Nucleotide Metabolism Flashcards by Barrett Thompson

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

Parkinson’s

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

Nucleotides

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

36 (68%)

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

IMP (inosine monophosphate)

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

Uric Acid/Urate

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

Energy Requirements
Regulation

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

Energy:
ATP —> AMP (aka 2 ATP eqs.)

Regulation:
(-) ADP and GDP

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

PRPS1 will not be feedback inhibited

- Overactivity causes Gout by forming products like Uric Acid

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

Rxn
Enzyme
Regulation

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

Enzyme:
GPAT

Regulation:
(-) ADP, GDP

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

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

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

Rxn:
AICAR —> FAICAR

Co-Factor:
- N-10 formyl tetrahydrofolate

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

Dihydrofolate Reductase inhibitors

Drugs:

Methotrexate
Methopterin
Aminopterin

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

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

Blood

- Intestinal Lining

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

Glutamine

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

Asparginine

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

Glutamine

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What disorder is caused by defective ADSL?

Succinylpurinemic Autism

* Sever psychomotor delay and Autism

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

IMP deyhdrogenase (IMPDH1)

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What happens if IMP dehydrogenase (IMPDH1) is inhibited?

DNA synthesis stops Abruptly

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How many DNA equivalents does it take to make:

IMP = 6 ATP

AMP = 8 ATP

GMP = 9 ATP

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

Its energetically expensive to make nucleotides from scratch.

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

FALSE

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

For nucleotide intercoversions

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How is production of GMP and AMP kept balanced?

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

False

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

- So that RNA can be recycled

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

It must either be converted to inosine or IMP

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

False, adenosine first has to converted to inosine

What disease is caused by a Adenosine Deaminase Deficiency?

SCID (severe combined immunodeficiency)

Why does adenosine deaminase deficiency cause SCID? | - what accumulates

- dATP accumulates | - dATP inhibits RIBONUCLEOTIDE REDUCTASE, this inhibits DNA synthesis

Why does prevention of DNA synthesis cause immune deficiency?

- Lymphocytes proliferate rapidly in response to infection with Ribonucleotide Reductase Inhibited they can no longer do this

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

It can replenish FUMARATE for TCA - Most important in skeletal muscle

What disease results from overproduction of uric acid?

GOUT

What is allopurinol used for? | - enzyme inhibited?

- To Treat Gout | - Xanthine Oxidase is inhibited

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

- Xanthine Oxidase inhibited - Hypoxanthine (from AMP and IMP) and Xanthine build up - Hypoxanthine and Xanthine are water soluble and are just peed out

What substrate is allopurinol an analogue of?

Hypoxanthine

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

- VERY little uric acid | - LOTs of Xanthine (can cause xanthine stones)

What enzymes are involved in the purine salvage pathway?

- HGPRT (MOST IMPORTANT) | - APRT

What disease results from loss of HGPRT enzyme?

- Lesch-Nyhan Syndrome

What happens physiologically to people with Lesch-Nyhan Syndrome?

- Rate of Purine Synthesis is incresased about 200x | - Uric acids levels rise causing gout

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

- 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

Does a disease state result from the loss of APRT?

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

What is the end product of purine metabolism. | - physiologic benefits?

- Uratic acid/Urate = end product | - Urate is a powerful antioxidant and takes care of ROS

What is the equivalent of IMP in pyrimadine metabolism?

UMP

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

Ribonucleotide Reductase **Takes off Ribose Hydroxyl Group

Could you make DNA without Ribonucleotide Reductase?

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

- Because Thymidine is not used in RNA

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

CPS1: Mitochondria Uses NH3 directly CPS2: Cytosol Gets NH3 from Gln

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

True

What is the inhibitor of CTP synthase?

Azaserine

What is the committed step in Pyrimidine synthesis?

CPS II rxn

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

- GPAT (purines) | - CPSII (pyrimidines)

What are the inhibitors and upregulators of CPSII?

(-) UDP, UTP (**note NOT CTP) (+) ATP, PRPP

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

NADPH

What is the most important residue in ribonucleotide reductase?

- Tyrosine in the active site

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

Alpha Subunit - ATP and dATP compete for binding here

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

Adensosine Deaminase

What molecule is needed to make thymine nucleotides?

dUMP **There is NO de novo pathway to thymine

How do Sulfonamide Drugs work?

- 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

How do Fluoro compounds work for cancer treatment?

1. F substituted for an H | 2. Thymidylate Synthase tries to attack but gets stuck because F is a bad leaving group

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

- 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

Azaserine and DON? - what do they do? - Enzyme

Glutamine analogs - Inhibit enzymes that use glutamine - e.g. CTP synthase

What is AZT?

Thymidine analogue used to block DNA synth. in AIDS