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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:
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4. Structural components of essential cofactors (NAD+,FAD, NADP+ , CoA) . 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. 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 to achieve 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-amino purine) - Guanine (2-amino-6-oxy purine), and some derivatives of them like:
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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 DNA or 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 with complementary 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
**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 in cancer 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. **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 cells could be more sensitive to accept those purine or pyrimidine structures (drugs). If not, this could be directed by using specific antibodies or other means in order to direct those agents to the target cells. Those agents will be labeled by these specific compounds or antibodies. And the cancer cell will have specific antigen to which the antibodies will attach. 2. Antiviral therapies. 3. Acyclovir and herpes. 4. Important inborn errors and pathologies. 5. Adenosine deaminase and SCIDS.
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** This is the pathway in general of purine Note : this compounds: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.
**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 & ** Question: what is the One-carbon Pool? GTP is the IMP (inosine monophosphate). ** This In general composed of tens of biochemical ** Answer:pathway is it's the tetrahydrofolate. So folate is reactions, but you are not required to memorize them but I want very important in the synthesis of Genes DNA Chromosomes. So if we have folate deficiency, all the you to remember the concept here. process will be stopped. Tetrahydrofolate is found in many forms, which are N-10 or N-5 methylene or ethylene or methyl tetrahydrofolate. We have also S-adenosylmethionine or abbreviated as SAM. Both (tetrahydrofolate and SAM) are 8| Page composed of one-carbon pool donor that can donate onecarbon pool.
** UMP is Uridine Monophosphate NOT Uracil 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 converted to deoxy-TMP. **Why to dTMP Not TMP? Because we don't need TMP at all, we need dTMP because it's in the DNA not in RNA. So it's more economical to the cell to synthesize the deoxy one directly without passing through the TMP. ** Aspartate (acidic amino acid) will form the skeleton of the purine and pyrimidine ring. ** Carbamoyl phosphate is composed of ammonia, carbon dioxide and phosphate. There is a very important enzyme which is carbamoyl phosphate synthetase that will synthesize the carbamoyl phosphate from ammonia, CO2 and ATP.
** This is a purine ring: These are the sources of each atom in the
purine ring:
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-This is the general scheme : (Ribose-5-phosphate PRPP (5-phosphoribosyl-1pyrophosphate)IMPAMP and GMP(the two purines we are talking about).
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If there is no control in the biosynthesis of purines then the cell will continue producing these purines and that could form a toxic material to the cell. So the synthesis must be controlled, it must be accelerated when the cell needs more of those purines and must be inhibited when the cell has a lot of those purines.
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That pathway (about purine biosynthesis) is called the conventional pathway. There is another pathway which is less expensive to synthesize purine rings or purine nucleotides called the salvage pathway. This pathway uses PRPP and a purine to synthesize a purine ribonucleotide.
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Purine compounds could be taken via diet; they could be obtained via the degradation of nucleotides or deoxynucleotides when the DNA is degraded. Using a very important enzyme called HYPOXANTHINEGUANINE PHOSPHORIBOSYL TRANFERASE (HGPRT) will lead the PRPP and the purines to give the purine nucleotides.
Any defect in this enzyme could lead to genetic diseases or a syndrome called LESCH-NYHAN syndrome or the GOUT that will cause pain.
You will learn more about it in pathology but when it is mentioned, you have to remember HGPRT that is important in salvage in purine synthesis.
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Uric acid is a compound which is important in our body. It is found in our cells & in our blood. It is important as an antioxidant agent when it is found under normal physiological concentration. But when it exceeds its normal physiological concentration, it will precipitate as urate in the joints of fingers and cause pain because of defects in guanosine phosphoribosyl pyrophosphate.
we will take more about it later . & we will continue the introduction next lecture .
Thank You Good luck everyone in this semester .. We hope the best to all of you .. And Forgive us if there is any mistake ..
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