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Molecules to Cells > ILA 14 Purine & Pyrimidine Metabolism > Flashcards

ILA 14 Purine & Pyrimidine Metabolism Flashcards

1
Q

Which bases are the purines?

A

Adenine & Guanine

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2
Q

Which bases are the pyrimidines?

A

Thymine, Uracil, & Cytosine

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3
Q

What is a nucleoside?

A

a nucleobase + a pentose sugar

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4
Q

What is a nucleotide?

A

a nucleoside with 1 to 3 phosphate groups

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5
Q

Where does the ribose 5-phosphate for purine synthesis come from?

A

Pentose Phosphate Pathway

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6
Q

In purine synthesis, ribose 5-phosphate is converted into what?

What enzyme catalyzes the reaction?

A

5-phosphoribosyl-1-pyrophosphate (PRPP)

PRPP Synthetase (ATP required)

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7
Q

In the 10 enzymatic reactions to convert PRPP to IMP, Gln, Gly, Asp, N10-formyltetrahydrofolate, and CO2 serve as what?

A

Carbon and Nitrogen donors

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8
Q

How many molecules each of Gln and N10-formyltetrahyrdofolate are required in the 10 steps to form IMP from PRPP?

A

2 each

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9
Q

What is the source of the carbon marked by the red arrow in a purine ring?

A

CO2

C6

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10
Q

What is the source of the Nitrogen marked by the red arrow in a purine ring?

A

Aspartate Amine

N1

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11
Q

What is the source of the two carbons marked by the red arrows in a purine ring?

A

N10-formyltetrahydrofolate

C2 and C8

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12
Q

What is the source of the two nitrogens marked by the red arrows in a purine ring?

A

Glutamine Amide

N3 and N9

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13
Q

What is the source of the section highlighted in red in a purine ring?

A

Glycine

N7, C4, and C5

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14
Q

What enzyme catalyzes the conversion of PRPP to 5-phospho-β-D-ribosylamine?

A

Glutamine-PRPP Amidotransferase

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15
Q

What is the committed step/rate-limiting step in purine synthesis?

A

conversion of PRPP to 5-phospho-β-D-ribosylamine

Glutamine-PRPP amidotransferase rxn

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16
Q

From Inosine 5’-monophosphate (IMP), the purine biosynthetic pathway branches to form what two compounds?

A

GMP & AMP

Kinase rxns for GDP/GTP & ADP/ATP respectively

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17
Q

What allosterically inhibits Glutamine-PRPP amidotransferase?

A

IMP, GMP, & AMP

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18
Q

What allosterically activates Glutamine-PRPP amidotransferase?

A

PRPP

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19
Q

Explain what is meant by purine nucleotide salvage pathways.

A
  • Synthesize nucleotides from intermediates in the degradative pathway for nucleotides
  • This is especially important in tissues that cannot perform the entire process of de novo synthesis

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20
Q

What enzyme is essential in the purine nucleotide salvage pathways?

A

Hypoxanthine-guanine phosphoribosyl transferase (HGPRTase)

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21
Q

What does HGPRTase do?

A
  • converts hypoxanthine (HX) to IMP
  • converts guanine to GMP

Both rxns require a PRPP and are inhibited by their end products

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22
Q

A deficiency in HGPRTase causes what syndrome?

A

Lesch-Nyhan Syndrome

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23
Q

Guanine and Adenine nucleotides are degraded to what compound primarily, then to what final compound?

A

Xanthine, and then eventually to Uric Acid

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24
Q

What enzyme catalyzes the conversion of hypoxanthine to xanthine?

A

Xanthine Oxidoreductase

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25
Q

Allopurinol, an anti-gout drug, targets what enzyme?

A

Xanthine Oxidoreductase

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26
Q

Deficiencies in which two enzymes in purine degradation cause immunodeficiencies?

A
  • Adenosine Deaminase (ADA)
  • Purine Nucleoside Phosphorylase

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27
Q

Adenosine deaminase deficiency can lead to what?

