Genetics Corrected

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    Introduction lecture in Genetics

    First, the Dr talked a little about the course, the textbook

    required, exams, and other doctors of the second and final

    materials.

    This lecture is a refreshment of basic knowledge of nucleic

    acids, so you have to know the basic information and the concept

    of the structure and the function of nucleic acids (DNA & RNA)

    As you know, DNA and RNA are composed of nucleotides.

    ** A nucleotide is composed of three major components:

    1. A nitrogenous base (examples: Adenine, Guanine, Cytosine,

    Uracil and Thymine*)

    2. A sugar.

    3. A phosphate group.

    *There is a difference between thymine and thiamine which is

    that Thymine is a nitrogenous base while thiamine isvitaminB1 derivative.

    **Nitrogenous bases are of two major categories:

    1. Purines (adenine and guanine).

    2. Pyrimidines (cytosine, uracil and thymine)

    We are going to see how these nitrogenous bases are

    synthesized and how they are broken down, because there are alot of genetic diseases which are concerned with the metabolism

    (synthesis and degradation or oxidation) of nitrogenous bases.

    As you know, any synthetic process is a multi-enzymatic

    reaction process as well as the degradation or oxidation process,

    so a deficiency in any of those enzymes as a result of defects in

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    the genes that are responsible for these enzymes will result in a

    genetic disease.

    There are famous genetic diseases related to defects in the

    biosynthesis or degradation of those nitrogenous bases that

    compose the gene, the DNA and the chromosome.

    **The Dr starts giving from the slides**

    - Some important functions of nucleotides:

    1. Incorporation into ribo and deoxy-ribonucleic acids.

    (Ribo=ribose sugar)

    (Deoxy=deoxyribose sugar ribose sugar without an oxygen

    at a specific carbon atom-.SO, as you see, nucleotides are

    important components in ribonucleic acid ((RNA )) or

    deoxyribonucleic acid ((DNA)) structures.

    And as you know DNA carries the genetic information within it

    in a gene form and those genes are carried in chromosomes that

    will be transmitted from one generation to another.

    2. Areservoir of energy for metabolic reactions (ATP, GTP)

    You know about ATP, GTP, UDP, UTP (NUCLEOTIDES) and

    they are important as energy currencies in the body.

    3. Carriers of activated intermediates (UDP-glucose)*.

    *UDP- glucose is involved in the synthesis of glycogen which

    requires a primer and glucose but the glucose can't be involved inthe synthesis of glycogen unless it's activated by being linked to a

    nucleotide. An example of these nucleotides is UTP which will

    attach to glucose to form UDP-glucose.

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    4. Structural components of essential cofactors (NAD+,FAD,

    NADP+ , CoA) .

    5. Regulators of metabolic enzymes.

    All the metabolic regulatory enzymes are regulated by different

    nucleotides. For example, High ATP could inhibit some enzymes &high ADP could activate some enzymes, especially in carbohydrate

    & fat metabolism.

    The pathway of purine synthesis is composed of many

    enzymes. We are not required to memorize those enzymes at all

    but I want you to remember the general overview of the metabolic

    pathway.

    There are objectives in the slides that we are going toachieve in this series of lectures, I want you to read them and

    know if we have covered them all. And if you have any problem,

    ask or read more about them in the book.

    1) THE PURINES

    - Adenine (6-aminopurine)

    - Guanine (2-amino-6-oxy

    purine), and some

    derivatives of them

    like:

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    It's useful to go to your book and look at the structures of CoA,

    FAD, NAD+ and NADP+. You will see that nucleotides are one of

    the principle components of these cofactors.

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    - Hypoxanthine (6-oxy purine)

    - Xanthine (2, 6-dioxy purine).

    You have to remember the structure of these rings. Because

    as a result of the resonance of these structures (YOU know what is

    resonance from organic chemistry ) there will be some change

    in these structures and that will cause mutations (as you will see).All Genetic diseases are caused by mutations.

    So you should know the structure of theses purine nitrogen

    bases, because there will be a base pairing process between

    complementary purines and pyrimidines in order to form the

    double stranded DNA which forms genes that form chromosomes.

