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DENF 1521 Biochemistry

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Purine and Pyrimidine Metabolism

Lesson 12.2
Synthesis of Pyrimidines

Instructions
  1. Please enter both your name & student identification number first below to be sure you get credit (before doing anything else).
  2. Then study Lesson 12.2 at your own pace. When Practice Exercises appear, click the appropriate button to choose your answer. Then press the "Get Feedback..." button to find out how you did. Continue to try again if you miss.
  3. After studying Lesson 12.2, and responding to all practice exercises, follow instructions at the end to submit your responses for Lesson 12.2 participation credit.
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Dental Biochemistry Brush
DB Bullet Lesson 12.2 Pyrimidine metabolism

12.2A Lesson objectives

The objectives of this lesson are to understand that:

  1. Synthesis of pyrimidine nucleotides starts with the synthesis of the pyrimidine ring
  2. Pyrimidine ring is then attached to a ribose phosphate
  3. UMP (uradylate) is synthesized from orotate
  4. Nucleotide monophosphates can be converted to diphosphates by nucleotide kinases
  5. CTP is formed by amination of UTP

12.2B Synthesis of the pyrimidine ring

In contrast to the synthesis of purines in which the purine ring is built onto a ribose ring, the synthesis of the pyrimidine nucleotides starts with the synthesis of the pyrimidine ring and then this is attached to a ribose phosphate. This is the most important distinction between pyrimidine and purine biosynthesis. The atoms comprising the pyrimidine ring are derived from carbamoyl phosphate and aspartate. The diagram below indicates the origin of the atoms in the ring. Note that C-2 and N-3 come from carbamoyl phosphate and the remaining atoms are from aspartate.

 

12.2C Synthesis of carbamoyl phosphate

Carbamoyl phosphate is synthesized from glutamate and HCO3- by the following reaction.

Glutamine + 2 ATP + HCO3- carbamoyl phosphate + 2 ADP + Pi + glutamine

This reaction occurs in the cytosol and is catalyzed by the enzyme carbamoyl phosphate synthetase II (CPS-II). This is not the same as the reaction which is part of the urea cycle (carbamoyl phosphate synthetase I (CPS-I). Remember that carbamoyl phosphate is formed as part of the urea cycle by a different reaction which occurs in the mitochondria and uses carbon dioxide and ammonia as reactants. In pyrimidine synthesis, the nitrogen is donated to form carbamoyl phosphate from glutamine instead of ammonia. The CPS-II domain is activated by ATP and inhibited by UDP, UTP, dUTP, and CTP.

 

Dental Biochemistry Brush
DB Bullet Lesson 12.2 Pyrimidine metabolism
Overview of pyrimidine synthesis
Practice
Exercise 1: 		The formation of carbamoyl phosphate to be used in the synthesis of pyrimidines occurs in the cytosol.

No response
True
False
Practice
Exercise 2: 		The pyrimidine ring is built directly onto a ribose molecule.

No response
True
False


Practice
Exercise 3: 		The synthesis of carbamoyl phosphate for pyrimidine biosynthesis involves the condensation of bicarbonate and

No response
Ammonia
Aspartate
Glutamine
ATP
Dental Biochemistry Brush
DB Bullet Lesson 12.2 Pyrimidine metabolism

12.2D Synthesis of orotate and UMP

The second step leading to the synthesis of the pyrimidines is the formation of N-carbamoylaspartate from carbamoyl phosphate and aspartate. This reaction is catalyzed by the enzyme aspartate transcarbamoylase. This allosteric enzyme is highly regulated. More information on aspartate transcarbamoylase is available at the following sites.

 

The next step in the biosynthetic pathway involves the cyclization of N-carbamoylaspartate to form orotate.

 

The next step in the biosynthesis of pyrimidines involves the attachment of orotate to 5-phosphoribosyl-1-pyrophosphate (PRPP) a molecule you should be familiar with from purine biosynthesis. The reaction involving these 2 compounds results in the formation of orotidylate and PPi and is catalyzed by the enzyme orotate phosphoribosyl transferase. This is followed by a decarboxylation in the next step. This reaction is catalyzed by orotidylate decarboxylase and results in the formation of uridylate (UMP) accompanied by the release of CO2. These reactions are illustrated below.

Dental Biochemistry Brush
DB Bullet Lesson 12.2 Pyrimidine metabolism
Pyrimidine biosynthesis
Practice
Exercise 4: 		Orotate is the first cyclical intermediate in the synthesis of pyrimidines.

No Response
True
False

Practice
Exercise 5: 		The committed step in the biosynthesis of pyrimidines is the formation of

No response
Carbamoyl phosphate
N-carbamoylaspartate
Uridylate
Orotate


Practice
Exercise 6: 		The enzyme aspartate transcarbamoylase catalyzes the formation of N-carbamoylaspartate.

No response
True
False


Dental Biochemistry Brush
DB Bullet Lesson 12.2 Pyrimidine metabolism

    12.2E Interconversion of nucleotide phosphates

    The synthesis pathways for purines and pyrimidines result in the synthesis of the monophosphate form of the nucleotides. As seen above, the pyrimidine biosynthesis pathway results in the formation of UMP. AMP and GMP were formed by the purine biosynthetic pathway. These nucleotide monophosphates can be converted to diphosphates and these diphosphates can be converted to triphosphates. These reactions are reversible reactions as indicated below.

    UMP + ATP UDP + ADP

     

    UMP Kinase
    AMP + ATP ADP + ADP

     

    Adenylate Kinase

12.2F Formation of CTP

    The synthesis of the triphosphonucleotide CTP starts with another triphosphonucleotide UTP. Amination of UTP at position 4 of the pyrimidine ring results in the synthesis of CTP. Glutamine is the source of the nitrogen atom and energy in the form of ATP is required. The reaction is shown below.

     

    Dental Biochemistry Brush
DB Bullet Lesson 12.2 Pyrimidine metabolism
    Interconversion of nucleotides
    Practice
    Exercise 7:     		A monophosphate such as UMP can be directly converted to a triphosphate (UTP) by a nucleotide kinase.

    No Response
    True
    False
    Practice
    Exercise 8:     		The precursor for the synthesis of CTP is

    No response
    CMP
    UMP
    UTP
    ATP


     

     
    Dental Biochemistry Brush
DB Bullet Lesson 12.2 Pyrimidine metabolism
 

12.2G Summary

      After completing this lesson you should understand that

        1. The synthesis scheme for pyrimidine nucleotides differs from that of purine nucleotides
        2. The pyrimidine ring in synthesized first and then added to a ribose phosphate forming orotate
        3. UMP (uradylate) is synthesized from orotate by decarboxylation
        4. Nucleotide monophosphates can be converted to diphosphates by nucleotide kinases
        5. CTP is formed by amination of UTP
        6. Aspartate transcarbamoylase catalyzes the committed step (formation of N-carbamoylaspartate)

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      Final Instructions


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      End Lesson 12.2
      Pyrimidine metabolism


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