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Week 14- SHANE > Purine and Pyrimidine Metabolism > Flashcards

Purine and Pyrimidine Metabolism Flashcards

1
Q

What is a nucleoside?

A

just the base and the sugar without any phosphate attached

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2
Q

What is a nucleotide?

A

base, sugar, and phosphate group

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3
Q

How many rings do purines have?

A

2

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4
Q

What is the first step in purine synthesis?

A

ribose-5-phosphate to phosphoribosyl pyrophosphate (PRPP) using PRPS1 and PRPS2 (use ATP)

regulated step

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5
Q

Where are the genes for PRPS1 and PRPS2 found?

A

on opposite ends of the X chromosome

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6
Q

What is the feedback inhibition for PRPS1 and PRPS2?

A

the end-products of the pathway, guanine and adenine nucleotides (ADP and GDP)

There is a disease in humans caused by mutants in PRPS1 that do not react to feedback inhibition. The enzyme is then called superactive and it overproduces PRPP and its products like uric acid, leading to a form of gout.

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7
Q

The first step requires what?

A

This first step in the pathway requires ATP converted to AMP, thus it consumes two ATP equivalents making it irreversible.

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8
Q

What is the second step in purine synthesis?

A

PRPP to 5-phosphoribosyl-1-amine via the enzyme GPAT

regulated step

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9
Q

What is the significance of the conversion of PRPP to 5-phosphoribosyl-1-amine?

A

it is the committed step of the pathway. Once you have 5-phosphoribosyl-1-amine, you have to go all the way to IMP. This is because the PRPP has additional uses in histidine and tryptophan biosynthesis and pyrimidine biosynthesis.

Once the amino group of glutamine is added, the pathway must go forward to IMP (inosinate)

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10
Q

What regulates the second step?

A

feedback inhibition via ADP and GDP

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11
Q

What can inhibit the action of GPAT?

A

Dawn and Azoserine are structural analogs of glutamine and have an azeto group to disrupt the enzyme

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12
Q

what stimulates the activity of GPAT?

A

increased levels of PRPP

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13
Q

What does the 9th step of purine synthesis do?

A

removes the carbon skeleton of aspartate that was attached to make SAICAR in step 8, just leaving behind the amino group and splitting off fumarate. The product is AICAR.

Enzyme: adenylosuccinate lyase (ADSL)

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14
Q

What then happens in step 10?

A

A formyl group is added to AICAR from N10-formyl tetrahydrofolate (THF) to form FAICAR

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15
Q

What then happens in step 11?

A

FAICAR undergoes ring closure by IMP synthase (i.e. no ATP) to make inosine monophosphate (IMP). IMP is the immediate precursor to AMP and GMP and represents a branch point in the pathway.

enzyme: IMP synthase

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16
Q

N10-formyl THF is needed for which steps of purine synthesis?

A

steps 4 and 10

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17
Q

What can block the action of N10-formyl THF at steps 4 and 10?

A

Inhibitors of dihydrofolate reductase (methotrexate- used in cancer treatment) can prevent these steps and block purine synthesis

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18
Q

Why are drugs like methotrexate that inhibit purine synthesis successful for fighting cancer?

A

Since bacteria and cancer cells are faster growing than normal human cells, methotrexate, methopterin and aminopterin are effective treatments for some cancers. These will harm faster growing tissues like the blood and the intestinal lining if given for too long a time.

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19
Q

How is AMP made from IMP?

A

1) Asparate is added to IMP (via GTP) to form adenylosuccinate (via adenylosuccinate synthetase)
2) Adenylosuccinate is acted upon by ADSL (same as used in step 9) to give off fumarate and form AMP (adenylate)

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20
Q

Homozygosity for mutations in the ADSL gene results in a clinical disorder called?

A

succinylpurinemic autism, a genetic autism. Caused by the buildup of SAICAR and adenylosuccinate which interfere with proper functioning of the brain

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21
Q

How is GMP made from IMP?

A

1) IMP dehydrogenase oxidizes the IMP to introduce oxygen to make xynthylate (through NAD+)
2) Glutamine is added to xynthylate to form GMP (guanylate) using GMP synthetase (uses ATP)

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22
Q

How many ATP equivalents does it take to form AMP de novo? GMP?

