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MSK_Y1_MT1 > MSK_MT1_TBL2 (Pyrimidine&Purine Metabolism) > Flashcards

MSK_MT1_TBL2 (Pyrimidine&Purine Metabolism) Flashcards

1
Q

N10- formyltetrahydrofolate.

A
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2
Q

AA required for purine de novo synthesis

A

GAG

  1. Glycine
  2. Aspartate
  3. Glutamine

Also requires:

  1. Folate derivative (Vit. B9)
  2. CO2
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3
Q

Pyrminidine Synthesis requires

A
  • glutamine
  • aspartate
  • tetrahydrofolate
    *
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4
Q

Difference between Cytosine (C) & Thyamine (T)

A
  • one methyl group
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5
Q

Difference between Cytosine (C) & Uracil (U)

A

At C-4 position, different group ( NH2 for Cystosine & C = O for Uracil)

  • uracil is also only in RNA
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6
Q

The Pyrimidines Basic Structure

A
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7
Q

The Foundations of Pyrimidines

A
  • Amide Donor (Glu)
  • 1 C Donor (CO2 & TFH)
  • 3 C & 1 N Donor (Asp)
  • PRPP
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8
Q

Pyrimidine Synthesis: Big Picture

A

Goals: TO CREATE

  1. CMP
  2. UMP
  3. TMP

From: Ribose phosphate via HMP shunt

Key points:

  • UMP synthesized first
  • UMP →→→ CMP & TMP
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9
Q

Pyrimidine De Novo Synthesis: Step 1

A

Make carbamoyl phosphate via CPS-II

  • activated by PRPP and inhibited by UTP
    • allosterically regulated by UTP (feedback inhibition)
  • CPS-II = cytosolic
  • uses Glutamine as N source
  • rate-limiting step
  • requires ATP
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10
Q

Pyrimidine De Novo Synthesis: Step 2

A

Make Orotic Acid

  • FIRST cyclic RING of pathway produced
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11
Q

Pyrimidine De Novo Synthesis: Step 3

A

Make UMP

  • Orotic Acid + PRPP = UMP
  • UMP is the FIRST pyrimidine of pathway
  • problems with enzyme UMP Synthase = Oroticaciduria
    • ​due to the accumulation of Orotic Acid that cant be converted to UMP
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12
Q

Orotic Aciduria-UMP Synthase Deficiency

A

Symptoms:

  • leads to orotic aciduria = ↑↑↑ orotic acid in urine
  • megaloblastic anemia (large/not functional RBC)
  • growth retardation
  • cognitive disabilities
  • renders both OPRT and OMP decarboxylase DYSFUNCT.
  • no B12/Folate Response (i.e normal anemia treatment does not work… suggests UMP Synthase Deficiency)

Treatment:

  • oral Uridine therapy (by pass the Synthase)
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13
Q

Inherited Disorders of Pyrimidine Nucleotide Metabolism

A
  1. Orotic Aciduria
  2. pyrimidine 5’-nucleotidase deficiency
    * ↑↑↑ blood pyrimidine ribonucleotides
  3. OTC
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14
Q

Ornithine Transcarbamlyase Deficiency (OTC)

A
  • to do with the UREA CYCLE but still makes impact
  • From the UREA CYCLE, we get EXCESS of carbamoyl phosphate which gets converted into an EXCESS of Orotic acid
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15
Q

Pyrimidine De Novo Synthesis: Step 4

A

Make UDP/UTP

  • revsible rxns
  • carried out by kinases (that add P)
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16
Q

Pyrimidine De Novo Synthesis: Step 5

A

Convert UTP → CTP

  • catalyzed by CTP synthetase: transaminates C= O → NH2 (donated from GLUTAMINE)
  • inhibited by CTP (feedback inhibition)
  • UTP & CTP make RNA
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17
Q

Pyrimidine De Novo Synthesis: Step 6

A

CDP → dCDP

  • ribonucleotide reductase = deoxygenates
  • Clinical Correlation:*

HYDROXYUREA = a drug that inhibits reductase so no dCDP is made

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18
Q

Thymidine

A
  • Only Used in DNA
  • Deoxythymidine is only required nucleotide
  • Synthesized from deoxyuridine
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19
Q

Thymidine Synthesis: Step 1

A

Convert UMP → dUDP

  • INVOLVES RIBONUCLEOTIDE REDUCASE
20
Q

Thymidine Synthesis: Step 2 & 3

A

Convert dUD**P → dU**MP (via phorphorylase)

Convert dU**MP → d**TMP (via thymidylate synthase)

  • thymidylate synthase requires THF to be the methyl donor

​

  • methotrexate inhibits dihydrofolate reductase ( = NO N5N10-MethyleneTHF)
  • 5-FdUMP inhibits dihydrofolate thymidylate synthase ( NO dihydrofolate = NO N5N10-MethyleneTHF)
21
Q

5-FdUMP

5-Fluorouracil (S phase)

A

DRUG: chemotherapy

  • mimics uracil strcuture
  • ​ INHIBITS Thymidylate synthase = ↓↓↓ dTMP (“thymineless death”)
    • ​permenant covalent bonding = inhibition

Enzyme normal function:

Methylates dUMP to dTMP requires THF

22
Q

Hydroxyurea (S phase)

A

​DRUG

  • INHIBITS Ribonucleotide reductase

Normal function of enzyme:

Reduces all NDPs to dNDPs for DNA synthesis

23
Q

Methotrexate (eukaryotic S phase)