A

Severe Combined Immunodeficiency (SCID)

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28
Q

What 3 compounds are used to form a pyrimidine ring? How many steps? What is formed?

A

4 enzymatic rxns in which Gln, Asp, and CO2 provide carbon and nitrogen atoms forming orotate (orotic acid)

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29
Q

In pyrimidine synthesis, the pyrimidine ring is added to PRPP to form what compound?

A

Orotidine 5’-monophosphate (OMP)

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30
Q

What enzyme catalyzes the conversion of Orotate to OMP?

A

Orotate phosphoribosyl transferase

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31
Q

What is the committed step and major regulated step of pyrimidine synthesis?

A

(Step 1) the carbamoyl phosphate synthetase II rxn

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32
Q

What enzyme catalyzes the conversion of OMP to UMP?

A

OMP decarboxylase

Slide 15

33
Q

Deficiencies in which two enzymes can cause orotic aciduria?

A
  • Orotate phosphoribosyl transferase
  • OMP decarboxylase

Slide 15

34
Q

UMP synthase is a bifunctional protein made up of which two enzymes?

A
  • Orotate phosphoribosyl transferase
  • OMP decarboxylase

Slide 15

35
Q

In a pyrimidine ring, the carbons and nitrogen marked by the red arrows are derived from what compound?

A

Aspartate

N1, C4, C5, & C6

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36
Q

In a pyrimidine ring, the carbon marked by the red arrow is derived from what compound?

A

CO2

C2

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37
Q

In a pyrimidine ring, the nitrogen marked by the red arrow is derived from what compound?

A

Glutamine amide

N3

Slide 16

38
Q

How is UMP converted to UDP and then to UTP?

A

Kinase reactions

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39
Q

How is UTP converted to CTP?

What enzyme?

A

CTP Synthetase

using an ATP and a Glutamine

Slide 17

40
Q

What stimulates Carbamoyl phosphate synthetase II (CPS II) in pyrimidine synthesis?

A

ATP & PRPP

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41
Q

What inhibits Carbamoyl phosphate synthetase II (CPS II)

A

UTP, UMP, & CTP

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42
Q

What inhibits OMP decarboxylase?

A

UMP

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43
Q

What inhibits CTP synthetase?

A

CTP

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44
Q

Pyrimidine nucleotides from nucleic acids are degraded to what two compounds?

A

Uracil & Thymine

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45
Q

What are the pyrimidine salvage pathways?

A
  • Uracil + PRPP –> UMP + PPi
  • Thymine + PRPP –> TMP + PPi

Both rxns catalyzed by pyrimidine phosphoribosyl transferase

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46
Q

If uracil is not salvaged, what is it degraded to?

A

β-alanine

CO2 & NH4 also produced

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47
Q

If thymine is not salvaged, what is it degraded to?

A

β-aminoisobutyrate

CO2 & NH4 are also produced

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48
Q

Why are defects of pyrimidine catabolism of limited clinical significance?

A

the catabolic end products are water soluble and are excreted in the urine

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49
Q

β-aminoisobutyrate in urine is used as a measure of what?

A

DNA breakdown

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50
Q

What enzyme converts ADP, GDP, CDP and UDP to their respective deoxyribonucleotides?

A

Nucleoside 5’-diphosphate (ribonucleotide) reductase

producing dADP, dGDP, dCDP, and dUDP

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51
Q

What is the rate-limiting step of deoxyribonucleotide synthesis?

A

the ribonucleotide reductase rxn

requires an NADPH

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52
Q

Inhibitors of ribonucleotide reductase are potent inhibitors of what cellular processes?

A

DNA Synthesis & Cell Replication

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53
Q

How is dTMP produced?

A
  1. dUMP is produced from either dCMP or dUDP
  2. dTMP is produced from dUMP by thyidylate synthase which requires N5,N10-methylene tetrahydrofolate

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54
Q

Describe Lesch-Nyhan syndrome.

