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MCG > SYLLABUS 19: Nucleotide & Deoxynucleotide Metabolism > Flashcards

SYLLABUS 19: Nucleotide & Deoxynucleotide Metabolism Flashcards

1
Q

what is the first pyrimidine made

A

UMP

UMP -> UDP -> UTP -> CTP via carbamyl phosphate

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2
Q

what is CPS-II

  1. where is it located
  2. what inhibits it
  3. what activates it
  4. what is its source of N
A

cabamoyl phosphate synthetase II: enzyme that catalyzes the 1st step of pyrimidine synthesis

  1. found in the **cytosol of all tissues **
  2. **inhibited **by **UMP or UTP **= end product inhibition
  3. **activated **by PRPP
  4. **glutamine **supplies its Nitrogen
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3
Q

first step of pyrimidine synthesis?

A

CPS-II catalyzes reaction

glutamine + CO2 + ATP -> carbamoyl phosphate + glutamate

UTP or UMP end-product inhibits this rxn; PRPP activates it

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4
Q

what inhibits or activates the 1st enzyme of pyrimidine synthesis?

A

CPS-II

PRPP activates it

UTP inhibits it

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5
Q

what is 2nd step of pyrimidine synthesis?

A

rate limiting step: aspartate transcarbamoylase does reaction:

carbamoyl phosphate + aspartate -> N-carbamoylaspartate

**inhibited **by production of **CTP, **stimulated **by ATP

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6
Q

what is rate limiting enzyme of pyrimidine synthesis?

what inhibits or stimulates it?

A

aspartate transcarbamylase

2nd step of the synthesis pathway

end-product inhibited by CTP, stimulated by ATP

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7
Q

what is orotate?

A

an intermediate in the pyrimidine synthesis pathway

the most abundant deficiency in urea cycle = ornithine transcarbamylase, causes high levels of orotate in the blood

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8
Q

what might cause high levels of orotate in the blood? why?

A

deficiency in ornithine transcarbamylase of the urea cycle

if the carbamoyl phosphate made in the 1st step of the urea cycle isn’t used b/c of a deficiency in ornithine transcarbamylase that leaves it not synthesized into orotate, it’ll make orotate leave the cyto, cross into the mito, and get excess of orotate in the blood

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9
Q

how are nucleoside mono/di/tri phosphates interconvertable?

A

via the nucleoside monophosphate kinases or nucleoside diphosphates that’re specific for each base

nucleoside monophosphate kinases:

GMP + ATP <-> GDP + ADP or CMP + AMP <-> CDP + ADP

nucleoside diphosphates:

GDP + ATP <-> GTP + ADP or CDP + ATP <-> CTP + ADP

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10
Q

how can a deoxynucleotide be converted to a ribonucleotide?

A

it’s not possible to convert a deoxynucleotide -> ribonucleotide but a ribonucleotide can -> deoxynucleotide by ribonucleotide reductase

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11
Q

function of ribunucleotide reductase?

A

catalyzes converstion of ribose to deoxyribose base for DNA

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12
Q

structure of ribunucleotide reductase?

A

2 major subunits, B1 and B2

B1 has:

activity site &

substrate specificity site &

substrate binding site

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13
Q

function of the overall activity site?

what can bind to it, what’s the effect?

A

overall activity site:

where ATP binds and stimulates the enzyme

thus controls activity of the whole enzyme

if dATP binds, it shuts off the enzyme

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14
Q

what controls activity of the ribunucleotide reductase enzyme? how?

A

ATP binds activity site -> sitmulates synthesis of deoxyribonucleotides

dATP binds activity site -> prevents more synthesis of deoxynucleotides

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15
Q

what function of substrate specificity site?

A

what binds here determines which ribonucleotide diphosphate will be converted to the deoxyribonucleotide diphosphate at the enzyme’s activity site

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16
Q

function of substrate binding site?

A

where substrate binds

substrate is ribonucleotide diphosphate (XDP) which through the RR enzyme becoase doxyribunucleotide diphosphate (dXDP)

17
Q

what’s the interplay between purines and pyrimidines in the RR activation?

A

if ATP, a purine, binds to the substrate specificity site, it activates RR so that it converts pyrimidine substrates to deoxypyrimidines

18
Q

structure of B2 subunit of ribonucleotide reductase?

A

has iron oxygen catalytic centers

has a Y* radical that’s formed in the catalytic mechanism

19
Q

how does the ribonucleotide reductase system work?

A

ATP binds to the overall activity site, turns on the enzyme

substrate binds to the B2 subunit, activating the Fe-O centers

B2 generates a Tyrosine radical

OH that was on C2 gets removed as H2O, generating a radical carbonium ion

Now add an H from the SH groups of B2 to the Carbonium ion

Regenerate teh H of the SH group

20
Q

is H from the C3 ever lost in the RR reaction?

A

no

21
Q

what’s the function of thioredoxin and thioredoxin reductase?

