Nucleotide Metabolism Part 1

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68 Terms

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purines

Bases with a double-ring structure.

Adenine and Guanine

<p>Bases with a double-ring structure.</p><p>Adenine and Guanine</p>
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pyrimidine

Cytosine, Thymine, uracil

Made up of one ring

<p>Cytosine, Thymine, uracil</p><p>Made up of one ring</p>
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adenine

A component of nucleic acids, energy-carrying molecules such as ATP, and certain coenzymes. Chemically, it is a purine base.

Has NH2 off carbon 6

<p>A component of nucleic acids, energy-carrying molecules such as ATP, and certain coenzymes. Chemically, it is a purine base.</p><p>Has NH2 off carbon 6</p>
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Guanine

A component of nucleic acids that carries hereditary information in DNA and RNA in cells. Chemically, it is a purine base.

Has a C=O off Carbon 6 and NH2 off carbon 2

<p>A component of nucleic acids that carries hereditary information in DNA and RNA in cells. Chemically, it is a purine base.</p><p>Has a C=O off Carbon 6 and NH2 off carbon 2</p>
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Cytosine

A component of nucleic acids that carries hereditary information in DNA and RNA in cells. Chemically, it is a pyrimidine base.

NH2 off 4 and a C=O off 6

<p>A component of nucleic acids that carries hereditary information in DNA and RNA in cells. Chemically, it is a pyrimidine base.</p><p>NH2 off 4 and a C=O off 6</p>
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thymine

A component of nucleic acid that carries hereditary information in DNA in cells. Chemically, it is a pyrimidine base.

Has methyl off 5, C=O off 2 and 3

<p>A component of nucleic acid that carries hereditary information in DNA in cells. Chemically, it is a pyrimidine base.</p><p>Has methyl off 5, C=O off 2 and 3</p>
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uracil

a nitrogen-containing base found in RNA (but not in DNA) and derived from pyrimidine

Thymine but no methyl off 5

<p>a nitrogen-containing base found in RNA (but not in DNA) and derived from pyrimidine</p><p>Thymine but no methyl off 5</p>
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1'

nucleotides always attach to this carbon in the sugar when forming the glycosidic bonds

<p>nucleotides always attach to this carbon in the sugar when forming the glycosidic bonds</p>
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De Novo and Salvage Pathways

biosynthesis from PRPP has one of these two pathways

<p>biosynthesis from PRPP has one of these two pathways</p>
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Beta-alanine

degredative product of pyrimidine degredation - useful metabolite

<p>degredative product of pyrimidine degredation - useful metabolite</p>
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uric acid

product of the purine degredation: nitrogenous waste excreted in the urine

<p>product of the purine degredation: nitrogenous waste excreted in the urine</p>
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D-ribose

main form of ribose that is present

<p>main form of ribose that is present</p>
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glyceraldehyde

the simplest aldose

used as template to assign L or D

<p>the simplest aldose</p><p>used as template to assign L or D</p>
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furthest chiral center

this determines if D or L for a carbohydrate

L have OH on the left

<p>this determines if D or L for a carbohydrate</p><p>L have OH on the left</p>
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PPP

main synthetic source of D-ribose

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PRPP

5-phosphoribosyl-1-pyrophosphate

the basic sugar for nucleotide metabolism that is for both purine and pyrimidine synthesis

<p>5-phosphoribosyl-1-pyrophosphate</p><p>the basic sugar for nucleotide metabolism that is for both purine and pyrimidine synthesis</p>
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R5P pyrophosphokinase

1st step of Purine syn.

converts R5P->PRPP

adds PPi to 1'OH

enzyme that converts R5P to PRPP

<p>1st step of Purine syn.</p><p>converts R5P-&gt;PRPP</p><p>adds PPi to 1'OH</p><p>enzyme that converts R5P to PRPP</p>
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R5P + ATP --> AMP + PRPP

net reaction of the ribose 5 phosphate pyrokinase reaction

<p>net reaction of the ribose 5 phosphate pyrokinase reaction</p>
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make ribose-1-phosphate to favor purine salvage pathway

phosphoribosyl transferase favors formation of this substance and why, when pyrimidine concentration is high

more on this later

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1) Uridine monophosphate (UMP)

2) Cytidine Triphosphate (CTP)

first two steps of the pyrimidine biosynthesis

<p>first two steps of the pyrimidine biosynthesis</p>
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apsartate, bicarbonate, Gln amide

3 sources of the 2N and 4C that make a 6 atom pyrimidine ring

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N1, C4-6

what in a pyrimidine comes from aspartate?

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N3

what in a pyrimidine comes from Gln amide?

