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Exercise and Fuels > Nucleotide Metabolism > Flashcards

Nucleotide Metabolism Flashcards

1
Q

What are the two means by which a cell can create nucleotides?

A

1) Can run a salvage pathway

2) Can make de novo

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2
Q

What are the derivatives needed for de novo pyrimidine synthesis?

A

1) Ribose
2) ATP
3) Asp and Gln
4) Bicarbonate

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3
Q

What is the step for preparing ribose as a donor?

A

ATP is bound to ribose to create PRPP

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4
Q

What compounds inhibit the creation of PRPP? Why would the reaction need to be stopped?

A

ADP and GDP

Excessive ADP and GDP levels will lead to heightened uric acid levels

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5
Q

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

A

Bicarbonate, ATP, and an NH4 donated by Gln lead to the creation of carbamoyl phosphate

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6
Q

Where does the creation of carbamoyl phosphate for pyrimidine synthesis occur in a cell and what enzyme catalyzes it?

A

In the cytosol

Carbamoyl phosphate 2

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7
Q

What is the second step in the de novo synthesis of pyrimidines? What is the component that must be added to permit this to happen?

A

Creation of ororate from carbamoyl phosphate; aspartate

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8
Q

What type of enzyme permits the closure of the pyrimidine ring and where do its products go?

A

A FMN dependent dehydrogenase enables closure of the ring; its electrons are donated to the electron transport chain

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9
Q

How can ororate levels be diagnostic for disease?

A

If a patient has an inherited OTCase deficiency in the mitochondria, excess Nitrogenous waste will be shunted into ororate synthesis

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10
Q

Which drug can inhibit the transformation of carbamoyl aspartate to ororate?

A

Leflunomide (used in rheumatoid arthritis treatment)

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11
Q

What is the third step in de novo synthesis of pyrimidines? What is the Km of this enzyme in comparison to the Km of the enzymes that perform a similar function in purine creation?

A

Ororate+PRPP–>OMP
The Km for PRPP in the pyramidal synthesis is lower than the purine synthesis, so pyrimidine synthesis is not prevented by high purine levels.

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12
Q

What is the other function of the enzyme that creates OMP?

A

It serves as the salvage enzyme for pyrimidine bases (takes T, U, or C and attaches it directly to the sugar if the base is available)

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13
Q

What is the fourth step in de novo pyrimidine synthesis?

A

Orotidylate decarboxylase removes a carboxyl group from OMP to form UMP.

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14
Q

How is cytosine derived from uracil?

A

CTP synthase conducts the reaction:

UTP+ATP+H2O+Gln–>CTP+ADP+Pi+Glu

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15
Q

How are RNA bases converted to DNA bases?

A

The RTP is reduced by ribonucleotide reductase, an enzyme with a free radical tyrosine. This introduces a S-S bond into the protein which must be reversed.

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16
Q

What complex resolves the electron changes that result from deoxygenating RNA?

A

Thioredoxin restores the ribonucelotide reductase, which in turn is restored by thioredoxin reductase. This enzyme must be restored in a series that centers around NADP+ –> NADPH

17
Q

What are two inhibitors of the mechanism to deoxygenate RNA?

A

dATP will inhibit the system (natural)

hydroxyurea (pharm) will also inhibit by annihilating the ribonucleotide reductase’s free radial tyrosine

18
Q

What are four distinguishing differences between de novo purine biosynthesis and de novo pyrimidine biosynthesis?

A
  • -purines are built stepwise directly on the sugar base
  • -formyl-THF is a necessary component
  • -Uses a CO2 dependent carboxylation
  • -the intermediate base is IMP
19
Q

What is the first main step in de novo purine synthesis? What are several inhibitors of this process?

A

PRPP + Gln –> 5-phosphoribosyl-1-amine + PPi

IMP, GMP, and AMP all will inhibit the process

20
Q

What is the road IMP must take to produce AMP?

A

IMP must react with aspartate and GTP to produce adenylosuccinate, which in turn yields fumarate and AMP

21
Q

What is the road IMP must take to produce GMP?

A

IMP must react with NAD to make XMP (enzyme-IMPDH)

XMP must react with ATP and Glutamine to make GMP

22
Q

How is TMP created from dUMP?

A

Methylene-THF binds covalently with uracil and will release its methylene group and a hydride to bind to uracil to make TMP. The complex cannot release untiil the reaction is complete.

23
Q

How does 5-FU work?

A

If a fluoride is attached to uracil, it will compete with regular uracil and occupy enzyme sites; since the fluoride cannot be removed to make TMP, the complex is trapped and cannot dissociate.

24
Q

How does methotrexate work?

A

After thyamine is produced, THF is changed to DHF. It must be restored by DHF-Reductase. Methotrexate blocks this enzyme; thus, folate deficiencies are forced on rapidly dividing cells.

25
Q

What is the clinical use of formyl-THF?

A

formyl-THF promotes the complex aggregation with 5-FU, speeding up cancer cell death; it serves as a rescue mechanism after methotrexate administration, as it is usually administered in doses sufficient enough to be fatal to patients

26
Q

What two enzymes function in purine salvage?

A

Hypoxanthine-guanine phosphoribosyl transferase

Adenine phosphoribosyl transferase

27
Q

The loss of which purine salvage enzymes is more phenotypically sensitive than the other? What is the disease that manifests and its symptoms?

A

HGPTase
Lesch-Nyhan Disease, results in excess uric acid in the blood.
Symptoms include irascible drive to self-mutilate and symptoms of gout

28
Q

What is the general fate of guanine when it is metabolized?

A

Guanine–>Xanthine–>Uric Acid–>Urate

Note: the amino group comes off after the base is liberated from the sugar

29
Q

What is the general fate of adenine when it is metabolized?

A

Adenine–>adenosine–>Inosine–>Hypoxanthine–>Xanthine–>Uric Acid–>Urate
Note: the amino group comes off before the base is liberated from the sugar

30
Q

Which of the enzymes in the purine breakdown is most susceptible to drug targets and how?

A

Xanthine oxidase/dehydrogenase–>using allopurinol, which has a similar chemical structure to xanthine transforms molybdenum from a +6 oxidation state to a +4 oxidation state—-in normal reactions the continued breakdown of xanthine helps restore molybdenum

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