A

enzymes with SH groups that regenerate the SHs of the ribonucleotide reductase used in catalytic mechanisms

it thus becomes oxidized to oxidized thioredoxin

thioredoxin reductase then reduces oxidized thioredoxin to restore SH to it

FADH2 finally reduces the oxidized thioredoxin reductase sulfurs to their SH form and makes FAD

NADPH reduces FAD to make NADP+ and regenerate FADH2

22
Q

how could chemotherapy work with the RR system of enzymes?

A

1) inhibit the free radical produced in the RR B2 subunit and thus inhibit DNA synthesis
2) specifically inhibit thioredoxin or thioredoxin reductase so that the SH groups of RR cannot be regenerated and again inhibit DNA synthesis

23
Q

purpose of regulating ribonucleotide reductase?

A

to ensure balance in amounts between the pyrimidine bases

24
Q

how is the ribonucleotide reductase reaction regulated by ATP?

A

allosteric regulation:

[ATP] in cells is the highest of the nucleotides. it’s a high energy signal, stimulates entire RR reaction by binding overall activity site.

since in high [ATP], ATP also binds spcificity site

ATP signal converts pyrimidines to deoxy-pyrimidines, so CDP -> dCDP and UP -> dUDP

25
Q

how does regulation of the Ribonucleotide Reductase occur beyond the 1st step?

A

ATP signals to convert pyrimidines to de-oxypyrimidines

dCDP + dUDP eventually are metabolized to dCTP + dTTP by nucleotisde dipohsphate kianse

as dTTP builds up, it displaces ATP from substrate specificity site

dTTP specifies formation of dGDP, via GDP -> dGDP

dGDP -> dGTP, which slows down formation of deoxypyrimidines

once enough dGTP is produced, displaces dTTP from substrate specificity site and specifies ADP -> dADP

dADP -> dATP and dGTP production decreases

once enough dATP accumulates, it’s a singal enough deoxynucleotides have been produced

dATP displaces ATP fomr overall activity site and shuts RR down

26
Q

what is SCIDS?

what causes it?

A

severe combined immunodeficiency syndrome, aka bubble boy syndrome

due to deficiency in adenosine deaminase, which degrades ATP and dATP to hypoxanthine and xanthine

27
Q

why does SCIDS occur re: its deficiency?

A

deficiency of enzyme that breaks down ATP or dATP to hypoxanthine or xanthine

this means do not have DNA synthesis

this means do not make antibodies

this means have no B and T cells, have low immune response, WBC don’t function and divide properly, and **get build up of dATP so inhibits ribonucleotide reductase **

28
Q

what are key diffs between CPS II and CPS I and what is significance of these diffs?

A

CPSI: urea cycle, gets N from NH4+, in the mito, activated by N-acetylglutamate - expulsion of NH3

CPS II: pyrimidine synthesis, gets N from Glutamine, actiavted by PRPP, inhibited by UTP - biosynthesis

29
Q

how is synthesis of UMP regulated?

A

end product inhibited by its own present - it binds to CPS II

30
Q

why does a defciency of ornithine transcarbamylase increase orotic acid levels?

A

if the carbamoyl phosphate made in the 1st step of the urea cycle isn’t used due to a deficiency of this enzyme, then get build up of carbamoyl phosphate

if that isn’t used in urea cycle, it’ll be used in the pyrimidine synthesis pathway, resulting in the manufacture of a lot of orotic acid

this also would eliminate the normal feedback on this pathway via the UTP/UMP on CPS-II since CPS-I is making all of the carbamoyl phosphate in this scenario

31
Q

why is deoxyribonucleotide ysnthesis decreased by free radical scavengers like hydroxy urea?

A

because free radical formation is critical to ribonucleotide reductase activity - so inhibiting free radcial fomaition would adversely impact synthesis of deoxyribonucleotides

32
Q

how is overall activity of RR regulated

A

by whether ATP or dATP binds to overall activity site; ATP activates, dATP inhibits RR activity by binding there

33
Q

how does dTTP affect substrat specificity of RR

A

as dTTP levels build up, it displaces ATP from substrate specificity site, specifies formation of dGDP via GDP -> dGDP which becomes dGTP

34
Q

how are reduced thiols of RR regenerated?

A

by thioredoxin, which provides H’s to reduce RR anew

Thioredoxin is reduced by Thioredoxin Reductase

Thioredoxin Reductase is reduced by FADH -> FAD

NADPH + H+ reduces FAD back to FADH, becomes NADP+

35
Q

why does a deficiency of adenosine deaminase cause SCIDS?

A

beacuse lack of this enzyme means ATP and dATP can’t be degraded to hypoxanthine and xanthine

this means that DNA synthesis cannot occur

this means antibody production is inhibited

this means the body lacks B and T cells, WBC don’t function properly, there’s a build up of dATP which inihibits ribonucleotide reductase activity

MCG (77 decks)

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