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FTM Exam 2 > DLA 30/Lectures 39-40 Purine and pyrimidine > Flashcards

DLA 30/Lectures 39-40 Purine and pyrimidine Flashcards

1
Q

6-mercaptopurine

Uses

Mechanism

A

Uses:

  • Chemotherapy
  • Treats leukemia

Mechanism:
-Inhibits purine biosynthesis = prevents nucelotide formation for DNA/RNA = slows proliferation

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2
Q

Thiopurine (mercaptopurine) S-methltransferae Polymorphism

A

Cause:
-Homozygous for genetic variants = Low TPMT activity

Result:

  • higher risk of myelosuppression when treated w/ standard doses of thiopurine
  • Need reduced dose of 6-mercatopurine (Normal dose = overdose)
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3
Q

Ribonucleotide

A

-Building blocks on RNA

1) Base
2) Ribose
4) Phosphate

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4
Q

Deoxyribonucleotide

A

-Building blocks on DNA

1) Base
2) Deoxyribose
3) Phosphate

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5
Q

What do inhibitor of purine and pyrimidine biosynthesis do?

A
  • Anticancer agents

- Antimicrobial agents

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6
Q

Purine nucleotide metabolism

A

DNA:
1) Amino acid –> purine nucleotide –> ATP and GTP –> dATP and dGTP –> DNA (During replication)

RNA:
1) Amino acid –> purine nucleotide –> ATP and GTP –> RNA (Transcription)

2) RNA –> Adenine, hypoxanthine and guanine –> uric acid

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7
Q

Purine Nucleotide denovo synthesis

A

-Forms purine nucleotides from amino acids (DNA metabolism)

  • Adenine and guanine synthesized
  • N10-Formyl-tetrahydrofolate donate C or N = purine ring (Derived from folic acid)
  • Needs ATP
  • Ribose derived from PPP

-Ribose phosphate –> (ATP PRPP synthase) –> phosphoribosyl pyrophosphate (PRPP) –> (Glutamine & Phosphotibosylamidotransferase) –> Phosphoribosylamine

  • First two enzymes = regulation enzymes of the pathway
  • PRPP = feedforward activator
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8
Q

Conversion of IMP to AMP and GMP

A

AMP:
IMP –> (GTP) –> monophosphate (AMP) –> (Kinase) –> Diphosphate (ADP) –> (Kinase) –> Triphosphate (ATP)

GMP:
IMP –> (ATP) –> monophophate (GMP) –> (Kinase) –> Diphosphate (GDP) –> (Kinase) –> Triphosphate (GTP)

  • Mycophenolic acids INHIBITS conversion of IMP –> GMP (Enzyme = IMP dehydrogenase)
  • ADP and GDP used for ribonucleotide reductase to form (dADP and DGDP)
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9
Q

Inhibitors of Bacterial Purine Nucleotide Synthesis

A

PABA analogs:

1) Suldonamides –> antibacterial agent
2) Trimethoprim –> inhibits Bacterial dihydrofolate reductase

-Decreases tetrahydrofolate = reduced availability for purine nucleotide synthesis

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10
Q

Inhibitors of Eukaryotic Purine Nucleotide Synthesis

A

Folate Analog:

1) Methotrexate –> Anti cancer
- Inhibits dihydrofolate reductase = reduced tetrahydrofolate = reduced availability for purine nucleotide synthesis = slows cell division

Side effects:
-Anemia, Gi disturbance, Scaly skin, hair loss, immune deficients

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11
Q

Folate Deficiency and effects

A

-Need to obtain it from diet for DNA synthesis and S phase of cell cycle (Cell divison)

  • Macrocytic Anemia = Folate Deficiency (decreases cell division)
  • Neural tube defects = Folate Deficiency (pregnant women)
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12
Q

Conversion of the Ribonucleotides to deoxyribonucleotides

Process, Needs, and inhibitors

A

Process:
-Ribonucelotide reductase converts purine and pyrimdine ribonucleotides –> deoxyribonucleotides
(very active just before S-Phase of cell cycle)

Requires:
-Needs NADPH+ and H+

Inhibitors:

  • High levels of dATP (SCIDS)
  • Hydroxyurea (Anti cancer agent)
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13
Q

Salvage/Recycling pathway of purines

A
  • Free purine bases –> purine nucleotides
  • Uses less energy than denovo synthesis pathway
  • Enzymes = HGPRT and APRT
  • Good for Brain
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14
Q

Adenine Phosphoribosyl transferase (APRT)

A

Adenine –> Adeniosine monophosphate (AMP)
Enzyme: Adenine Phosphoribosyl transferase (APRT)

PRPP donates ribose-phosphate to form AMP

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15
Q

Lesch-Nyan Syndrome

Cause/symptoms

A

Cause:
-Absence of Hypoxanthine Guanine Phosphoribosyl Transferase (HGPRT) = purines not reused (salvage pathways inhibited) = increased degradation/Uric acid
“Hes Got Problems Repressed Thriving”
“Hes got purine recycle that!”

