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MS 1 Unit VI MCP > Nucleotide Metabolism (Purines and Pyrimidines) > Flashcards

Nucleotide Metabolism (Purines and Pyrimidines) Flashcards

1
Q

Ribonucleosides

A
  • Adenine (A)- Adenosine, AMP
  • Guanine (G)- Guanosine, GMP
  • Uracil (U)- Uridine, UMP
  • Cytosine (C)- Cytidine, CMP
  • Hypoxanthine- Inosine, IMP
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2
Q

Deoxyribonucleoside

A
  • Adenine (A)- Deoxyadenosine, dAMP
  • Guanine (G)- Deoxyguanosine, dGMP
  • Uracil (C)- Deoxyuridine, dUMP
  • Cytosine (C)- Deoxycytidine, dCMP
  • Thymine (T)- Deoxythymidine, dTMP
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3
Q

Purine bases

A
  • adenine
  • guanine
  • hypoxanthine
  • xanthine
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4
Q

Pyramidine bases

A
  • uracil
  • cytosine
  • thymine
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5
Q

PRPP

A
  • 5’-Phosphoribosyl-1-pyrophosphate is an intermediate of major significance in nucleotide metabolism
  • formed from ribose 5-phosphate (from glucose metabolism, pentose phosphate shunt or can do nucleoside degradation) and adenosine triphosphate (ATB) catalyzed by PRPP synthetase
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6
Q

PRPP required for:

A
  • de novo synthesis of pyrimidine and purine nucleotides
  • salvage pathways for purine nucleotides
  • biosynthesis of nucleotide coenzymes, NAD and FAD
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7
Q

Synthesis of purines

A
  • base- the purine ring is built on a molecule of PRPP
  • the precursprs of the ring are glutamine (glutamine amino transfer reactions), glycine, CO2, aspartate (aspartate to malate conversion), and two one carbon fragments from the one carbon folate pool(from THF)
  • synthesis of inosine 5’-monophosphate (IMP). The formation of IMP is a ten-step process that uses six high-energy phosphate bonds. Energetically expensive
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8
Q

Inhibition of IMP synthesis

A
  • azaserine (analog of glutamine) blocks amide transfer from glutamine
  • sulfonamides (analogs of p-aminobenzoic acid) block the biosynthesis of folic acid in bacteria and prevent its formation. This blocks nucleotide synthesis
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9
Q

Important features of IMP biosynthesis

A
  • the first step is the rate limiting and regulated step
  • two steps require folate, and are blocked by drugs that block folate biosynthesis in bacteria
  • the nucleotide ring is made from glutamine, glycine, carbon dioxide, asparate, and two one-carbon fragments from the one carbon folate pool
  • two steps require glutamine amino transfer reactions that are inhibited by azaserine
  • this is an expensive process and we would just as soon salvage all of our nucleotides/ 90% of our nucleotides are salvaged
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10
Q

De novo synthesis of purine nucleotides is regulated by feedback inhibition

A
  • the enzymes that catalyze the first two steps of IMP synthesis- PRPP synthetase and PRPP amidotransferase- are both inhibited by IMP, GMP, and AMP
  • PRPP amindotransferase has two allosteric sites, one for IMP or GMP and one for AMP. IF both sites are occupied, then inhibition is synergistic
  • inhibition: the synthesis of adenylosuccinate from IMP is inhibited by AMP, and the synthesis of XMP is inhibited by GMP
  • substrate channeling and intracellular localization, the purinosome
  • nucleoside monophosphate kinase- GMP + ATP GDP + ADP
  • nucleoside diphosphate kinase- GDP + ATP GTP + ADP
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11
Q

Salvage pathways for purine nucleotides

A

-ribose phosphate transfer enzymes. There are two specific enzymes that catalyze the transfer of the ribose phosphate from PRPP to free purine bases, which are formed by the degradation of nucleotides
-HGPRT- catalyzes the formation of nucleotides from either hypoxanthine or guanine, inhibited by IMP and GMP
Hypoxanthine + PRPP -> IMP + PPi
Guanine + PRPP -> GMP + PPi

-adenine phosphoribosyl transferase (APRT)- catalyzes the formation of AMP from adenine, inhibited by AMP
Adenine + PRPP -> AMP + PPi

-nucleoside kinase- only adenosine in humans and not widely used
Adenosine + ATP -> AMP + ADP

-about 90% of the free purine in the body is salvaged and recycled

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12
Q

Purinosome

A
  • in humans, purine biosynthetic machinery localized to the purinosome
  • presence of this organelle is regulated by purine abudance
  • all ten steps catalyzed by six different enzymes localize in these organelles along with the purine salvage pathway enzymes
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13
Q