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C2

what in a pyrimidine comes from HCO3-

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carbamoyl phosphate synthetase II

catalyzes the first step in pyrimidine synthesis:

1) glutamine + HCO3- + 2 ATP --> 2 ADP + Pi + Carbamoyl Phosphate

only step that requires ATP

<p>catalyzes the first step in pyrimidine synthesis:</p><p>1) glutamine + HCO3- + 2 ATP --&gt; 2 ADP + Pi + Carbamoyl Phosphate</p><p>only step that requires ATP</p>
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glutamine + HCO3- + 2 ATP --> 2 ADP + Pi + Carbamoyl Phosphate

carbamoyl phosphate synthetase II net reaction

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carbamoyl phosphate

product of the carbamoyl phosphate synthetase II reaction - same product in the urea cycle

<p>product of the carbamoyl phosphate synthetase II reaction - same product in the urea cycle</p>
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aspartate transcarbamoylase (ATCase)

This enzyme adds aspartate to Carbamoyl Phosphate to produce carbamoyl aspartate.

Carbamoyl phosphate + Aspartate --> Pi + Carbamoyl Aspartate

<p>This enzyme adds aspartate to Carbamoyl Phosphate to produce carbamoyl aspartate.</p><p>Carbamoyl phosphate + Aspartate --&gt; Pi + Carbamoyl Aspartate</p>
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Carbamoyl phosphate + Aspartate --> Pi + Carbamoyl Aspartate

aspartate transcarbamoylase (ATCase) net reaction

<p>aspartate transcarbamoylase (ATCase) net reaction</p>
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carbamoyl aspartate

product of the aspartate transcarbamoylase (ATCase) reaction

<p>product of the aspartate transcarbamoylase (ATCase) reaction</p>
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Dihydroorotase

catalyzes the removal of water from N-carbamoylaspartate to close the pyrimidine ring

carbamoyl phosphate --> H2O + Dihydrorotate

<p>catalyzes the removal of water from N-carbamoylaspartate to close the pyrimidine ring</p><p>carbamoyl phosphate --&gt; H2O + Dihydrorotate</p>
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carbamoyl phosphate --> H2O + Dihydrorotate

Dihydroorotase net reaction

<p>Dihydroorotase net reaction</p>
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dihydroorotate

product of the Dihydroorotase net reaction

<p>product of the Dihydroorotase net reaction</p>
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Dihydroorotate dehydrogenase

Enzyme involved in converting carbamoyl phosphate to orotic acid (with addition of aspartate)

Inhibited by leflunomide

Dihydroorotate + Quinone --> Reduced Quinone + Orotate

<p>Enzyme involved in converting carbamoyl phosphate to orotic acid (with addition of aspartate)</p><p>Inhibited by leflunomide</p><p>Dihydroorotate + Quinone --&gt; Reduced Quinone + Orotate</p>
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Dihydroorotate + Quinone --> Reduced Quinone + Orotate

Dihydroorotate dehydrogenase net reaction

Quinone could be NADH

<p>Dihydroorotate dehydrogenase net reaction</p><p>Quinone could be NADH</p>
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orotate

product of the Dihydroorotate dehydrogenase net reaction

<p>product of the Dihydroorotate dehydrogenase net reaction</p>
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orotate phosphoribosyl transferase

catalyzes:

orotate + PRPP --> PPi + Orotidine 5' Monosphosphate (OMP)

this is the irreversible step

<p>catalyzes:</p><p>orotate + PRPP --&gt; PPi + Orotidine 5' Monosphosphate (OMP)</p><p>this is the irreversible step</p>
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orotate + PRPP --> PPi + Orotidine 5' Monosphosphate (OMP)

orotate phosphoribosyl transferase net reaction

<p>orotate phosphoribosyl transferase net reaction</p>
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Orotidine 5' Monosphosphate (OMP)

product of the orotate phosphoribosyl transferase net reaction

<p>product of the orotate phosphoribosyl transferase net reaction</p>
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OMP decarboxylase

last enzyme used in pyrimidine synthesis

- makes 1st pyrimidine ring= UMP

-OMP--> UMP + CO2

Very efficient enzyme that does not require any cofactors for decarboxylation as it does not have a high energy intermediate

<p>last enzyme used in pyrimidine synthesis</p><p>- makes 1st pyrimidine ring= UMP</p><p>-OMP--&gt; UMP + CO2</p><p>Very efficient enzyme that does not require any cofactors for decarboxylation as it does not have a high energy intermediate</p>
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OMP--> UMP + CO2

OMP decarboxylase net reaction

<p>OMP decarboxylase net reaction</p>
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Uridine Monophosphate (UMP)

STEP 6: DECARBOXYLATION OF OMP PRODUCT:

