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MSK_Y1_MT1 > MSK_MT1_TBL2 (Pyrimidine&Purine Metabolism) > Flashcards

MSK_MT1_TBL2 (Pyrimidine&Purine Metabolism) Flashcards

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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

Study These Flashcards
A

Convert UMP → dUDP

  • INVOLVES RIBONUCLEOTIDE REDUCASE
20
Q

Thymidine Synthesis: Step 2 & 3

Study These Flashcards
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)

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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)

Study These Flashcards
A

​DRUG

  • INHIBITS Ribonucleotide reductase

Normal function of enzyme:

Reduces all NDPs to dNDPs for DNA synthesis

23
Q

Methotrexate (eukaryotic S phase)

Study These Flashcards
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

Study These Flashcards
A

FOLATE

  • essential for thymidine production*
  • ALLOWS RECYLING of THF
25
Folate Deficiency
* ↓↓↓ **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
Vitamin B12 Deficiency
* *needed* to **recycle THF** from N5-Methyl-THF * deficiency = "**Methyl Folate Trap**" 1. **Megaloblastic Anemia**: NO dTMP synthesis 2. **Demyelination**: neurological disfunction
27
Homocysteine and MethylMalonic Acid
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
Pyrimidine Salvage Synthesis
* Pyrimidine synthesis is **COSTLY** (requires 5 mole ATP for 1 mol UMP) * **nucleosides salvagable** * primary enzymes = **nucleoside kinases**
29
Pyrimidine Catabolism
1. De-phosphorylation 2. phosphoroLYSIS 3. De-Amination
30
AA needed for Purine Synthesis
1. Glycine 2. Aspartate 3. Glutamine
31
First commited step in Purine Synthesis
PRPP → phosphoribosylamine
32
First Compound with Complete Purine Ring
IMP
33
Purine De Novo Synthesis: Step 1
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
Purine De Novo Synthesis: Step 2 (High Yield)
Step 2: **Displacement** of Pyrophosphate **by N Group in Glutamin**e * catalyzed by **amidophospho ribosyltransferase** *_OR_* **Glutamine** phosphoribosyl **amido transferase** * **_committed_** & **_rate-limiting step_** : amide N of Glutamine → **N-9** in purine ring
35
Purine De Novo Synthesis: Step 3 - 6
Step 3 to 6: Synthesis of **IMP** **requires:** 1. **Glycine** 2. **Tetrahydro** **folate** 3. **Glutamine** 4. CO2 5. **Aspartate**
36
Branch Point Synthesis
Ribavarin & Mycophenolate INHIBIT *_IMP DEHYDROGENASE_* = NO GMP
37
Deoxygenation of ADP & GDP
* via **Ribonucleotide reductase**
38
Purine Pathway Regulation
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
Purine Fates & Salvage
Salvages bases: **adenine, guanine, hypoxanthine** Converts back into nucleotides: **AMP, GMP, IMP** **Requires PRPP**
40
Catabolism Step 1: dephosphorylation
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
Catabolism Step 3: deamination
* **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
Catabolism Step 2: phosphorolysis
* pentose **sugar** **removed**: converts purine **nucleoside** → respective **base** * catalyzed by **purine nucleoside phosphorylase (PNP)**
43
AMP catabolism is **differentially** **regulated** per tissue...
* **heart**: produces ***_adenosine_* (***diffusable)* * coronary **vasodilator:** facilitates oxygen delivery to damaged tissue * skeletal **muscle**: produces ***_IMP_*** (NOT *diffusible*) * facilitates net r**esynthesis of ATP** following exercise
44
AMP & GMP catabolism = ↑↑↑ of **hypoxanthine** and **xanthine**
* AMP → **hypoxanthine** * GMP → **xanthine** * these bases *_oxidized_* to uric acid (urate) by **xanthine dehydrogenase (XDH)** * uses **NAD+ as electron acceptor** (preferentially) * XDH → **XO**
45
46
Adenosine Deaminase (**ADA**) **Deficiency**
* _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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