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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
Allopurinol, an anti-gout drug, targets what enzyme?
**Xanthine Oxidoreductase** ## Footnote Slide 14
26
Deficiencies in which two enzymes in purine degradation cause immunodeficiencies?
* **Adenosine Deaminase (ADA)** * **Purine Nucleoside Phosphorylase** ## Footnote Slide 14
27
Adenosine deaminase deficiency can lead to what?
**Severe Combined Immunodeficiency (SCID)** ## Footnote Slide 14
28
What 3 compounds are used to form a pyrimidine ring? How many steps? What is formed?
**4 enzymatic rxns** in which **Gln**, **Asp**, and **CO2** provide carbon and nitrogen atoms forming **orotate (orotic acid)** ## Footnote Slide 15
29
In pyrimidine synthesis, the pyrimidine ring is added to PRPP to form what compound?
**Orotidine 5'-monophosphate (OMP)** ## Footnote Slide 15
30
What enzyme catalyzes the conversion of Orotate to OMP?
**Orotate phosphoribosyl transferase** ## Footnote Slide 15
31
What is the committed step and major regulated step of pyrimidine synthesis?
**(Step 1) the carbamoyl phosphate synthetase II rxn** ## Footnote Slide 15
32
What enzyme catalyzes the conversion of OMP to UMP?
**OMP decarboxylase** ## Footnote Slide 15
33
Deficiencies in which two enzymes can cause **orotic aciduria**?
* Orotate phosphoribosyl transferase * OMP decarboxylase ## Footnote Slide 15
34
UMP synthase is a bifunctional protein made up of which two enzymes?
* Orotate phosphoribosyl transferase * OMP decarboxylase ## Footnote Slide 15
35
In a pyrimidine ring, the carbons and nitrogen marked by the red arrows are derived from what compound?
**Aspartate** | N1, C4, C5, & C6 ## Footnote Slide 16
36
In a pyrimidine ring, the carbon marked by the red arrow is derived from what compound?
**CO2** | C2 ## Footnote Slide 16
37
In a pyrimidine ring, the nitrogen marked by the red arrow is derived from what compound?
**Glutamine amide** | N3 ## Footnote Slide 16
38
How is UMP converted to UDP and then to UTP?
**Kinase reactions** ## Footnote Slide 17
39
How is UTP converted to CTP? | What enzyme?
**CTP Synthetase** | using an ATP and a Glutamine ## Footnote Slide 17
40
What stimulates Carbamoyl phosphate synthetase II (CPS II) in pyrimidine synthesis?
**ATP** & **PRPP** ## Footnote Slide 18
41
What inhibits Carbamoyl phosphate synthetase II (CPS II)
**UTP, UMP, & CTP** ## Footnote Slide 18
42
What inhibits OMP decarboxylase?
**UMP** ## Footnote Slide 18
43
What inhibits CTP synthetase?
**CTP** ## Footnote Slide 18
44
Pyrimidine nucleotides from nucleic acids are degraded to what **two** compounds?
**Uracil** & **Thymine** ## Footnote Slide 19
45
What are the pyrimidine salvage pathways?
* Uracil + PRPP --> UMP + PPi * Thymine + PRPP --> TMP + PPi | Both rxns catalyzed by pyrimidine phosphoribosyl transferase ## Footnote Slide 20
46
If uracil is not salvaged, what is it degraded to?
**β-alanine** | CO2 & NH4 also produced ## Footnote Slide 21
47
If thymine is not salvaged, what is it degraded to?
**β-aminoisobutyrate** | CO2 & NH4 are also produced ## Footnote Slide 21
48
Why are defects of pyrimidine catabolism of limited clinical significance?
the catabolic end products are water soluble and are excreted in the urine ## Footnote Slide 21
49
β-aminoisobutyrate in urine is used as a measure of what?
**DNA breakdown** ## Footnote Slide 21
50
What enzyme converts ADP, GDP, CDP and UDP to their respective deoxyribonucleotides?
**Nucleoside 5'-diphosphate (ribonucleotide) reductase** | producing dADP, dGDP, dCDP, and dUDP ## Footnote Slide 22
51
What is the rate-limiting step of deoxyribonucleotide synthesis?
the ribonucleotide reductase rxn | requires an **NADPH** ## Footnote Slide 22
52
Inhibitors of ribonucleotide reductase are potent inhibitors of what cellular processes?
**DNA Synthesis** & **Cell Replication** ## Footnote Slide 22
53
How is dTMP produced?
1. dUMP is produced from either dCMP or dUDP 2. dTMP is produced from dUMP by **thyidylate synthase** which requires N5,N10-methylene tetrahydrofolate ## Footnote Slide 22
54
Describe Lesch-Nyhan syndrome.
* 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 ## Footnote Slide 23
55
Severe Combined Immunodeficiencies (SCIDS) can be caused by a deficiency in which two enzymes? | What process are the enzymes part of?
* Purine nucleoside phosphorylase * Adenosine deaminase | Part of Purine degradation ## Footnote Slide 23
56
What is tumor lysis syndrome?
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 ## Footnote Slide 23
57
Deficiencies in orotate phosphoribosyl transferase and/or OMP decarboxylase (collectively known as UMP synthase) can cause what?
**Hereditary Orotic Aciduria** ## Footnote Slide 23
58
How does hereditary orotic aciduria present?
* severe anemia * growth retardation * high levels of orotate in urine | Can be treated by feeding with uridine ## Footnote Slide 23
59
How is **gout** characterized?
* 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 ## Footnote Slide 24
60
How does von Gierke's disease also cause gout? | Glucose-6-Phosphatase deficiency
* 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 ## Footnote Slide 25
61
What is allopurinol? | Use? Function?
* a purine analog used in tx of gout * inhibits xanthine oxidoreductase * reduces production of uric acid ## Footnote Slide 26
62
What is cytosine arabinoside (AraC)? | Use? Function?
* 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 ## Footnote Slide 26
63
What is 6-Mercaptopurine (6-MP)? | Use? Function?
* 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 ## Footnote Slide 26
64
What is Acyclovir (acycloguanosine)? | Use? Function?
* 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 ## Footnote Slide 27
65
What is AZT (3'-azido-3'-deoxythymidine, Zidovudine)? | Use? Function?
* a pyrimidine analog used to control HIV infections * AZT is phosphorylated to AZT-triphosphate which blocks HIV replication by inhibiting HIV-DNA polymerase ## Footnote Slide 27
66
What is Methotrexate (MTX)? | Use? Function?
* 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 ## Footnote Slide 28

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