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Biochem 1 > Pyrimidine Metabolism > Flashcards

Pyrimidine Metabolism Flashcards

1
Q

Can pyrimidine derivatives be absorbed form the diet?

A

They are poorly absorbed from the diet

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2
Q

What is the main site of de novo pyrimidine ring synthesis?

A

Liver

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3
Q

The liver secretes pyrimidine _____ and ______.

How are they utilized by the blood and other tissue after

A
  • bases and nucleosides

- via salvage pathways

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4
Q

What is the rate limiting step in assembling the pyrimidine ring?

A

The first step - carbamoyl phosphate catalyzed by aspartate

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5
Q

What is the first step of pyrimidine synthesis

A

Assembly of the ring structure, then combining it with PRPP to form a nucleotide structure

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6
Q

What forms the ring structure in pyrimidine synthesis?

A

Condensation of carbamoyl phosphate with aspartate

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7
Q

What are the AA needed in pyrimidine synthesis?

A

Glutamine, Aspartate

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8
Q

All de novo pyrimidine nucleotide synthesis proceeds through which nucleosides?

A

UMP, UDP. UTP

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9
Q

How is UTP converted to CTP

A

From the NH2 from glutamine

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10
Q

What must happen to CTP to form pyrimidine deoxyribonucleotides?
What is the round-about pathway that happens next?

A 
We go backwards:
CTP is dephosphorylated to CDP
CDP is reduced to dCDP
dCDP is dephosphorylated to dCMP
dCMP is deaminated to dUMP
dUMP is methylated to dTMP
dTMP is re-phosphorylatted to dTDP --> dTTP --> DNA
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11
Q

How is carbamoyl phosphate formed?

A
  • From CO2 and an amino group from glutamine
  • 2 ATPs needed to provide energy for the reaction (one of the P groups goes to the carbamoyl phosphate)
  • Catalyzed by carbamoyl phosphate synthetase II (CPSII)
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12
Q

How is CPSII regulated?

A

Allosterically inhibited by UTP and activated by PRPP

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13
Q

What is the pathway for CPS-I vs CPS-II?

A

Urea cycle vs pyrimidine biosynthesis

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14
Q

What is the source of nitrogen for CPS-I vs CPS-II?

A

NH4+ vs glutamine

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15
Q

What is the location for CPS-I vs CPS-II?

A

Mitochondria vs cytosol

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16
Q

What is the activator for CPS-I vs CPS-II?

A

N-acetylglutamte vs PrPP

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17
Q

What is the inhibitor for CPS-I vs CPS-II?

A

nothing vs UTP

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18
Q

Why is compartmentation important for CPS-I and CPS-II?

A

Makes it possible to regulate two pathways differently even though they share a common intermediate

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19
Q

When carbamoyl phosphate and aspartate combine what do they form?

A

Pyrimidine ring structure, orotate

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20
Q

Orotate combines with PRPP to form ______

What happens after it forms?

A

a nucleotide

it is decarboxylated to yield UMP

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21
Q

Where do the atoms in th pyrimidine ring come from?

A

Glutamine and aspartate (and CO2)

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22
Q

Which enzyme is involved in the conversion of CDP to dCDP?

A

ribonucleotide reductase

it also makes dADP and dGDP

23
Q

Allosteric effectors change the substrate specificity of the enzymes. What does this mean for the enzyme?

A

The enzyme can exist in several different conformations, each of which favors binding of a specific substrate

24
Q

Allosteric effectors change the substrate specificity of the enzymes. What is the purpose of this?

A

Helps make sure that balanced levels of the t4 deoxynucleotide triphosphates are maintained for DNA synthesis

25
Q

The allosteric (regulatory) site binds to

A

triphosphates

26
Q

The catalytic site binds to

A

diphosphates

27
Q

How does the triphosphate binding affect diphosphate binds?

