Purine and Pyrimidine Metabolism

Purines and pyrimidines are heterocyclic aromatic compounds, which, along with sugar and phosphate groups, form the important components of nucleotides. Purines include adenine and guanine, while pyrimidines include thymine (in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure), uracil (in RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure), and cytosine. Purine nucleotide synthesis follows a series of reactions using carbon donors, amino acids (e.g., glutamine, aspartate), and bicarbonate. The de novo pathway generates inosine monophosphate (IMP), which is the precursor of adenosine monophosphate (AMP) and guanosine monophosphate (GMP). Purine synthesis is regulated in the 1st 2 steps. Synthesis of pyrimidine nucleotides also follows different reactions, producing uridine monophosphate (UMP), which is converted to uridine triphosphate (UTP) and cytidine triphosphate (CTP). For thymine, a part of deoxyribonucleotides, ribonucleoside reductase is required to reduce the ribose moiety. Degradation of nucleotides result in xanthine then uric acid production in purines, while pyrimidines produce the amino acids, β-alanine, and β-aminobutyrate.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Overview

Basic terms

Nitrogenous base:

  • Purine: 
    • Adenine (A)
    • Guanine (G)
  • Pyrimidine: 
    • Thymine (T)
    • Uracil (U) 
    • Cytosine (C)
  • Other minor bases:
    • Hypoxanthine
    • Xanthine

Nucleosides: 2 components:

  • A nitrogenous base: 
    • Adenine, guanine, thymine, and cytosine in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
    • Adenine, guanine, uracil, and cytosine in RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
  • Pentose sugar: 
    • Ribose 
    • Deoxyribose

A beta-N-glycosidic bond links the 1st carbon of the pentose sugar and N9 of a purine or N1 of a pyrimidine (e.g., adenosine, guanosine, cytidine, thymidine, uridine, inosine).

Nucleotides: 3 main components:

  • Nitrogenous base 
  • Pentose sugar
  • Phosphate groups (varying number)

These molecules form the DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure backbone (e.g., adenosine monophosphate, guanosine monophosphate, cytidine monophosphate)

> 1 phosphate groups:

Esterification of the phosphate groups forms the corresponding nucleoside diphosphates and triphosphates (e.g., adenosine triphosphate (ATP), adenosine diphosphate (ADP)).

Nucleic acid: 

Polymer of nucleotides (e.g., ribonucleic acid ( RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure)).

Mnemonics

  • NucleoSide: base + Sugar
  • NucleoTide: base + sugar + phosphaTe

Biomedical importance

The main functions of nucleotides:

  • Form the building blocks of nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids
  • Act as cosubstrates and coenzymes in biochemical reactions
  • Involved in cell signaling pathways and also act as intracellular second messengers
  • Provide chemical energy in the form of nucleoside triphosphates such as ATP (energy in reactions such as amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids, protein, and cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane synthesis) 

Synthesis of Purines

Building the structure (de novo synthesis)

  • Nucleotides are formed from simple molecules: amino acids (e.g., glutamine), carbon donors (e.g., formyl tetrahydrofolate), and bicarbonate. 
  • Purine nucleotide synthesis is a multireaction process beginning with the conversion of ribose-5-phosphate to 5-phosphoribosyl-1-pyrophosphate (PRPP).
  • The major site of synthesis is the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver (intracytoplasmic).
Atom sources for purine synthesis

Atom sources for purine synthesis
THF: tetrahydrofolate

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Step 1

Synthesis of PRPP

  • PRPP is the substrate for purine synthesis.
  • Ribose-5-phosphate is converted to PRPP, with phosphates coming from ATP (reaction of which produces AMP).
  • Enzyme: PRPP synthetase/ribose phosphate pyrophosphokinase
  • Clinical correlation: PRPP overactivity: X-linked disorder associated with overproduction of nucleotides, manifesting with ↑ uric acid and neurodevelopmental anomalies
Synthesis of phosphoribosyl pyrophosphate

Synthesis of phosphoribosyl pyrophosphate (PRPP):
Ribose-5-phosphate (R5P) is converted to PRPP. The phosphates come from ATP and then produce AMP. The enzyme for the conversion is PRPP synthetase.