A
  • X-linked; almost exlusively males
  • severe/complete deficiency of HGPRTase
  • inhibition of purine salvage pathways causing accumulation of uric acid
  • hyperuricemia & excessive uric acid synthesis
  • neuro problems: spasticity, mental retardation, self-mutilation like finger biting

A mild HGPRTase deficiency can be a cause of gout

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55
Q

Severe Combined Immunodeficiencies (SCIDS) can be caused by a deficiency in which two enzymes?

What process are the enzymes part of?

A
  • Purine nucleoside phosphorylase
  • Adenosine deaminase

Part of Purine degradation

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56
Q

What is tumor lysis syndrome?

A

Patients undergoing cancer treatment can show increased serum and urine uric acid due to the degradation of nucleic acids and nucleotides from destruction of tumor cells.

Allopurinol is often included in tx protocols to limit uric acid buildup

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57
Q

Deficiencies in orotate phosphoribosyl transferase and/or OMP decarboxylase (collectively known as UMP synthase) can cause what?

A

Hereditary Orotic Aciduria

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58
Q

How does hereditary orotic aciduria present?

A
  • severe anemia
  • growth retardation
  • high levels of orotate in urine

Can be treated by feeding with uridine

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59
Q

How is gout characterized?

A
  • high uric acid in urine
  • hyperuricemia
  • increased PRPP synthetase activity causing increased flux through de novo purine synthesis –> increased uric acid levels
  • decreased HGPRTase activity preventing salvage of hypoxanthine & guanine –> increased uric acid levels
  • Tophi (crystal deposits of sodium urate) form in joints and soft tissues causing inflammatory rxn

leads to gouty arthritis or chronic joint destruction

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60
Q

How does von Gierke’s disease also cause gout?

Glucose-6-Phosphatase deficiency

A
  • elevated glucose-6-phosphate increased flux through PPP –> increases ribose-5-phosphate
  • elevated ribose-5-phosphate drives synthesis of PRPP
  • elevated PRPP drives de novo purine sythesis leading to increased uric acid levels

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61
Q

What is allopurinol?

Use? Function?

A
  • a purine analog used in tx of gout
  • inhibits xanthine oxidoreductase
  • reduces production of uric acid

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62
Q

What is cytosine arabinoside (AraC)?

Use? Function?

A
  • a pyrimidine analog used in tx of multiple cancers
  • must be metabolized to cytosine arabinoside triphosphate (araCTP) to be effective
  • araCTP inhibits DNA strand elongation

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63
Q

What is 6-Mercaptopurine (6-MP)?

Use? Function?

A
  • a purine analog used as an anti-tumor drug
  • HGPRTase converts 6-MP to 6-MP ribonucleotide 5’-monophosphate which inhibits glutamine-PRPP amidotransferase & conversion of IMP to AMP and GMP
  • 6-MP is a substrate for xanthine oxido reductase so low-dose 6-MP is combined w/ allopurinol to prevent its conversion to uric acid

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64
Q

What is Acyclovir (acycloguanosine)?

Use? Function?

A
  • a purine analog used for HSV tx
  • acycloguanosine is converted to acycloguanosine monophosphate by HSV-specific thymidine kinase which is only present in infected cells
  • the resulting acycloguanosine triphosphate is incorporated into the replicating DNA chain & causes termination

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65
Q

What is AZT (3’-azido-3’-deoxythymidine, Zidovudine)?

Use? Function?

A
  • a pyrimidine analog used to control HIV infections
  • AZT is phosphorylated to AZT-triphosphate which blocks HIV replication by inhibiting HIV-DNA polymerase

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66
Q

What is Methotrexate (MTX)?

Use? Function?

A
  • a Folic acid analog used in tx of multiple cancers and Rheumatoid Arthritis
  • MTX inhibits dihydrofolate reductase (DHFR) preventing the generation of tetrahydrofolate (THF)
  • decreased levels of THF inhibit de novo pathway of purine & pyrimidine synthesis & synthesis of dTTP

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