L21 - Pyrimidines

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Last updated 10:00 PM on 8/25/26
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23 Terms

1
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Nucleotides Vs. Nucleosides

Major purine bases

Major pyrimidine bases

Nucleotides have a nitrogenous base, a pentose, and 1+ phosphate

Nucleosides have everything except a phosphate group

Purines: Adenine and Guanine

Pyrimidines: Thymine, Cytosine, and Uracil

<p>Nucleotides have a nitrogenous base, a pentose, and 1+ phosphate</p><p>Nucleosides have everything except a phosphate group</p><p>Purines: Adenine and Guanine</p><p>Pyrimidines: Thymine, Cytosine, and Uracil</p>
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<p>What structure is this? Purine or Pyrimidine?</p>

What structure is this? Purine or Pyrimidine?

Adenine; Purine

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<p>What structure is this? Purine or Pyrimidine?</p>

What structure is this? Purine or Pyrimidine?

Guanine; Purine

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<p>What structure is this? Purine or Pyrimidine?</p>

What structure is this? Purine or Pyrimidine?

Thymine: Pyrimidine

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<p>What structure is this? Purine or Pyrimidine?</p>

What structure is this? Purine or Pyrimidine?

Cytosine: Pyrimidine

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<p>What structure is this? Purine or Pyrimidine?</p>

What structure is this? Purine or Pyrimidine?

Uracil: Pyrimidine

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Importance of nucleotides

Carry chemical energy; A nucleotides make up many enzyme cofactors (Co-A, NAD+, FAD, etc.), they also serve as signaling molecules

<p>Carry chemical energy; A nucleotides make up many enzyme cofactors (Co-A, NAD<sup>+</sup>, FAD, etc.), they also serve as signaling molecules</p>
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Nucleotide biosynthesis pathways

Dietary: Ingested nucleic acids are degraded via nucleases

de novo pathways: Begins with metabolic precursors

  • AAs, ribose 5-phosphate, CO2, and NH3

  • Bases are synthesized while on ribose

  • Pyrimidine ring is synthesized as orotate

  • Glu provides most amino groups

  • Gly is the precursor for purines

  • Asp is the precursor for pyrimidines

Salvage pathways: Recycle free bases and nucleosides released from nucleic acid breakdown

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Phosphoribosyl-pyrophosphate Synthetase

Also known as Ribose Phosphate Pyrophosphokinase

Catalyzes the formation of 5-phosphoribosyl-1-pyrophosphate (PRPP), an important intermediate in many pathways

ribose 5-phosphate + ATP → PRPP + AMP

<p>Also known as <strong>Ribose Phosphate Pyrophosphokinase</strong></p><p>Catalyzes the formation of 5-phosphoribosyl-1-pyrophosphate (PRPP), an important intermediate in many pathways</p><p>ribose 5-phosphate + ATP → PRPP + AMP</p>
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Pyrimidine Biogenesis General Pathway + info

Glutamine + CO2 → Carbamoyl Phosphate → Orotic Acid → UMP → UPD → dUDP or CTP

Notes: dUDP → dTMP

Orotate (Pyrimidine ring) formation allows pyrimidine synthesis

Ribose 5-phosphate is attached after the ring is formed

Aspartate and Carbamoyl phosphate provide the atoms for the ring structure of many molecules, including: Carbamoyl-aspartate, Orotate, OMP, UDP/UTP, CTP, and TMP

<p>Glutamine + CO<sub>2</sub> → Carbamoyl Phosphate → Orotic Acid → UMP → UPD → dUDP or CTP</p><p>Notes: dUDP → dTMP</p><p>Orotate (Pyrimidine ring) formation allows pyrimidine synthesis</p><p>Ribose 5-phosphate is attached after the ring is formed</p><p>Aspartate and Carbamoyl phosphate provide the atoms for the ring structure of many molecules, including: Carbamoyl-aspartate, Orotate, OMP, UDP/UTP, CTP, and TMP</p>
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CPS-II (Activation of Pyrimidine Biosynthesis)

Carbamoyl phosphate synthetase II; cytosolic CPS that makes carbamoyl phosphate needed for pyrimidine synthesis (CPS-I is in Urea cycle [mitochondria])

Glutamine-dependent

Uses a transfer tunnel to move unprotonated ammonia from glutamine hydrolysis site to biosynthetic site; Tunnel prevents ammonia protonation and carbamate transfer in carbamoyl phosphate synthesis.

