genetics corrected

7/31/2019 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 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 throughthe 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 thepurine ring:

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** It is important to know how the synthesis of purine is

regulated.

- -This is the general scheme :

- (Ribose-5-phosphate PRPP (5-phosphoribosyl-1-

pyrophosphate)

IMP

AMP and GMP(the two purineswe 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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How this pathway is regulated?!!

When a lot of IMP is converted to GMP via xnthylate ,the end

product which is the GMP will come and inhibit this enzyme that

convert IMP to GMP ,so no more IMP is converted to GMP

because the cell has excess of GMP.

The same thing if the cell has excess AMP, so no need to

convert IMP to adenylo-succinate then to AMP, so AMP will come

by feedback inhibition and inhibit this enzyme that converts IMP

to adenylo-succinate.

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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** There is another site of regulation (ribose -5-phosphatePRPP)

It is inhibited by the end products (AMP, GMP and IMP )


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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 HYPOXANTHINE-

GUANINE PHOSPHORIBOSYL TRANFERASE (HGPRT) will lead thePRPP 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 painbecause 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 ..

**Done By :

Bara' Al-Zu'bi

Haya Al-Rawabdeh

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genetics corrected

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