A

DRUG = chemotherapy/ immunosuppressant

  • INHIBITS Dihydrofolate reductase (DHFR) = ↓ Thymidine
  • mimics DHF

normal function of enzyme:

  • Converts DiHydroFolate to TetraHydroFolate
  • Without DHFR, thymidylate synthesis will eventually stop

RESCUE (chemoprotectant):

Leucovorin : another way of making THF

24
Q

Vitamin B12

A

FOLATE

  • essential for thymidine production*
  • ALLOWS RECYLING of THF
25
Q

Folate Deficiency

A
  • ↓↓↓ dTMP production = ↓↓↓ DNA production
    • RNA is okay b/c it does not need T

Leads to:

  1. Macrocytic Anemia ( fewer but larger RBC)
  2. Neural Tube Defects in pregnancy
26
Q

Vitamin B12 Deficiency

A
  • needed to recycle THF from N5-Methyl-THF
  • deficiency = “Methyl Folate Trap”
  1. Megaloblastic Anemia: NO dTMP synthesis
  2. Demyelination: neurological disfunction
27
Q

Homocysteine and MethylMalonic Acid

A

Homocysteine

  • require BOTH Folate & B12 to produce methionine
  • therefore, you will see ↑↑↑ homocysteine in BOTH deficiencies (↓↓↓)

Methyl Malonic Acid

  • only B12 to convert MMA → succinyl CoA
  • therefore, ↑↑↑ MMA in B12 Deficiency (B12 ↓↓↓)
  • folate deciciency = normal MMA
28
Q

Pyrimidine Salvage Synthesis

A
  • Pyrimidine synthesis is COSTLY (requires 5 mole ATP for 1 mol UMP)
  • nucleosides salvagable
  • primary enzymes = nucleoside kinases
29
Q

Pyrimidine Catabolism

A
  1. De-phosphorylation
  2. phosphoroLYSIS
  3. De-Amination
30
Q

AA needed for Purine Synthesis

A
  1. Glycine
  2. Aspartate
  3. Glutamine
31
Q

First commited step in Purine Synthesis

A

PRPP → phosphoribosylamine

32
Q

First Compound with Complete Purine Ring

A

IMP

33
Q

Purine De Novo Synthesis: Step 1

A

Step 1: Create PRPP

  • starting with ribose-5-phosphate (from PPP):
    • anomeric carbon of ribose (C-1’) serves as foundation
  • R5P → PRPP catalyzed by 5’- PhosphoRibosyl-1-PyroPhosphate (PRPP) synthetase
  • Since, PRPP used elsewhere, it is NOT Commited Step
34
Q

Purine De Novo Synthesis: Step 2

(High Yield)

A

Step 2: Displacement of Pyrophosphate by N Group in Glutamine

  • catalyzed by amidophospho ribosyltransferase OR Glutamine phosphoribosyl amido transferase
  • committed & rate-limiting step : amide N of Glutamine → N-9 in purine ring
35
Q

Purine De Novo Synthesis: Step 3 - 6

A

Step 3 to 6: Synthesis of IMP

requires:

  1. Glycine
  2. Tetrahydro folate
  3. Glutamine
  4. CO2
  5. Aspartate
36
Q

Branch Point Synthesis

A

Ribavarin & Mycophenolate INHIBIT IMP DEHYDROGENASE = NO GMP

37
Q

Deoxygenation of ADP & GDP

A
  • via Ribonucleotide reductase
38
Q

Purine Pathway Regulation

A
  1. feedback regulation of PRPP synthetase, ATase, and both branch point pathways
  2. (cross-regulation): stimulation of branch point synthesis by end-product of opposite branch
    • ATP stimulates IMP → GMP (ie ↑ ATP = ↑ GMP)
    • GTP stimulates IMP → AMP (ie ↑ GTP = ↑ AMP)
39
Q

Purine Fates & Salvage

A

Salvages bases: adenine, guanine, hypoxanthine

Converts back into nucleotides: AMP, GMP, IMP

Requires PRPP

40
Q

Catabolism Step 1: dephosphorylation

A

Step 1 of Catabolism

  • phosphate removed: monophosphate → respective nucleoside
    • catalyzed by family of 5’-nucleotidases (5’-NT)
  • once relieved of charged phosphate, resulting nucleoside can readily cross cell membrane
41
Q

Catabolism Step 3: deamination

A
  • amino group removed from _C-6 of A_denine or _C-2 of G_uanine
  • catalyzed by AMP deaminase, adenosine deaminase (ADA), or guanase
42
Q

Catabolism Step 2: phosphorolysis

A
  • pentose sugar removed: converts purine nucleoside → respective base
  • catalyzed by purine nucleoside phosphorylase (PNP)
43
Q

AMP catabolism is differentially regulated per tissue…

A
  • heart: produces adenosine (diffusable)
    • coronary vasodilator: facilitates oxygen delivery to damaged tissue
  • skeletal muscle: produces IMP (NOT diffusible)
    • facilitates net resynthesis of ATP following exercise
44
Q

AMP & GMP catabolism = ↑↑↑ of hypoxanthine and xanthine

A
  • AMP → hypoxanthine
  • GMP → xanthine
  • these bases oxidized to uric acid (urate) by xanthine dehydrogenase (XDH)
    • uses NAD+ as electron acceptor (preferentially)
  • XDH → XO
45
Q
A
46
Q

Adenosine Deaminase (ADA) Deficiency

A
  • results in SCID: severe combined immunodeficiency
    • both T-cell & B-cell dysfunction
  • dATP = potent RR inhibitor
  • In ADA deficiency, dATP accumulates

MSK_Y1_MT1 (13 decks)

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