred to an infectious disease clinic where they begin him on a nucleoside analog. These drugs inhibit DNA synthesis because they lack which of the following properties required for the normal DNA polymerization?

A. 5′- phosphate

B. 3′ – hydroxyl

C. 7- methyl guanosine triphosphate

D. Poly (A) tail

E. A consensus sequence

Answer- The correct option is B) – 3′-hydroxyl group .The replication proceeds with the polymerization of nucleotides which are linked together by 3′-5’phosphodiester linkage. The initiation of DNA synthesis requires priming by a short length of RNA, about 10–200 nucleotides long. This priming process involves the nucleophilic attack by the 3′-hydroxyl group of the RNA primer on the phosphate of the first entering deoxynucleoside triphosphate with the splitting off of pyrophosphate. The 3′-hydroxyl group of the recently attached deoxyribonucleoside monophosphate is then free to carry out a nucleophilic attack on the next entering deoxyribonucleoside triphosphate again at its phosphate moiety, with the splitting off of pyrophosphate (Figure-1). Of course, selection of the proper deoxyribonucleotide whose terminal 3′-hydroxyl group is to be attacked is dependent upon proper base pairing with the other strand of the DNA molecule according to the rules proposed originally by Watson and Crick .When an adenine deoxyribonucleoside monophosphoryl moiety is in the template position, a thymidine triphosphate will enter and its  phosphate will be attacked by the 3′-hydroxyl group of the deoxyribonucleoside monophosphate most recently added to the polymer. By this stepwise process, the template dictates which deoxyribonucleoside triphosphate is complementary and by hydrogen bonding holds it in place while the 3′-hydroxyl group of the growing strand attacks and incorporates the new nucleotide into the polymer (Figure-1).

DNA Replication

Figure-1- 3’OH group of the pre-existing nucleotide makes a 3′-5′ phosphodiester linkage with the 5-‘phosphate of the incoming nucleotide.

AZT (Azidothymidine) is marketed under the name Retrovir. It was the first drug approved for the treatment of AIDS and HIV infection in 1987. It does not cure AIDS but slows the progression of the disease by inhibiting the replication of the virus. AZT C10H13N5Ois a nucleoside analog of thymidine C10H14N2O5. It lacks an OH group at 3′ position. AZT inhibits  reverse transcriptase, the viral enzyme that allows the RNA genome of the virus to be replicated as DNA. Without the 3′-OH group, further DNA polymerization is inhibited (figure-2) and  this is how AZT reduces viral load by inhibiting the replication of viral genome.

5′-phosphate is not the correct option. 3′-OH is the receiving group for the incoming 5′-phosphate of the template directed new nucleotide. The incoming nucleotide enters in the triphosphate form but is incorporated in the monophosphate form.

7- Methyl Guanosine triphosphate and poly (A) tail are present in the messenger RNA to stabilize the transcript. A consensus sequence is a DNA sequence that is found at the promoter region and functions to bind RNA polymerase for the transcription of the genes.

Hence out of the given options, 3′-OH group is the most suited option.

aztthymidine

Figure-2- Zidovudine is a structural analog of thymidine but lacks 3′- OH group, instead has N3 , thus the incoming deoxyribonucleotide fails to make a 3-5′ phosphodiester linkage and further polymerization is inhibited.

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