Nucleoside Analogs and Deoxyadenosine Analogs

by Kevin Ahern, PhD

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    00:00 Well we’ve now gone through all the different considerations of the synthesis of nucleotides and nucleosides, and you’ve learned something about the importance of these structures as they relate to the ability of enzymes like DNA polymerase and RNA polymerase to use them to make DNA and RNA. Use of that knowledge to design derivatives of the nucleotides and inhibit specific enzymes like DNA polymerase or like RNA polymerase can be effective as a way of killing or stopping infective agents that affects human health. So these nucleoside and nucleotide analogs that I’m going to describe are designed for that purpose. Now, there are nucleoside analogs, not nucleotides for the most part that are given as medications, although they become nucleotides because the nucleosides can readily cross the cell membrane. Nucleotides cannot do that so the difference between a nucleotide and a nucleoside, I’ll remind you, is that a nucleotide has a phosphate and a nucleoside does not. So AMP is a nucleotide because it has a phosphate on the upper left portion of it and adenosine is the equivalent molecule without the phosphate that’s a nucleoside. So all of the medications I described to you here are designed as nucleosides, their aim to cross that cell membrane barrier, and then when they get inside the cell, they have to be phosphorylated by various kinases in order to compete with the native substrates: ATP, GTP, UTP, CTP for binding on the polymerases. So, that phosphorylation is critical and going after it gets into the cell. Now, the analogs are phosphorylated, as I said, inside the cell and the salvage systems that we talked about earlier are critical in that process. Let us now consider some of these individual nucleotide, nucleoside analogs to understand what they do and how their structure relates to their ability to function as an antimicrobial agent. Deoxydenosine has a structure like you see on the screen. It’s lacking hydroxyl at position 2 which is what gives it its deoxy name. It has an adenine linked as a base. A derivative of this compound on this didanosine or DDI looks like the structure you see on the left. It has 2 subtle differences between deoxyadenosine. First, in the place of adenine, it contains the modified bass hypoxanthine.

    02:26 Hypoxanthine was the form of adenine that was found in the salvage reactions. It behaves very much like, as far as the cell is concern, very much like an adenine at that point. The second difference is that the 3 prime portion of the ribose ring lacks a hydroxyl. Now, if you remember your molecular biology with DNA polymerase and RNA polymerase, that 3-prime hydroxyl is necessary for the attachment of the next nucleotide during the building of, in this case, a DNA molecule.

    02:59 The hydroxyl at the 5 prime position can be used to link the modified nucleotide to the previous nucleotide but when there is no treat from hydroxyl, the next nucleotide cannot be attached to it. That means that during the synthesis of DNA, didanosine is what we call as a chain terminator.

    03:19 Now, in order for this thing to function, it has to first of all be phosphorylated, so we’re putting this in as a nucleoside. It gets phosphorylated and used by DNA polymerase and there is where it terminates the DNA chain. This compound is used primarily as an anti-HIV treatment because the HIV DNA polymerase will recognize this as a substrate to build DNA but it gets stuck because it cannot extend as chain once it has been built in to the growing DNA molecule. Another related compound is vidarabine or something known as ara-A. Ara-A has a hydroxyl at position 2. It has an adenine as its base, so it’s very much like the deoxyadenosine. However, that hydroxyl is in an odd position. You can see it pointing up and if we had a ribo version that would be pointing down. This compound right here contains the sugar arabinose in place of deoxyribose. The similarity allows this molecule to be bound by a viral DNA polymerase but it cannot function and cannot be added properly to a DNA molecule being synthesized. It is therefore a competitive inhibitor for dATP and therefore gums up the viral polymerase and stops it from being able to function.

    04:40 This compound is therefore used as an antiviral agent. Herpes virus is one virus that this is commonly used to treat.

    About the Lecture

    The lecture Nucleoside Analogs and Deoxyadenosine Analogs by Kevin Ahern, PhD is from the course Purine and Pyrimidine Metabolism.

    Included Quiz Questions

    1. They are commonly competitive inhibitors of nucleotides when present in cells.
    2. They are commonly partial agonists of nucleotides when present in cells.
    3. Nucleotides move into cells more easily than these nucleoside analogs.
    4. These analogs are dephosphorylated once they enter the cell.
    5. These analogs cannot be phosphorylated because of their structure.
    1. Viral replication in the infected cells
    2. Viral adhesion to the cell surface receptors present on the outer surface of the cell membrane
    3. Viral replication by halting the movement of ribosomes
    4. Viral replication by halting the assembly of viral proteins
    5. Viral replication by facilitating the formation of defected viral protein coats
    1. Zalcitabine
    2. Phosphorodiamidate Morpholino
    3. Methotrexate
    4. Anthracycline
    5. Levofloxacin

    Author of lecture Nucleoside Analogs and Deoxyadenosine Analogs

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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