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Step 2

Formation of 5-phosphoribosylamine (PRA)

  • PRPP + glutamine → PRA
  • The pyrophosphate group of PRPP is released in this reaction.
  • Rate-limiting step
  • Enzyme: amidophosphoribosyltransferase
  • The enzyme is inhibited by:
    • AMP
    • Guanosine monophosphate (GMP)
    • Inosine monophosphate (IMP)

Step 3

5-Phosphoribosylamine conversion to glycinamide ribonucleotide (GAR)

  • Subsequent steps are additions to form 5- or 6-membered ring.
  • Glycine is added to PRA to form GAR.
  • Glycine contributes C4, C5, and N7.
  • Enzyme: GAR synthetase (GARS)/phosphoribosylamine glycine ligase

Step 4

Formylation of GAR to formylglycinamide ribonucleotide (FGAR)

  • Formyltetrahydrofolate formylates the amino group of GAR to form FGAR, contributing C8 of purine.
  • Enzyme: GAR transformylase/phosphoribosyl glycinamide formyltransferase

Step 5

Conversion of FGAR to formylglycinamidine ribonucleotide (FGAM)

  • In this adenosine triphosphate (ATP)-dependent reaction, glutamine donates the N3, forming FGAM.
  • Enzyme: FGAM synthetase/phosphoribosyl formyl glycinamide synthase

Step 6

Formation of the purine imidazole ring

  • This is an ATP-dependent reaction that leads to the formation and closure of the purine ring.
  • 5-Aminoimidazole ribonucleotide (AIR) is formed from this reaction.
  • Enzyme: AIR synthetase/phosphoribosyl formyl glycinamide cyclo-ligase

Step 7

Carboxylation of AIR

  • This is an ATP-dependent carboxylation of AIR to carboxy aminoimidazole ribonucleotide (CAIR), in the presence of bicarbonate
  • C6 of purine is contributed by bicarbonate. 
  • Enzyme: AIR carboxylase/N5-CAIR synthase

Step 8

Formation of 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide (SAICAR)

  • The addition of aspartate forms an amide bond with C6 to form SAICAR.
  • N1 of purine is contributed by aspartate. 
  • Enzyme: SAICAR synthetase/N5-carboxy aminoimidazole ribonucleotide mutase

Step 9

Elimination of fumarate

  • 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is formed by the cleaving off the fumarate group. 
  • Enzyme: Adenylosuccinate lyase/5-phosphoribosyl-4-(N-succinyl carboxamide)-5-aminoimidazole lyase

Step 10

Formylation to form 5-formaminoimidazole-4-carboxamide ribonucleotide (FAICAR)

  • Formylation occurs by reaction between the amino group of AICAR and N10-formyl tetrahydrofolate to form FAICAR.
  • C2 of the purine ring is contributed by N10-formyl tetrahydrofolate.
  • Enzyme: AICAR transformylase

Step 11

Cyclization to form IMP

  • Inosine monophosphate is formed by the enzymatic closure of the larger ring of FAICAR with the release of water.
  • Inosine monophosphate is the precursor of AMP and GMP.
  • Enzyme: IMP cyclohydrolase
Table: Summary of de novo purine synthesis
Step Reaction Added atom Enzyme Product
1 Ribose-5-phosphate → PRPP PRPP synthetase PRPP
2 PRPP + glutamine → 5-phosphoribosylamine N9 (from glutamine) Amidophosphoribosyltransferase PRA
3 PRA conversion to GAR C4, C5, N7 (from glycine) GAR synthetase GAR
4 Formylation of GAR to FGAR C8 (from formyl THF) GAR transformylase FGAR
5 Conversion of FGAR to FGAM N3 (from glutamine) FGAM synthetase FGAM
6 Ring closure, forming AIR AIR synthetase AIR
7 Carboxylation of AIR C6 (from bicarbonate) AIR carboxylase AICAR
8 Formation of SAICAR N1 (from aspartate) SAICAR synthetase SAICAR
9 Fumarate removed AICAR formed Adenylosuccinate lyase AICAR
10 FAICAR formed C2 (from formyl-THF) AICAR transformylase FAICAR
11 IMP formed IMP cyclohydrolase IMP
AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide
AIR:5-aminoimidazole ribonucleotide
FGAM: formylglycinamidine ribonucleotide
FGAR: formylglycinamide ribonucleotide
GAR: glycinamide ribonucleotide
IMP: inosine monophosphate
PRPP: phosphoribosyl pyrophosphate
PRA: 5-phosphoribosylamine
SAICAR: 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
THF: tetrahydrofolate