<p>STEP 6: DECARBOXYLATION OF OMP PRODUCT:</p>
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ATCase and Dihydrootase

2 reactions in UMP formation that have a hydration rxn

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intramitochondrial enzyme

dihydrotate dehyrogenase is this type of enzyme that gets power from quinone reduction

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irreversible

orotate phosphoribosyl transferase's reaction step is this - enzyme also abbreviated as OPRT

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substrate channeling between 1-3 on same peptide and 5-6 on same peptide, enzymes

this helps increase efficiency of UMP synthesis

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preferential transition state binding

Binding to the transition state with greater affinity to either the product or reactants

OMP and active site of OMP decarboxylase bind and release energy to stabilize the transition state:

therefore can form UMP with no high energy intermediates and. cofactors

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Lysine and Aspratate

amino acids used by OMP decarboxylase - in decarboxylation rxn

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Orotic aciduria

Caused by OMPT and/or OMP decarboxylase deficiencies - the last two steps of the UMP formation

Orotic acid in urine, megaloblastic anemia that is not corrected with B12 or folic acid and no hyperammonemia

only inherited affect in pyrimidine formation

<p>Caused by OMPT and/or OMP decarboxylase deficiencies - the last two steps of the UMP formation</p><p>Orotic acid in urine, megaloblastic anemia that is not corrected with B12 or folic acid and no hyperammonemia</p><p>only inherited affect in pyrimidine formation</p>
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inherited

orotic aciduria is the only this type of defect in pyrimidine formation

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uridine and cytidine

two ways to treat orotic aciduria

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nucleoside monophosphate kinase

Catalyzes this:

UMP + ATP --> ADP + UDP

<p>Catalyzes this:</p><p>UMP + ATP --&gt; ADP + UDP</p>
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nucleoside diphosphate kinase

catalyzes this:

UDP + ATP --> ADP + UTP

<p>catalyzes this:</p><p>UDP + ATP --&gt; ADP + UTP</p>
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CTP synthetase

enzyme that converts UTP to CTP

UTP + ATP + Glutamine + H2O --> CTP + ADP + Pi + Glutamate

<p>enzyme that converts UTP to CTP</p><p>UTP + ATP + Glutamine + H2O --&gt; CTP + ADP + Pi + Glutamate</p>
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UTP + ATP + Glutamine + H2O --> CTP + ADP + Pi + Glutamate

ctp synthetase net reaction

<p>ctp synthetase net reaction</p>
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CTP and Glutamate

two major products from the CTP synthetase net reaction

<p>two major products from the CTP synthetase net reaction</p>
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glutamine

source of amide nitrogen to make CTP from UTP on the C4 in plants

<p>source of amide nitrogen to make CTP from UTP on the C4 in plants</p>
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ATCase reaction

major flux point for pyrimidine synthesis in bacteria

<p>major flux point for pyrimidine synthesis in bacteria</p>
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Carbamoyl phosphate synthetase II

major flux point for pyrimidine synthesis in animals

<p>major flux point for pyrimidine synthesis in animals</p>
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UDP and UTP

inhibitors of Carbamoyl phosphate synthetase II in animals

<p>inhibitors of Carbamoyl phosphate synthetase II in animals</p>
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ATP and PRPP

Carbamoyl phosphate synthetase II positive regulators (metabolism)

<p>Carbamoyl phosphate synthetase II positive regulators (metabolism)</p>
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UMP and CMP

two inhibit OMP decarboxylase - minor level of control

<p>two inhibit OMP decarboxylase - minor level of control</p>
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ADP and GDP

two compounds that inhibit purine synthesis at the ribose phosphate pyrophosphate kinase step

control level of PRPP; therefore inhibit pyrimidine synthesis too

<p>two compounds that inhibit purine synthesis at the ribose phosphate pyrophosphate kinase step</p><p>control level of PRPP; therefore inhibit pyrimidine synthesis too</p>
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purines (A,G) activate, pyrimidines (C,T) inhibit

in prokaryotes describe ATCase activity in terms of purines and pyrimidines

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T-state

this state of ATCase is favored by the binding of CTP to it at an allosteric site

2 substrate binding sites movement to one another is inhibited and cannot react with substrate

c3 dimers close

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R-state

this state of ATCase is favored by the binding of by the binding of ATP to it to the r2 site

c3 dimers further apart

have proximity of substrate binding sites and can react

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c3 dimers

distance of these between each others affects atcase activity

too close in T

far enough for reactivity in R - immediate proximity

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aspartate and carbamoyl phosphate

these are in the two homotropic binding sites of ATCase, the two substrates of the reaction

have possible reaction in R-state

affected by hetertropic states/regulatory dimers of CTP and ATP