Synthesis of pyrimidine nucleotides

A

-base- not built on PRPP, instead pyrimidine ring is formed and then reacts with PRPP to form the nucleotide
-the precursors of the ring are carbamoylphosphate and aspartate
-the formation of uridine 5’ monophosphate- the first compound in the pathway is carbomoylphosphate (synthesized in cytosol from glutamine and carbon dioxide, in liver as an intermediate in urea synthesis, but this synthesis takes place in the mitochondria and is catalyzed by a different enzyme
(first three steps by single enzyme complex, next two by another enzyme complex- substrate channeling)
-UMP is coverted to UTP in two steps
-UTP to form CTP- glutamine amino-transferase, activated by GTP)

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14
Q

Regulation of pyrimidine synthesis

A
  • enzyme- a single protein that consists of three identical subunits catalyzes the first three steps of the synthesis
  • the last two steps are catalyzed by another multifunctional enzyme
  • pyrimidine nucleotides- decrease the aspartate transcarbamoylase and dihydroorotase activities of the multifunctional enzyme, but the molecular basis for decrease in activity is unknown
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15
Q

Salvage pathways for pyrimidine nucleotides

A
  • uracil can be concerted to UMP:
  • catalyzed by a nucleoside phosphorylase, uridine phosphorylase: uracil + ribose 1-phosphate -> Uridine + Pi
  • second reaction catalyzed by uridine kinase: uridine +ATP -> UMP + ADP
  • cytidine can also be phosphorylated by uridine kinase
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16
Q

Enzymes that use glutamine as a NH3 donor

A

1) CPSII- carbamoyl phosphate synthase II- produce carbamyol phosphate in the cytosol, pyrimidine biosynthesis
2) CTP Synthase-pyrimidine biosynthesis (interconverts UTP and CTP)
3) FGAR Aminotransferase
4) GMP Synthase
5) PRPP Aminotransferase- important for purine
6) Asparagine Synthase

17
Q

Deoxyribonucleotides

A
  • found in DNA, ordinarily low and they increase at the time of DNA replication- 99.9% cells aren’t making, only cells in S phase
  • formed by reduction of only ribonucleoside diphosphates
18
Q

Ribonucleotide reductase

A
  • reduction of ribonucleoside diphosphates
  • regulation- by ribo and deoxyribonucleotides in a complex fashion- ensures that proper ratios and levels of deoxyribonucleotides are present for the synthesis of DNA
  • products are dADP, dCDP, dGDP, dUDP
  • inhibited by hydroxyurea- chemo agent
  • cells fo not want to incorporate deoxy-U into DNA, so this molecule is efficiently dephosphorylated to dUMP state
19
Q

Thymidylate synthase

A
  • dTMP is formed from dUMP in a reaction catalyzed
  • in this reaction, a methylene group from N5N1–methylenetetrahydrofolate is oxidized to dihydrofolate
  • tetrahydrofolate is regenerated by dihydrofolate reductase in a reaction that requires NADPH
  • this enzymes is also carefully regulated in a cell cycle dependent manner, and is made by cells in S- phase
  • methyl group comes from conversion of Serine to Glycine which generates N5, N10 methylene THF
  • serine can be easily synthesized from intermediates of glycolosis: so one carbon groups can be funneled right out of glycolosis and onto dUMP to make dTMP
20
Q

5- Fluorouracil

A
  • undergoes conversion to nucleoside 5’ monophosphate F-UMP in cells
  • F-UMP can be phosphorylated to the nucleoside diphosphate- reduced to deoxyribonucleotide
  • F-dUMP-reduced nucleoside diphosphate is dephosphylated to 5-fluorodeoxyuridine 5’-monophosphate (F-dUMP), which is critical form for antineoplastic activity
  • F-dUMP interacts with thymidylate synthase and N5N10-methylenetetrahydrofolate
  • inhibition: the transfer of a methylene group to the pyrimidine ring is blocked by the fluorine atom. Therefore, thymidylate synthase is trapped in a complex with F-dUMP, and synthesis of dTMP is inhibited
21
Q

Methotrexate

A
  • an analog of folic acid that inhibits dihydrofolate reductase
  • the regeneration of tetrahydrofolate is blocked, and synthesis of dTMP is inhibited
22
Q

Salvage pathway for the synthesis of thymine deoxyribonucleotides

A

-thymine phosphorylase converts thymine to thymindine
Thymine + Deoxyribose 1-phosphate -> Thymidine + Pi
-thymidine kinase converts thymidine to dTMP
Thymidine +ATP -> dTMP + ADP

23
Q

Degradation of Purine and Pyrimidine Nucleotides

A
  • nucleotides remove the 5’-phosphates from purine and pyrimidine ribo- and deoxyribonucleotides, converting them to ribo- and deoxyribonucleosides
  • nucleoside phosphorylase catalyze the phosphorolysis of nucleosides to free bases and ribose 1-phosphate or deoxyribose 1-phosphate
24
Q