Role of folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12

  • Folic acid is composed of p-aminobenzoic acid, glutamine, and pteridine and is available for utilization in its active form: tetrahydrofolic acid (TH4).
  • Lack of folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 leads to decreased nucleotide synthesis.
  • 2 important consequences of folic acid deficiency are megaloblastic anemia Megaloblastic anemia Megaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies. Megaloblastic Anemia and spina bifida in newborns (due to maternal folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency).
Structure of folate

Structure of folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12

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Adenine and Guanine Formation

Inosine monophosphate is converted to adenine and guanine as AMP and GMP. Formed from GMP, guanosine triphosphate (GTP) provides the energy to convert IMP to AMP.

Synthesis of guanosine monophosphate

  • Step 1: dehydrogenation of IMP
    • Dehydrogenation of IMP forms xanthosine monophosphate (XMP).
    • H+ ions are released (and accepted by NAD+).
    • Enzyme: IMP dehydrogenase
  • Step 2: amidation of XMP
    • Amidation of XMP (amide from glutamine) and hydrolysis of ATP occur, yielding GMP. 
    • Enzyme: GMP synthetase
  • Clinical correlation:
    • Mycophenolate, an immunosuppressant, inhibits IMP dehydrogenase (IMPDH), reducing proliferation of immune cells.
Conversion of imp to gmp and then to gtp

Conversion of IMP to GMP and then to GTP:
NAD+: nicotinamide adenine dinucleotide (oxidized)
NADH: nicotinamide adenine dinucleotide (reduced)
NDPK: nucleoside diphosphate kinase
PPi: pyrophosphate

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Synthesis of AMP

  • Step 1: Donation of the amino group by aspartate
    • The amino group of aspartate (links to IMP) + GTP hydrolysis → adenylosuccinate
    • Enzyme: adenylosuccinate synthetase
  • Step 2: Elimination of fumarate to form AMP
    • Adenylosuccinate is enzymatically converted to AMP by the removal of fumarate. 
    • Enzyme: adenylosuccinase/adenylosuccinate lyase
Conversion of imp to amp and finally to atp

Conversion of IMP to AMP and then to ATP:
NDPK: nucleoside diphosphate kinase
Pi: inorganic phosphate

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Regulation of synthesis

Synthesis of IMP, ATP and GTP is regulated to control the amount of purine nucleotides produced.

  • The enzyme PRPP synthetase (step 1) is inhibited by ADP and GDP.
  • The enzyme amidophosphoribosyltransferase (step 2) is inhibited by:
    • AMP
    • GMP
    • IMP
  • The enzyme adenylosuccinate synthetase (AMP synthesis) is inhibited by AMP.
  • The enzyme IMP dehydrogenase (in GMP synthesis) is inhibited by GMP.
  • External factors affecting purine synthesis include purine analogs:
    • Thiopurines (inhibit de novo purine synthesis) 
      • 6-Mercaptopurine (6-MP): antineoplastic and immunosuppressive agent
      • 6-Thioguanine
      • Azathioprine (immunosuppressant): undergoes nonenzymatic reduction into 6-MP 
    • Fludarabine
    • Cladribine
Regulators of purine metabolism

Regulators of purine metabolism

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Salvage Pathway of Purines

Building the structure

  • Generation of nucleotides from the breakdown of nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids
  • Free purines are converted back to their respective nucleotides through salvage pathways. 
  • PRPP is an essential component in this pathway. 
  • The 2 main enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes involved are:
    1. Adenine phosphoribosyltransferase (APRT)
    2. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

Reactions

  • The brief summary of the salvage pathway is:
    • Adenine + PRPP ⇋ AMP + PPi (enzyme: APRT)
    • Guanine + PRPP ⇋ GMP + PPi (enzyme: HGPRT)
    • Hypoxanthine + PRPP ⇋ IMP + PPi (enzyme: HGPRT)
  • Clinical correlation: Lesch-Nyhan syndrome: X-linked recessive disorder caused by defect in HGPRT (unable to salvage purine bases → ↑ uric acid)
Salvage pathway that recycles nucleotides for utilization

The salvage pathway that recycles nucleotides for utilization

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Importance

  • In tissues like erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes and the brain, the salvage pathway is important owing to the absence of de novo purine synthesis.
  • The pathway economizes intracellular energy expenditure. 