    So any defect in the base pairing will cause defects in the

    genetic information flowing from DNA to RNA or from DNA to DNAor from RNA to protein.

    ** It's important to remember and recognize:

    1) The system of numbering the Carbon atoms in these purine

    rings.

    2) The side chains that are located on either C or N atoms.

    Also, these side chains are important in forming H-bonds withcomplementary nitrogen bases. So any change in the structure,

    because of the resonance, will change the chemistry of these side

    chains and that will affect the base pairing process.

    (For example, instead of pairing with thymine, adenine could

    base pair with cytosine) which will lead to mutations that will

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    result in mistaken protein molecules which will cause defected

    phenotype (external appearance) because the gene itself or the

    genotype has been changed.

    2. The Pyrimidines

    The Pyrimidines are:

    Uracil = 2,4-dioxy pyrimidine

    Thymine = 2,4-dioxy-5-methyl pyrimidine

    Cytosine = 2-oxy-4-amino pyrimidine

    Orotic acid = 2,4-dioxy-6-carboxy pyrimidine

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    **You are required to remember the structure, numbering

    system and the positions of the side chains.

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    Now, we come to some important uses for nitrogen bases and

    some of the medical importance of them:

    1. Critical in cancer treatment: most of the drugs that are used incancer treatment are analogous to those purine & pyrimidine

    nitrogen bases.

    They are not exactly the same but they are homologous

    (analogous) to the structure of those nitrogen bases so they could

    be incorporated during the DNA replication of cancer cells or

    could be incorporated in the replication of a cell which is infected

    by a virus .

    Once they are incorporated ( not the authentic nitrogen

    base but the analogous one which is the drug that is used

    in cancer treatment ) in the DNA or the RNA of those cells , the

    base pairing will be different from normal thus the DNA replication

    or transcription will be stopped and thus the cancer cell growth

    will be stopped.

    2. Antiviral therapies.

    3. Acyclovir and herpes.

    4. Important inborn errors and pathologies.

    5. Adenosine deaminase and SCIDS.

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    **Question: Why don't these drugs affect the DNA of other

    cells?

    (I couldn't hear the question but I conclude it from the answer)

    **Answer: they could go to most cells, but the cancer cellscould be more sensitive to accept those purine or pyrimidinestructures (drugs). If not, this could be directed by using specificantibodies or other means in order to direct those agents to thetarget cells. Those agents will be labeled by these specificcompounds or antibodies. And the cancer cell will have specificantigen to which the antibodies will attach.

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    6. Lesch-Nyhan Syndrome.

    7. Hyperuricemia.

    ** This is the pathway in general of purinecompounds:

    **As you see, the pathway starts from ribose-5-P which

    comes from the Hexose monophosphate shunt (Pentose

    Phosphate Pathway).

    **The parent compound that is converted finally to ATP &

    GTP is the IMP (inosine monophosphate).** This pathway is composed of tens of biochemical

    reactions, but you are not required to memorize them but I want

    you to remember the concept here.

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    Note : this figure is important and everything was said by the DR is

    exactly like what is written in it so I didn't write what the Dr said

    except for the other things that are not mentioned.

    ** Question: what is the One-carbon Pool?** Answer: In general it's the tetrahydrofolate. So folate is

    very important in the synthesis of Genes DNAChromosomes. So if we have folate deficiency, all theprocess will be stopped. Tetrahydrofolate is found in manyforms, which are N-10 or N-5 methylene or ethylene or methyltetrahydrofolate. We have also S-adenosylmethionine orabbreviated as SAM. Both (tetrahydrofolate and SAM) arecomposed of one-carbon pool donor that can donate one-

    carbon pool.

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    ** UMP is Uridine Monophosphate NOTUracil monophosphate.

    -The difference between them: Uridine is a nucleoside (nitrogen

    base+ sugar) but Uracil is a nitrogen base.

    ** Somewhere in the pathway, after we form a pyrimidine

    parent compound (Orotate) then it will attach to PRPP to form UMP

    which will be converted to UTP by phosphorylation 2 times which

    will be converted to CTP by amination- deamination process.

    -Also, UMP will be