Nucleotidases

A
  • remove 5’ phosphates from purine and pyrimidine ribo- and deoxyribonucleotides, converting them to ribo- and deoxyribonucleosides
  • AMP is degraded by two pathways: it may first be deaminated to IMP, with IMP then hydrolyzed to inosine, or it may be hydrolyzed to adenosine first, with the adenosine then deaminated to inosine
  • GMP is hydrolyzed to guanosine
  • cytidine monophosphate (CMP) may be deaminated to UMP and then hydrolyzed to uridine, or it may be hydrolyzed to cytidine and then deaminated to uridine.
  • UMP is hydrolyzed to uridine
25
Q

Nucleoside phosphorylases

A

-catalyze the phosphorolysis of nucleosides to free bases and ribose 1-phosphate or deoxyribose 1-phosphate
-in phosphorolysis, a bond is cleaved by the addition of Pi across it:
Inosine + Pi -> Hypoxanthine + Ribose 1 phosphate
Guanosine + Pi -> Guanine + Ribose 1 phosphate
Uridine + Pi -> Uracil + Ribose 1 phosphate
Thymidine + Pi -> Thymine + Deoxyribose 1-phosphate

-nucleoside phosphorylases readily catalyze the reverse reaction, the conversion of a free base to a nucleoside. The reverse reaction is important in salvage pathways, especially of uracil and thymine

26
Q

Purine Degradation

A
  • the final product of purine degradation is uric acid, which is produced via the following pathway
  • hypoxanthine-from the breakdown of AMP, is oxidized to xanthine by the enzyme xanthine oxidase
  • guanine- from the breakdown of GMP, is deaminated to xanthine
  • xanthine is oxidized to uric acid by xanthine oxidase
  • oxygen (O2) is required and superoxide is formed. The O2 is converted to hydrogen peroxide by superoxide dismutase
  • xanthine oxidase contains molybdenum, which is why this element is reqired in trace amounts in humans. This enzyme also contains iron and sulfur. This is the only known use of molybdenum in humans
27
Q

Purine Degradation Overview

A

1) dephosphoylation
2) deamination
3) separation of the base from the ribose
4) oxidation to uric acid
the first three don’t necessarily happen in any specific order

28
Q

Degradation of Pyrimidines

A
  • the final products of pyrimidine degradation of Beta-alanine (from uracil) and Beta-aminoisobutyrate (from thymine)
  • they also undergo dephosphorylation, separation of base from ribose, deamination and degredation of the base
29
Q

Beta- aminoisobutyric acid

A

-marker for cancer cell death

30
Q

Gout

A
  • precipitation of sodium urate crystals in the joints and kidneys
  • sodium urate crystals precipitate because the serum levels of urate exceed its solubility limit
  • elevated uric acid levels may be due to one of several disorders
  • in some patients, PRPP synthetase is abnormal and is not responsive feedback inhibition by purine nucleoside diphosphates
  • partial deficiency of HGPRT leads to increased cellular levels of PRPP which leads to increased de novo synthesis of purines
  • this partial deficiency does not cause any of the neurologic symptoms of Lesch Nyhan syndrome
31
Q

Effect of Gout

A
  • inflammation and erosion of the joints occur when leukocytes engulf the deposited crystals and consequently rupture, releasing lysosomal enzymes
  • sodium urate crystals in the urinary tract impair renal function
32
Q

Treatment of Gout

A
  • Allopurinol- is an important drug in the treatment of gout: it blocks the production of uric acid. Also colchicine is used
  • allopurinol is oxidized by xanthine oxidase to oxypurinol
  • oxypurinol binds tightly to xanthine oxidase, inhibiting its ability to oxidize xanthine or hypoxanthine- suicide inhibition
  • often given as a pretreatment for chemo: during chemo large quantities of nuclotides are released from killed cancer cells-> uricemia and gout
33
Q

Lesch-Nyhan syndrome

A
  • hereditary X-linked recessive condition due to a severe or complete deficiency of HGPRT activity
  • increased synthesis of purines= little HGPRT so hypoxanthine and guanine are not salvaged, also intracellular levels of PRPP increase, while those IMP and GMP decrease leads to de novo synthesis of purines
  • several forms of HGPRT deficency - one form normal levels but inactive, some patients have unstable so higher activity in young red blood cells
  • symptoms: hyperuricemia, gout, urinary tract stones,mental retardation, spasticity, and self-mutilation
  • treatment with allopurinol reduces the uric acid formation but does not alleviate the neurologic symptoms
34
Q

Adenosine deaminase deficiency

A
  • in cells of people with ADA deficiency, deoxyadenosine and adenosine are abundant because they are not degraded to deoxyinosine and inosine
  • they are however efficiently converted to nucleotides in white blood cells
  • the high levels of dATP inhibit ribonucleotide reductase which inhibits DNA snythesis
  • therefore white blood cells cannot proliferate
  • ADA deficiency is associated with severe combined immunodeficiency (SCID)
  • bone marrow transplantation ans enzyme replacement have been used to treat SCID. Gene therapy is an experimental treatment

MS 1 Unit VI MCP (12 decks)

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