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MBOD Week 14 BT > Nucleotide Metabolism > Flashcards

Nucleotide Metabolism Flashcards

1
Q

What disease could possible be treated by targeting the adenosine A2A receptor?

A

Parkinson’s

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2
Q

Purine and Pyrimadines are parent compounds for what group of molecules?

A

Nucleotides

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3
Q

How many of the 53 enzymes involved in Purine metabolism are related to human disease?

A
  • 36 (68%)
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4
Q

What is the precursor for Adenine and Guanine monophosphate (AMP and GMP)?

A

IMP (inosine monophosphate)

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5
Q

The degration route of Purines (A and G) ultimately creates what?

A

Uric Acid/Urate

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6
Q

What enzyme catalyzes the first step of the de novo synthesis of Purines?

  • Energy Requirements
  • Regulation
A

Enzyme:
PRPS1 or PRPS2
Rxn: (Ribose-5P —> PRPP)

Energy:
ATP —> AMP (aka 2 ATP eqs.)

Regulation:
(-) ADP and GDP

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7
Q

What happens if PRPS1 has its regulatory binding sites for ADP and GDP altered?
- disease

A
  • PRPS1 will not be feedback inhibited

- Overactivity causes Gout by forming products like Uric Acid

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8
Q

What is the COMMITTED step in the de novo synthesis of Purines?

  • Rxn
  • Enzyme
  • Regulation
A

Rxn:
PRPP —-> 5-phosphoribosyl-1-amine

Enzyme:
GPAT

Regulation:
(-) ADP, GDP

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9
Q

Why is GPAT considered the enzyme that catalyzes the commited step in de novo Purine synthesis?

A
  • Once the Amino from Glutamine is added it’s only fate is to go the IMP (inosine monophosphate)
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10
Q

What reaction is catalyzed by AICAR transformylase and what is its cofactor?

A

Rxn:
AICAR —> FAICAR

Co-Factor:
- N-10 formyl tetrahydrofolate

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11
Q

What group of inhibitors affect the action of AICAR transformylase?
- examples of drugs?

A
  • Dihydrofolate Reductase inhibitors

Drugs:

  • Methotrexate
  • Methopterin
  • Aminopterin
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12
Q

N-10 Formyl Tetrahydrofolate is not acted on directly by Dihydrofolate Reducatase so why is it affected by inhibitors of this enzyme?

A
  • N-10 Formyl Tetrahydrofolate can be converted to N5N10 methyleneTHF to supply thymidylate synthase
  • This deplete N-10 FormylTHF inhibiting Purine synthesis
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13
Q

What tissues are most likely to be affected by Dihydrofolate Reductase Inhibitors?

A
  • Blood

- Intestinal Lining

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14
Q

What is the donor of the amine group to 5-phosphoribosyl-1-amine via GPAT in the committed step of Purine de Novo synth.

A

Glutamine

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15
Q

What is the amino group donor that Adenylosuccinate Synthase uses to convert IMP to Adenyosuccinate for AMP production?

A

Asparginine

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16
Q

What is the amino group donor that GMP syntase uses to convert xanthylate to GMP?

A

Glutamine

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17
Q

What disorder is caused by defective ADSL?

A
  • Succinylpurinemic Autism

* Sever psychomotor delay and Autism

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18
Q

What is the rate limiting enzyme in the de novo synthesis of guanine nucleotides?

A
  • IMP deyhdrogenase (IMPDH1)
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19
Q

What happens if IMP dehydrogenase (IMPDH1) is inhibited?

A
  • DNA synthesis stops Abruptly
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20
Q

How many DNA equivalents does it take to make:

  • IMP
  • AMP
  • GMP
A

IMP = 6 ATP

AMP = 8 ATP

GMP = 9 ATP

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21
Q

Why is it better for the cell to recover its own nucleotides than to synthesis more new one?

A
  • Its energetically expensive to make nucleotides from scratch.
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22
Q

T or F: nucleotide diphosphate kinase is nucleotide specific for the base

A

FALSE

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23
Q

Most ADP gets converted to ATP by oxidative phosphorylation, so why is Nucleoside Diphosphate Kinase still needed?

A
  • For nucleotide intercoversions
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24
Q

How is production of GMP and AMP kept balanced?

A
  • GTP (presence indicates cell has plenty) is used to make AMP
  • ATP is used to make GMP by the same principle
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25
Q

T or F: most nucleic acids that are eaten are absorbed and incorporated into cellular components

A

False

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26
Q

What is the main reason that we need to degrade purines?

A
  • So that RNA can be recycled
27
Q

What must adenosine first get converted to to get acted upon by nucleoside phosphorylase during purine breakdown?

A

It must either be converted to inosine or IMP

28
Q

T or F: AMP can be turned into adenosine, then to xanthine to generate uric acid

A

False, adenosine first has to converted to inosine

29
Q

What disease is caused by a Adenosine Deaminase Deficiency?

A

SCID (severe combined immunodeficiency)

30
Q

Why does adenosine deaminase deficiency cause SCID?

- what accumulates

A
  • dATP accumulates

- dATP inhibits RIBONUCLEOTIDE REDUCTASE, this inhibits DNA synthesis

31
Q

Why does prevention of DNA synthesis cause immune deficiency?