<p>Carbamoyl phosphate synthetase II; cytosolic CPS that makes carbamoyl phosphate needed for pyrimidine synthesis (CPS-I is in Urea cycle [mitochondria])</p><p>Glutamine-dependent</p><p>Uses a transfer tunnel to move unprotonated ammonia from glutamine hydrolysis site to biosynthetic site; Tunnel prevents ammonia protonation and carbamate transfer in carbamoyl phosphate synthesis.</p>
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Carbamoyl pools in the cell

Mitochondrial pool: Urea

Cytosolic pool: Pyrimidine Nucleotides

Application: Urea cycle disorders (Ex. OTC enzyme disorder) may cause carbamoyl phosphate accumulation and leakage from the mitochondria into the cytosolic pool. Causes a downstream increase of orotic acid, causing orotic aciduria

<p>Mitochondrial pool: Urea</p><p>Cytosolic pool: Pyrimidine Nucleotides</p><p>Application: Urea cycle disorders (Ex. OTC enzyme disorder) may cause carbamoyl phosphate accumulation and leakage from the mitochondria into the cytosolic pool. Causes a downstream increase of orotic acid, causing orotic aciduria </p>
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Formation of Carbamoyl-aspartate (Step 1 Pyrimidine Biosynthesis)

Aspartate + Carbamoyl phosphate → N-Carbamoylaspartate (+ Pi) via Aspartate Transcarbamoylase (ATCase)

First committed step, regulated by CTP (Product inhibited)

<p>Aspartate + Carbamoyl phosphate → <em>N</em>-Carbamoylaspartate (+ P<sub>i</sub>) via<strong> Aspartate Transcarbamoylase</strong> <strong>(ATCase)</strong></p><p>First committed step, regulated by CTP (Product inhibited)</p>
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Formation of Orotate (Step 2 Pyrimidine Biosynthesis)

N-Carbamoylaspartate → L-Dihydroorotate (+ H2O) via Dihydroorotase (DHO)

L-Dihydroorotate → Orotate via Dihydroorotate Dehydrogenase (DHODH) (Needs NAD+)

<p><em>N</em>-Carbamoylaspartate → <sub>L</sub>-Dihydroorotate (+ H<sub>2</sub>O) via <strong>Dihydroorotase (DHO)</strong></p><p><sub>L</sub>-Dihydroorotate → Orotate via <strong>Dihydroorotate Dehydrogenase (DHODH)</strong> (Needs NAD<sup>+</sup>)</p>
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Formation of Orotidylate (OMP) (Step 3 Pyrimidine Biosynthesis)

Orotate → Orotidylate/Orotidine 5’-monophosphate via Orotate Phosphoribosyl transferase (Needs PRPP)

N-1 of ring attacks PRPP

Know Structure

<p>Orotate → Orotidylate/Orotidine 5’-monophosphate via <strong>Orotate</strong> <strong>Phosphoribosyl transferase</strong> (Needs PRPP)</p><p>N-1 of ring attacks PRPP</p><p>Know Structure</p>
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Formation of Uridine 5’-triphosphate (UTP) (Step 4 Pyrimidine Biosynthesis)

OMP → UMP (+ CO2) via orotidylate decarboxylase (Without enzyme this reaction would take billions of years)

UMP → UTP (Needs 2ATP)

