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Hematology > Biochemistry-Purine:Pyrimidine Synthesis > Flashcards

Biochemistry-Purine:Pyrimidine Synthesis Flashcards

1
Q

What processes require rapid DNA and RNA synthesis?

A

Embryogenesis, hematopoiesis, rapidly regenerating tissues (enterocytes), tumor growth.

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2
Q

How do you number pyrimidines?

A

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3
Q

How do you number purines?

A

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4
Q

What is this molecule?

A

Nitrogenous base + Sugar + Phosphate = Nucleotide

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5
Q

What is this molecule?

A

This is the purine nucleoside: adenosine.

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6
Q

What is this molecule?

A

This is the purine nucleotide: inosinic acid (IMP). Note that the nitrogenous base is actually called hypoxanthine.

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7
Q

What is this molecule?

A

This is the purine nucleotide: guanylic acid (GMP)

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8
Q

What is this molecule?

A

This is the purine: uric acid. Note that this is the product of purine breakdown and we do not have a way to further break it down.

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9
Q

What molecule is this?

A

This is the pyrimidine nucleoside: Cytidine

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10
Q

What molecule is this?

A

This is the pyrimidine nucleotide: uridylic acid (UMP)

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11
Q

What molecule is this?

A

This is the pyrimidine nucleotide: orotidylic acid (OMP)

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12
Q

What are the purine bases, their nucleosides and their nucleotides?

A

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13
Q

What are the pyrimidine bases, their nucleosides and their nucleotides?

A

*

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14
Q

What are 2 ways we get ribonucleotides?

A

1) De novo synthesis 2) Salvage

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15
Q

What has a higher concentration in the body: ribonucleotides or deoxyribonucleotides?

A

Ribonucleotides

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16
Q

What enzymes are responsible for the steps a, b and c shown below?

A

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17
Q

What happens to the nucleotides and bases that are not salvaged?

A

They are converted to uric acid and secreted in the urine (2/3) and feces (broken down by bacteria).

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18
Q

A patient presents with a chills, a fever and a painful swollen big toe. He has had a history of this in the past, but attacks are becoming more frequent. What will be the ultimate result of his condition if he does not receive treatment?

A

There are 4 phases of gout: 1) Asymptomatic hyperuricemia 2) Acute attacks of gouty arthritis 3) Intercritical periods 4) Chronic tophaceous gout (permanent deformities of the joint) happens without treatment.

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19
Q

What is the saturation point of uric acid in the serum?

A

7mg/dL

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20
Q

What do you use to treat the acute phase of gout?

A

NSAIDs for the acute phase. Colchisine is a microtubule inhibitor that prevents migration of PMNs to site of inflammation, prevents phagocytosis and prevents release of inflammatory mediators

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21
Q

A mother brings in her 3-9 month old child who can’t hold his head up or sit unsupported. He cannot crawl and is diagnosed with cerebral palsy. As he gets old her begins to demonstrate serious self-injurious behavior. What is most likely causing the disease in this kid?

A

Lesch-Nyhan Syndrome. This is an inherited X-linked AR deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Deficiency in HGPRT results in over production of uric acid resulting in debilitating neurological symptoms.

22
Q

What ingredients go into making the purine ring?

A

*

23
Q

What pathway supplies the scaffold on which the nucleotides are build?

A

Hexose monophosphate shunt generates ribose-5-phosphate

24
Q

What regulates the activation step in nucleotide synthesis?

A

PRPP synthetase and ATP activate ribose-5-phosphate to PRPP. PRPP synthetase is inhibited by ADP, GDP and other nucleotides.

25
Q

What is the committed step in nucleotide synthesis? What regulates it?

A

Glutamine phosphoribosyl amidotransferase (glutamine:PRPP amidotransferase or PRA synthase) It converts PRPP to PRA with water and glutamine. It is inhibited by AMP, GMP and IMP. It is activated by PRPP. Note that AMP + IMP/GMP synergistically inhibits the enzyme.

26
Q

What molecule is the branch point from which you make AMP and GMP?

A

IMP. Aspartate is added to IMP by the enzyme adenylosuccinate synthetase, then adenylosuccinase pops off fumarate to form AMP. IMP is oxidized by the enzyme IMP dehydrogenase to form XMP, then ATP and glutamine react with XMP to form GMP by the enzyme GMP synthetase.

27
Q

What inhibits synthesis of AMP and GMP?

A

AMP competitively inhibits adenylosuccinate synthetase. GMP competitively inhibits IMP dehydrogenase.

28
Q

What is reciprocal substrate utilization?

A

ATP is used in the synthesis of GMP and GTP is used in the synthesis of ATP. Excess of one (ATP or GTP) will drive increased synthesis of the other.

29
Q

What things regulate purine synthesis?

A

*

30
Q

What enzyme defect can cause gout due to decreased regulation by GMP, IMP and AMP?

A

PRPP synthetase mutations. GMP, IMP and AMP are responsible for feedback inhibition of PRPP synthetase. If they cannot effectively inhibit the enzyme, it will be hyperactive and you will have increased purine synthesis and consequently increased uric acid production.