A

It determines which diphosphate can bind in the catalytic site

28
Q

ATP activates reduction of

A

CDP to dCDP

29
Q

dTTP activates reduction of

A

GDP to dGDP

30
Q

dGTP activates reduction of

A

ADP tp dADP

31
Q

aADTP inibitis

A

reduction of all substrates

32
Q

What are two substrates for pyrimidine nucleoside phosphorylase?

A

cytosine and uracil

33
Q

Can pyrimidine ring structure be broken down in human cells?

A

yes

34
Q

What are cytosine and uracil degraded to

A

b-alanine

35
Q

Cancer chemotherapeutic agents work on non-proliferating or proliferating cells?
Why?

A

Proliferating cells.

B/c of DNA synthesis

36
Q

What is the key to inhibiting DNA synthesis?

A

blocking dTMP synthesis

37
Q

The synthesis from dTMP from dUMP requires addition of a _________ to the pyrimidine ring

A

methyl group

obtained from tetrahydrofolate

38
Q

Which enzyme carries out the methyl transfer reaction

A

thymidylate synthase

39
Q

Why is the methyl transfer reaction unique?

A

It oxidized FH4 to FH2

40
Q

Which enzyme reduces FH2 back to FH4

A

dihydrofolate reductase

41
Q

What is the importance of dihydrofolate reductase and thymidylate synthase?

A

Important in cancer chemotherapy
Inhibition of these enzymes selectively kills/inhibits proliferating cells including cancer cells

(but also some normal proliferating cells eg epithelial cells in stomach and intestine, bone marrow cells that produce RBC and WBC and hair follicle cells)

42
Q

What is 5-FU?

A

5-flurouracil
an analogue of uracil and thymine
a fluorine atom in place of methyl group of thymine

43
Q

What does e5-FU inhibit?

What does this inhibition cause?

A

thymidylate synthase -

reduces the availability of dTMP and dTTP which slows or prevents cell proliferation

44
Q

What does methotrexate inhibit?

What does inhibition cause?

A

dihydrofolate reductase

prevents conversion of FH2 back to FH4
In proliferating cells, all single cell metabolism is shut down, killing the cell

45
Q

Does methotrexate affect proliferating or non-proliferating cells?
Why?

A

Proliferating cells

proliferating cells - lots of dTMP being made for DNA synthesis therefore FH2 accumulates and FH4 is depleted

non-proliferating cells - very little dTMP made, FH2 does not accumulate

46
Q

What does Thio IMP do to the de novo purine synthesis pathway?

A

inhibits several key enzymes

47
Q

All thymidine kinase (TK) genes are evolutionarily related except?

A

herpes TK genes

48
Q

Herpes TK can phosphorylate purine nucleoside analogues known as _________

A

acyclovirs

49
Q

How do acyclovir nucleotides work?

A

kill cells by inhibiting all DNA synthesis

50
Q

In gout, what is the gene defect, metabolite that accumulates and clinical symptoms?

A

multiple causes
uric acid
painful joints

51
Q

In SCID, what is the gene defect, metabolite that accumulates and clinical symptoms?

A

adenosine deaminase (purine salvage pathway)
deoxyadenosine and derivatives thereof
loss of immune system, including no T or B cells

52
Q

In immunodeficiency disease, what is the gene defect, metabolite that accumulates and clinical symptoms?

A

purine nucleoside phosphorylase (purine salvage pathway)
purine nucleosides
Partial loss of immune system

53
Q

In Lesch-Nyhan syndrome, what is the gene defect, metabolite that accumulates and clinical symptoms?

A

hypoxanthine-guanine phosphoribosyltransferase (purine salvage pathway)
purines, uric acid
mental retardation, self mutilation

54
Q

In hereditary orotic aciduria, what is the gene defect, metabolite that accumulates and clinical symptoms?

A

UMP synthase (de novo pyrimidine synthesis)
Orotic acid
Growth retardation

Biochem 1 (22 decks)

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