A

AMP- 8
GMP- 9

For this reason it is best for the cell to recover these nucleotides from used mRNA and recycle them rather than making them from the de novo pathway.

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23
Q

How is GTP and ATP made from GMP and AMP?

A

1) first adenylate kinase and guanylate kinase are used to make ADP (AK1-3) and GDP (GUK1-3). These reactions require ATP
2) Once the diphosphates are formed, a non-specific enzyme nucleoside diphosphate kinase (NME1-4) converts them on to the triphosphate forms. This enzyme also requires ATP, but is it not base specific and it is not sugar specific

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24
Q

What is the main way to form ATP?

A

oxidative phosphorylation, so the enzymes like NME1-4 tend to work on non-adenine forms of diphosphate nucleiosides to make the triphosphate forms

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25
Q

What are the regulated steps of pure synthesis?

A

1) PRPS1 and GPAT are inhibited by AMP, GMP, and IMP
2) At the junction where IMP can go to either GMP or AMP, the first step in each branch is inhibited by the product.
3) GMP inhibits IMP dehydrogenase and AMP inhibits adenylosuccinate synthetase
4) To keep production of these nucleotides balanced GTP is needed for AMP production and ATP is needed for GMP synthesis. Therefore, if there is too much ATP it stimulates the production of more GMP and too much GTP stimulates the production of more AMP

26
Q

What other things are PRPP used for the synthesis of?

A

pyrimidines and histidine

27
Q

T or F. Feeding of labeled nucleic acids shows that most nucleic acids eaten are not absorbed and incorporated into cellular component

A

T. Thus, the body has ways to degrade them

28
Q

Once AMP is made, what are the first two possible steps of how is it degraded?

A

1) 5’- nucleotidase acts on AMP to make adenosine via H20 input and Pi output or
2) it can be converted to IMP via AMP deaminase

29
Q

What happens to the adenosine?

A

it is acted on by ADA (adenosine deaminase) using H20 and giving off NH4+ to make INOSINE

inosine is also made from IMP using nucleotidase using H20 and giving off Pi

30
Q

Adenosine deaminase deficiency can cause what?

Treatment?

A

SCID (severe combined immunodeficiency)- bubble boy

can be treated with gene therapy but there is a risk of causing leukemia because the gene can block a tumor supressor

31
Q

What happens to inosine once formed?

A

it is converted to hypoxanthine using purine nucleotide phosphorylase (PNP) by adding Pi and giving off ribose-1-p

32
Q

What happens to hypoxanthine once formed?

A

xanthine oxidase acts to convert it to xanthine (via O2 and H20 input, H202 output)

33
Q

How is xanthine made from XMP degradation?

A

XMP is broken down to xanthine using nucleotidase and PNP

34
Q

What are the steps of GMP degradation to xanthine?

A

1) conversion to guanosine via 5’-nucleotidase
2) conversion to guanine via PNP
3) conversion to xanthine via guanosine deaminase (using H20 and giving off NH4+)

35
Q

What then happens to xanthine following breakdown of XMP, AMP, IMP, or GMP?

A

xanthine oxdiase converts it to uric acid via O2 and H20 input and H2O2 ouput

note that high levels of uric acid causes gout. So blocking xanthine oxidase can be used as treatment. hypoxanthine is more soluble so less likely to form stones

36
Q

How is uric acid degraded?

A

it is dehydrogenated to urate

37
Q

What is the purine nucleotide cycle?

A

AMP to IMP using AMP deaminase (and H20 giving off NH3)

IMP to adenylosuccinate via GTP input via adenylosuccinate synthase

adenylosuccinate to AMP via adenylosuccinate lyase (by giving off FUMARATE**- the main product)

38
Q

What is the fumarate made from the purine nucleotide cycle used for?

A

TCA cycle in muscle. Thus, a deficiency in AMP deaminase would cause myopathy

39
Q

How is the synthesis of uric acid blocked using allopurinol?

A

Allopurinol is an analog hypoxanthine. Allopurinol can be acted upon by xanthine oxidase to convert it to alloxantlhine which then inhibits xanthine oxidase.

Treatment for gout

40
Q

What does HGPRT do?