Catabolism of Purine Nucleotides

Nucleic acid ( RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure/ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure) is broken down by nucleases to nucleotides. To degrade purine nucleotides, the phosphate and ribose are removed first, with further reactions leading to xanthine and then to uric acid.

Guanosine monophosphate

  • Conversion of nucleotide to nucleoside (GMP to guanosine) by the enzyme nucleotidase, resulting in phosphate removal
  • Guanosine is further broken down:
    • Reaction leads to guanine and ribose-1-phosphate. 
    • Enzyme: purine nucleoside phosphorylase
  • Deamination of guanine leads to the formation of xanthine.
Degradation of guanine

Degradation of guanine

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AMP

  • Conversion from nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids ( RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure/ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure to AMP to bases) can have different pathways, using different deaminases.
  • 1st pathway:
    • AMP → adenosine: catalyzed by the enzyme purine nucleotidase, with removal of the phosphate
    • Adenosine converted to inosine by adenosine deaminase (ADA)
    • Inosine is degraded by purine nucleoside phosphorylase (PNP) to hypoxanthine and ribose-1-phosphate.
    • Hypoxanthine is oxidized to xanthine by xanthine oxidase.
  • 2nd pathway:
    • AMP → inosinic acid or IMP: catalyzed by AMP deaminase
    • IMP is converted to inosine by nucleotidase.
    • Inosine is degraded by PNP to hypoxanthine and ribose-1-phosphate.
    • Hypoxanthine is oxidized to xanthine by xanthine oxidase.
  • Clinical correlation:
    • ADA deficiency: leads to ↑ deoxy-ATP, deoxy-GTP (toxic to immune cells such as T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells)
    • PNP deficiency: leads to ↑ deoxy-ATP, deoxy-GTP (toxic to immune cells such as T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells) and also associated with developmental delay
Degradation of adenine

Degradation of adenine

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Xanthine

  • Both adenosine and guanosine are converted to xanthine.
    • Adenosine → inosine → hypoxanthine → xanthine
    • Guanosine → guanine → xanthine
  • Xanthine oxidase:
    • Catalyzes hypoxanthine to xanthine and xanthine to uric acid reactions
    • The end product, uric acid, is excreted in the urine.
  • Clinical correlation: allopurinol, an inhibitor of xanthine oxidase, is used for gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout treatment.
Degradation of guanine and hypoxanthine into uric acid

Degradation of guanine and hypoxanthine into uric acid

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Pyrimidine Synthesis

Building the structure (de novo synthesis)

  • Pyrimidine base is synthesized first and then incorporated into the nucleotide (the ring is completed before being linked to ribose-5-phosphate). 
  • Sources of the carbon and nitrogen atoms of pyrimidine:
    • Glutamine and bicarbonate contribute N3 and C2, respectively, which combine to form carbamoyl phosphate.
    • Aspartate contributes N1, C6, C5, and C4
Sources of the carbon and nitrogen atoms in pyrimidine synthesis

Sources of the carbon and nitrogen atoms in pyrimidine synthesis

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Step 1

Synthesis of carbamoyl phosphate

  • This reaction occurs in the cytoplasm. 
  • The nitrogen of glutamine and carbon of bicarbonate react to form carbamoyl phosphate. 
  • Enzyme: carbamoyl phosphate synthetase II

Step 2

Synthesis of carbamoyl aspartate

  • Rate-limiting step 
  • Carbamoyl phosphate reacts with aspartate to yield carbamoyl aspartate.
  • Atoms C2 and N3 are derived from carbamoyl phosphate. 
  • Enzyme: aspartyl transcarbamoylase (ATCase)
    • Activated by ATP
    • Inhibited by cytidine triphosphate (CTP)
The rate-limiting step of pyrimidine synthesis

Rate-limiting step of pyrimidine synthesis:
Reaction converts carbamoyl phosphate to carbamoyl aspartate, catalyzed by aspartyl transcarbamoylase (ATCase). Subsequent reactions eventually lead to the end product, cytidine triphosphate (CTP). The ATCase is activated by ATP and inhibited by CTP.