A
  • Lymphocytes proliferate rapidly in response to infection with Ribonucleotide Reductase Inhibited they can no longer do this
32
Q

Why is the cycle of turning AMP to IMP then back to AMP important?
- what tissue is this most important in?

A

It can replenish FUMARATE for TCA

  • Most important in skeletal muscle
33
Q

What disease results from overproduction of uric acid?

A

GOUT

34
Q

What is allopurinol used for?

- enzyme inhibited?

A
  • To Treat Gout

- Xanthine Oxidase is inhibited

35
Q

What intermediates of Purine breakdown build up as a result of Allopurinol use?
- why is this not an issue

A
  • Xanthine Oxidase inhibited
  • Hypoxanthine (from AMP and IMP) and Xanthine build up
  • Hypoxanthine and Xanthine are water soluble and are just peed out
36
Q

What substrate is allopurinol an analogue of?

A

Hypoxanthine

37
Q

What would you expect to happen to serum and urine concentrations of xanthine and uric acid when taking allopurinol?

A
  • VERY little uric acid

- LOTs of Xanthine (can cause xanthine stones)

38
Q

What enzymes are involved in the purine salvage pathway?

A
  • HGPRT (MOST IMPORTANT)

- APRT

39
Q

What disease results from loss of HGPRT enzyme?

A
  • Lesch-Nyhan Syndrome
40
Q

What happens physiologically to people with Lesch-Nyhan Syndrome?

A
  • Rate of Purine Synthesis is incresased about 200x

- Uric acids levels rise causing gout

41
Q

Why does Lesch-Nyhan Syndrome cause increased purine synthesis?
- explain inc. synth. and gout.

A
  • Because there’s no recovery by HGPRT so they must make purines de Novo
  • Gout results because they don’t reuse any breakdown products and they all go to uric acid
42
Q

Does a disease state result from the loss of APRT?

A

No - its not that important because AMP is converted to inosine anyways which is acted on by HGPRT

43
Q

What is the end product of purine metabolism.

- physiologic benefits?

A
  • Uratic acid/Urate = end product

- Urate is a powerful antioxidant and takes care of ROS

44
Q

What is the equivalent of IMP in pyrimadine metabolism?

A

UMP

45
Q

What enzyme is required to make deoxynucleotides (from ribonucleotides)?

A

Ribonucleotide Reductase

**Takes off Ribose Hydroxyl Group

46
Q

Could you make DNA without Ribonucleotide Reductase?

A

No

47
Q

Why is Thymidine a target that is specific to DNA synthesis only?

A
  • Because Thymidine is not used in RNA
48
Q

What is different about CPSI (urea cycle) and CPSII (pyrimadine synth)?

  • Location
  • Substrates
A

CPS1:
Mitochondria
Uses NH3 directly

CPS2:
Cytosol
Gets NH3 from Gln

49
Q

T or F: Uridine nucleotides are REQUIRED to make Cytidine nucleotides

A

True

50
Q

What is the inhibitor of CTP synthase?

A

Azaserine

51
Q

What is the committed step in Pyrimidine synthesis?

A

CPS II rxn

52
Q

What enzymes catalyze the committed steps in Purine and Pyrimidine synth?

A
  • GPAT (purines)

- CPSII (pyrimidines)

53
Q

What are the inhibitors and upregulators of CPSII?

A

(-) UDP, UTP (**note NOT CTP)

(+) ATP, PRPP

54
Q

What is the ultimate source of electrons to turn ribose to deoxyribose?

A

NADPH

55
Q

What is the most important residue in ribonucleotide reductase?

A
  • Tyrosine in the active site
56
Q

What subunit of Ribonucleotide Reductase is under regulatory control?
- Molecules that bind here

A

Alpha Subunit

  • ATP and dATP compete for binding here
57
Q

Deficiency of what enzyme can cause accumulation of dATP leading to SCID?

A

Adensosine Deaminase

58
Q

What molecule is needed to make thymine nucleotides?

A

dUMP

**There is NO de novo pathway to thymine

59
Q

How do Sulfonamide Drugs work?

A
  • Block Folate Biosynth (in bacteria etc.)
  • Humans don’t make our own folate so we aren’t affected

**NOTE: bacteria can’t acquire folate from their environment

60
Q

How do Fluoro compounds work for cancer treatment?

A
  1. F substituted for an H

2. Thymidylate Synthase tries to attack but gets stuck because F is a bad leaving group

61
Q

Why are fluoro compounds like 5 flurouracil more specific in targeting DNA synthesis than methotrexate and other dihydrofolate reducatase inhibitors?

A
  • THF is needed for a lot of enzymes so methotrexate and others may shut down many important (good) processes
  • 5 fluorouracil JUST affects dTMP synthesis
62
Q

Azaserine and DON?

  • what do they do?
  • Enzyme
A

Glutamine analogs

  • Inhibit enzymes that use glutamine
  • e.g. CTP synthase
63
Q

What is AZT?

A

Thymidine analogue used to block DNA synth. in AIDS

MBOD Week 14 BT (5 decks)

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