Symptoms:

  • “Self mutilation” (Biting of lips/fingers)
  • Hyperuricemia
  • Developmental delay
  • “Failure to thrive”
  • Orange colored crystals
  • Uric acid levels elevated
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16
Q

Hyperuricemia and Gout

Cause

Symptoms

Diagnosis

Advised

A

Cause:

  • Purine degradation
  • Uric acid = end product of purine (all products that are degraded)
  • Hyperuricemia = monosodium urate = gout

Symptoms:

  • Pain/warmth in joints
  • Big toe
  • Renal stones

Diagnosis:
-Needle shaped monosodium urate crystals

Advised:

  • Reduce beer and meat intake bc it increases uric acid
  • Allopurinol (prevents uric acid formation)
17
Q

Formation of Uric acid

Pathway

A

AMP –> Adenosine –> (Adenosine deaminase) –> Inosine –> (Purine nucleoside phosphorylase PNP) –> Purine base hypoxanthine –> xanthine –> (xanthine oxidase) –> uric acid

GMP –> (5’nucleotidase) –> Guanosine –> (Purine nucleoside phosphorylase PNP) –> Guanine –> (Gaunase) –> Xanthine –> (Xanthine oxidase) –> Uric acid

*Allopurinol inhibits xanthine oxidase = prevents uric acid formation

18
Q

2 Causes of Hyperuricemia

A

Uric acid levels = saturated

1) Overproduction of uric acid = gout
- Increase levels of PRPP
- Deficiency of HGPRT = less recycling of purines (Lesch)

2) Loss of excretion of uric acid = gout
- Renal disease
- Higher risk in men
- Lactic acidosis

19
Q

SCID (AR)

Cause/symptoms/treatment

A

Cause:
-Adenosine deaminase deficiency
-Adenosine accumulation = increased dATP levels = inhibit ribonucleotide reductase = reduced rates of cell
division in the lymphocytes

Symptoms:

  • immunoglobulins = low (decrease in immunity)
  • pneumonia
  • Improper T and B cell functioning = severe infections

Treatment:

  • enzyme/bone marrow replacement
  • Gene therapy
20
Q

Purine nucleoside phosphorylase (PNP) deficiency

A
  • Purine degradation can’t occur
  • Effects T-cell lymphocytes
  • Repeated Infections
21
Q

Pyrimidine metabolism

Pathway

A

Amino acid –> (Pyrimidine nucleotide denovo synthesis) –> Pyrimidine nucleotides UTP, CTP –> dUMP –> (Methylene tetrahydrofolate) –> dTMP and dCTP –> DNA replication

• The synthesis of thymidine requires one-carbon
groups as methylene tetrahydrofolate (THF)

• Donors of C and N atoms for the pyrimidine
ring are Aspartate, Glutamine and CO2

22
Q

Pyrimidine biosynthesis and regulation

A

CPS-II (carbamoyl phosphate synthetase-II)

  • Regulates
  • Inhibited by UTP (by feedback inhibition)
  • activated by ATP and PRPP

OPRT and OMP decarboxylase = UMP synthase

23
Q

Formation of CTP and CDP

A

UTP –> (CTP synthetase) –> CTP –> CDP

-CDP and UDP used to form deoxyribonucleotides (DNA) by ribonucleotide reductast

24
Q

Synthesis of thymidine (dTMP) and Inhibitors

A

dUMP –> (thymidylate synthase) –> Thymidine

-dTMP NEEDS methylene tetrahydrofolate (THF) (one
carbon donor) which converts to dihydrofolate

25
Q

5 Fluorouracil

A

Anti cancer drug

  • Irreversibly binds to thymidylate synthase = inactivation
  • Suicide inhibitor
26
Q

Folate Analog (Methotrexate)

Folate deficiency

A

Anti cancer drug
-Competitively inhibits dihydrofolate reducatase = deficiency in folate = prevents formation of purine and thymine biosynthesis

-Folate deficiency =
MACROCYTIC ANEMIA
Decreased cell division
Higher neural tube defects

-Folate active in S-phase

27
Q

Ortotic Aciduria due to defect in pyrimidine biosynthesis

A
  • Reduced dna synthesis/cell division
  • Deficiency of OPRT or OMP decarboxylase (UMP synthase)

Symptoms:

  • Macrocytic, megablastic anemia (Uridine improves anemia)
  • Smaller height and weight (poor growth)
  • Elevated orotic acid excretion
  • NORMAL BLOOD AMMONIUM LEVELS ** (How to figure out Difference w other ortotic aciduria defect)
  • Decreased RBC formation
28
Q

Ortotic Aciduria due to defect in Urea Cycle Defect

A
  • Hyperammonemia Type II
  • Deficiency of ornithine transcarbamoylase of urea cycle
  • Increased carbamoyl phosphate formed
  • Diffuses into the cytosol = formation of orotic acid

-ELEVATED AMMONIUM LEVELS (Must look at to distinguish it from other ortotic aciduria defect)

29
Q

Pyramidine Salvage and degradation

What enzyme recycles nucleotides

A

PRPP

FTM Exam 2 (25 decks)

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