A

involved in “recovery” of nucleotides. acts in two places:

1) can combine PRPP and hypoxanthine to reform IMP
2) can combine PRPP with guanine to reform GMP

41
Q

What does APRT do?

A

combines Adenine with PRPP to reform AMP

42
Q

Complete loss of HGPRT causes what?

A

a disease called Lesch-Nyhan syndrome which causes gout due to buildup of PRPP which goes to de novo purine synthesis

neurological defect (source unknown) also which causes patients to bite lips and fingers

43
Q

Why does absence of APRT not cause gout?

A

Absence of this enzyme does not cause gout, probably because adenosine deaminase converts adenosine to inosine so the flux through this pathway is lower than for the HGPRT salvage of hypoxanthine and guanine.

44
Q

What are the pyrimidines?

A

cytosine, uracil and thymine

45
Q

What are the first step in de novo synthesis of pyrimidines?

A

“The CPS II reaction”- located in the cytosol and uses two ATPs.

The first is used to activate bicarbonate to carboxyphosphate. In the second step, glutamine donates its amide nitrogen to displace the phosphate and form carbamate with glutamine instead of ammonia as nitrogen source (mitochondrial CPSI uses ammonia). In the final step, the second ATP reacts with the carbamate to form carbamoyl phosphate and ADP.

The CPSII enzyme has three active sites, one for glutamine hydrolysis to release ammonia, one for bicarbonate phosphorylation and one for carbamate phospohorylation. The substrates “channel” through the protein from one site to the next without being released into the environment.

46
Q

What inhibits/stimulates CPSII?

A 
inhibits= UDP, UTP (Not CTP!)
stimulates= ATP, PRPP
47
Q

What happens to carboxyl phosphate once formed?

A

it is combined with aspartate to form a pyrimidine ring (followed by 5 rxns to form UMP)

48
Q

What happens to UMP?

A

Uridine monophosphate kinase (UMPK) converts UMP to UDP

49
Q

What happens to UDP?

A

the general nucleoside diphosphate kinase forms UTP

50
Q

How do you make CTP from UTP?

A

through the action of CTP synthetase using glutamine+H20 as an NH3 donor (and ATP)

51
Q

What enzyme converts riboses to deoxyriboses?

A

ribonucleotide reductase (acts on all four NDPs)- have to convert the diphosphate forms (i.e. ADP) to dNDP before making dNTP (via general nucleoside diphosphate kinase)

works at 2- carbon

52
Q

The electrons for the conversion of the 2’ -OH to -H come from where?

A

NADPH. The electrons move to the ribonucleotide reductase in a short electron transfer chain composed of thioredoxin and thioredoxin reductase

All three proteins have paired sulfhydryl groups that undergo reversible oxidation to form a disulfide bond that can be reduced back to free SH groups.

53
Q

What binds to the activity conferring site of ribonucleotide reductase to turn it on? shut it off?

A

on- ATP

off- dATP

54
Q

What is the essential AA to ribonucleotide reductase?

A

tyrosine in the active site. If phenylalanine is substituted for tyr, the enzyme is dead

55
Q

What is the only function of thymine?

A

to make DNA

56
Q

How does the body make thymine nucleotides?

A

through dUMP by the action of thymidylate synthase. There is no de novo pathway to thymine. dUMP is converted to dTMP by thymidylate synthase. dTMP is then phosphorylated twice to make dTTP

57
Q

What is oxidized in order to reduce dUMP to dTMP?

A

tetrahydrofolate intermediate N5,N10 methylene-THF is oxidized to dihydrofolate

58
Q

How is the oxidized dihydrofolate re-reduced to THF?

What drugs block this reconversion?

A

by dihydrofolate reductase using NADPH

methotrexate, methopterin, trimethoprim and aminopterin

59
Q

How is THF reconverted to N5,N10 methylene-THF?

A

through input of serine and output of glycine using serine hydroxymethyl transferase

60
Q

How are fluoro-drugs (aka 5 fluorouracil) used to disrupt thymine deoxy-nucleotide synthesis?

A

substituting a H+ for F+ on N5,N10 methylene-THF will inhibit the activity of thymidylate synthase because it won’t dissociate

Week 14- SHANE (11 decks)

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