UMP is phosphorylated to UDP/UTP by kinases

Know Structure

<p>OMP → UMP (+ CO<sub>2</sub>) via <strong>orotidylate</strong> <strong>decarboxylase</strong> (Without enzyme this reaction would take billions of years)</p><p>UMP → UTP (Needs 2ATP)</p><p>UMP is phosphorylated to UDP/UTP by <strong>kinases</strong></p><p>Know Structure</p>
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Formation of Cytidine 5’-triphosphate (CTP) (Step 5 Pyrimidine Biosynthesis)

UTP + Gln + ATP → CTP + Glu + ADP + Pi via Cytidylate Synthetase (CS2 in humans)

Used for DNA and RNA nuc synthesis

Activated by GTP

<p>UTP + Gln + ATP → CTP + Glu + ADP + P<sub>i</sub> via <strong>Cytidylate Synthetase (CS2 in humans)</strong></p><p>Used for DNA and RNA nuc synthesis</p><p>Activated by GTP</p>
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Formation of dTMP

Related to nuc synthesis so use dTMP

dUMP → dTMP via thymidylate synthase

Requires N5,N10-Methylenetetrahydrofolate which turns into Dihydrofolate during dTMP synthesis

To recover

<p>Related to nuc synthesis so use dTMP</p><p>dUMP → dTMP via <strong>thymidylate synthase</strong></p><p>Requires <em>N</em><sup>5</sup>,<em>N</em><sup>10</sup>-Methylenetetrahydrofolate which turns into Dihydrofolate during dTMP synthesis</p><p>To recover</p>
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N5,N10-Methylenetetrahydrofolate recovery

N5,N10-Methylenetetrahydrofolate → Dihydrofolate via Thymidylate Synthase

Dihydrofolate → Tetrahydrofolate via Dihydrofolate Reductase

Tetrahydrofolate → N5,N10-Methylenetetrahydrofolate via Serine Hyderoxymethyltransferase

<p><em>N</em><sup>5</sup>,<em>N</em><sup>10</sup>-Methylenetetrahydrofolate → Dihydrofolate via<strong> Thymidylate Synthase</strong></p><p>Dihydrofolate → Tetrahydrofolate via<strong> Dihydrofolate Reductase</strong></p><p>Tetrahydrofolate → <em>N</em><sup>5</sup>,<em>N</em><sup>10</sup>-Methylenetetrahydrofolate via <strong>Serine Hyderoxymethyltransferase</strong></p>
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The CAD Complex

Formed by the first three enzymes associated with Pyrimidine Biogenesis Pathway:

  • CPS-II

  • Aspartate Transcarbamoylase (ATCase)

  • Dihydroorotase

CPS-II inhibited by UTP and activated by PRPP

<p>Formed by the first three enzymes associated with Pyrimidine Biogenesis Pathway:</p><ul><li><p><strong>C</strong>PS-II</p></li><li><p><strong>A</strong>spartate Transcarbamoylase (ATCase)</p></li><li><p><strong>D</strong>ihydroorotase</p></li></ul><p>CPS-II inhibited by UTP and activated by PRPP</p>
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What type of inhibition controls ATCase

Aspartate transcarbamoylase catalyzes the first reaction in pyrimidine biosynthesis

Inhibited by end-product CTP

Accelerated by ATP

<p>Aspartate transcarbamoylase catalyzes the first reaction in pyrimidine biosynthesis</p><p>Inhibited by end-product CTP</p><p>Accelerated by ATP</p>
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CTP synthetase

Two forms CS1 is related to lipid synthesis; CTP Synthetase 2 (CS2) specifically

Catalyzes UTP → CTP; Activated by GTP (Balancing amounts of C/G)

Enzyme deficiency affects cell growth and development

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Catabolism of Pyrimidines

Pathways for degradation all lead to NH4+ production/Urea synthesis

Carbons of thymine are degraded into Succinyl-CoA

Carbons of cytosine and uracil are degraded to Acetyl-CoA

<p>Pathways for degradation all lead to NH4+ production/Urea synthesis</p><p>Carbons of thymine are degraded into Succinyl-CoA</p><p>Carbons of cytosine and uracil are degraded to Acetyl-CoA</p>