31
Q

How are purine bases salvaged?

A

The purine base adenine reacts with PRPP and the enzyme APRT to form the nucleotide AMP. Hypoxanthine and Guanine both react with PRPP and the enzyme HGPRT to form the nucleotides IMP and GMP respectively.

32
Q

What enzymes are responsible for the breakdown of adenine and guanine nucleotides to uric acid?

A

Adenine nucleotides -> Hypoxanthine. Xanthine oxidase takes hypoxanthine to xanthine and then xanthine to uric acid. Guanine nucleotides are broken down straight to xanthine and then xanthine oxidase takes it to uric acid.

33
Q

How is allopurinol an effective medication for management of gout?

A

It competitively inhibits xanthine oxidase, preventing breakdown of hypoxanthine and xanthine. Patients will have build up of hypoxanthine and xanthine; hypoxanthine is more soluble than uric acid and xanthine has about the same solubility so it is excreted easier. Additionally, this build up causes increases in the nucleotide precursors and decreases the rate of de novo synthesis. This is good because increased de novo synthesis generates more uric acid.

34
Q

What enzyme deficiencies in purine metabolism result in immunodeficiency diseases?

A

Purine nucleoside phosphorylase deficiency and adenosine deaminase deficiency (results in severe combined immunodeficiency disease, SCID)

35
Q

How is energy production in the muscle supported by purine metabolism?

A

Purine-nucleotide cycle. When muscle contracts you generate ADP. 2 ADPs combine to form ATP and AMP by the enzyme adenylate kinase. AMP -> IMP by AMP deaminase. IMP -> adenylosuccinate by the enzyme adenylosuccinate synthetase and Asp + GTP. Adenylosuccinate -> fumarate by the enzyme adenylosuccinase and creates another plug into the TCA cycle for energy.

36
Q

Why are males at higher risk for generation of gout?

A

Males have higher levels of muscle mass. This means that through the purine-nucleotide cycle, more AMP and IMP is generated which can be degraded to uric acid.

37
Q

What structures make up the pyrimidine ring?

A

*

38
Q

What ingredients go into making pyrimidines?

A

Gln + CO2 + 2ATP go to carbamoyl phosphate via the enzyme CPS II

39
Q

Where do the first 3 reactions of pyrimidine synthesis take place? What about the last 2?

A

ATC, DHO and DHODH all catalyze reactions on the single polypeptide CAD. The last two, OPRT & OMPDC, take place on the single polypeptide UMP synthase.

40
Q

What regulates the first stamp in pyrimidine synthesis?

A

UTP and CTP inhibit CPS II

41
Q

A patient presents with anemia and high levels of orotic acid in his urine. What is causing his condition? How do you correct the anemia?

A

Hereditary orotic aciduria is a condition where UMP synthase is lacking and you get build up of orotic acid in the blood. Since they are not making UTP and CTP, they are not making pyrimidine nucleotides and erythropoiesis shuts down in the bone marrow. Giving the patient uridine will inhibit CPS II, decrease the amount of orotic acid forming and increase UTP available for use in erythropoiesis.

42
Q

Once UMP completes the formation of UTP, how do you get CTP? What stimulates this enzyme?

A

CTP Synthetase. GTP stimulates this enzyme. This makes sense because G’s bind with C’s in DNA and if you have lots of G’s you need more C’s.

43
Q

Why don’t pyrimidines cause gout?

A

They are degraded all the way down to CO2 and H2O.

44
Q

What enzyme is necessary to bring a nucleoside to a deoxynucleoside that can be used for DNA synthesis?

A

Ribonucleotide reductase.

45
Q

What happens to DNA synthesis if the hexose monophosphate shunt is turned off?

A

You get loss of NADPH available to reduce thioredoxin in the enzyme ribonucleotide reductase. Reduced thioredoxin is responsible for making a deoxyribonucleoside from a ribonucloeside. If you can’t reduce thioredoxin, you can’t make DNA.

46
Q

What cancer would you use hydroxyurea to treat with?

A

CML. It inactivates ribonucleotide reductase by scavenging the radicals used to make deoxyribonucleosides from ribonucleosides.

47
Q

Why is folate important in DNA synthesis?

A

Tetrahydrofolate is needed to convert dUMP to dTMP by the enzyme thymidylate synthase. Also note, that NADPH from the hexose monophosphate shunt is necessary to convert dihydrofolate back to THF.

48
Q

How does methotrexate help in treating cancer?

A

It binds dihydrofolate reductase and inhibits it. Now the cell can no longer make THF from dihydrofolate and DNA synthesis is stopped.

49
Q

How does fluorouracil help in treating cancer?

A

It inhibits thymidylate synthase and prevents formation of dTMP and thus prevents DNA synthesis.

50
Q

What is rescue therapy?

A

You give methotrexate for cancer in high doses just until the patient almost dies. Right then you give leucovorin, which is basically THF, to turn pyrimidine synthesis back on and restart DNA synthesis.

Hematology (33 decks)

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