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Step 3

Formation of the pyrimidine ring

  • A molecule of water is eliminated, and carbamoyl aspartate is converted to a ring compound (dihydroorotate).
  • Enzyme: dihydroorotase

Step 4

Oxidation of dihydroorotate

  • Removal of hydrogen atoms (dehydrogenation) from the C5 and C6 positions produces orotic acid.
  • Enzyme: dihydroorotate dehydrogenase
  • Coenzyme: NAD 

Step 5

Formation of orotidine-5-monophosphate (OMP)

  • Orotic acid + ribose-5-phosphate → orotidine monophosphate or orotidylic acid
  • PRPP is the donor of ribose-5-phosphate.
  • Enzyme: orotate phosphoribosyltransferase (OPRT)

Step 6

Decarboxylation to form uridine monophosphate (UMP)

  • Orotidine monophosphate undergoes decarboxylation.
  • UMP is produced by the removal of C1 in the form of CO2 , making uridine the first pyrimidine to be synthesized.
  • Enzyme: OMP decarboxylase
  • Subsequent steps form the triphosphates uridine triphosphate (UTP) and cytidine triphosphate (CTP).
Table: Summary of de novo pyrimidine synthesis
Step Enzyme Product
1 Carbamoyl phosphate synthetase II Carbamoyl phosphate
2 Aspartyl transcarbamoylase* Carbamoyl aspartate
3 Dihydroorotase Dihydroorotic acid
4 Dihydroorotate dehydrogenase Orotic acid
5 Orotate phosphoribosyltransferase OMP
6 OMP decarboxylase Uridine monophosphate
*catalyzes the rate-limiting step
OMP: orotidine-5-monophosphate
Summary of pyrimidine synthesis

Summary of pyrimidine synthesis, enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
1. CPS II: carbamoyl phosphate synthetase II
2. ATCase: aspartyl transcarbamoylase
3. Dihydroorotase
4. Dihydroorotate (DHO) dehydrogenase
5. Orotate phosphoribosyltransferase
6. Orotidine-5-monophosphate (OMP) decarboxylase

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Synthesis of uridine triphosphate and cytidine triphosphate

UTP and CTP are used in the synthesis of RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure.

UTP:

  • Step 1: 
    • Phosphorylation of UMP by ATP produces uridine diphosphate (UDP)
    • Enzyme: nucleoside monophosphate kinase (UMP/CMP kinase) 
  • Step 2: 
    • UDP is phosphorylated to uridine triphosphate (UTP) by ATP.
    • Enzyme: nucleoside diphosphate kinase (NDPK)

CTP:

  • UTP is converted to CTP (cytidine triphosphate) by the addition of an amino group from glutamine.
  • This reaction requires ATP.
  • Enzyme: CTP synthetase 
    • Activated by GTP
    • Inhibited by CTP
Synthesis of utp and ctp (triphosphates)

Synthesis of UTP and CTP (triphosphates)

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Deoxyribonucleotides and thymine

DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure is different from RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure, as DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure has deoxyribose, instead of ribose, and thymine (5-methyluracil), instead of uracil.

Deoxyribonucleotides are generated from their corresponding ribonucleotides.

  • Ribonucleotide reductases (RNRs) reduce ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphosphates (dNDPs).
  • dNDPs in turn, are converted to deoxyribonucleoside triphosphates (dNTPs) by nucleoside diphosphate kinase (NDPK).

Thymine is a pyrimidine present in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure; thus, the ribose moiety of the corresponding nucleotide requires reduction.

  • Step 1:
    • UDP → dUDP
    • Enzyme: ribonucleotide reductase
  • Step 2: 
    • dUDP → dUTP
    • Enzyme: NDPK
  •  Step 3:
    • dUTP → deoxyuridine monophosphate (dUMP)
    • Enzyme: dUTP diphosphohydrolase
  • Step 4:
    • dUMP is methylated to deoxythymidine monophosphate (dTMP).
    • Enzyme: thymidylate synthase
    • Requires methylene tetrahydrofolate (as the methyl donor)
  • Step 5:
    • dTMP is phosphorylated to dTTP (by ATP).
    • Phosphorylation occurs in 2 rounds.

Clinical correlation: 5-fluorouracil: antimetabolite agent (used in cancers) that inhibits thymidylate synthase and decreases DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis

Formation of thymine in the form of dttp

Formation of thymine in the form of deoxythymidine triphosphate (dTTP)
dTDP: deoxythymidine diphosphate
dTMP: deoxythymidine monophosphate
dTTP: deoxythymidine triphosphate
dUDP: deoxyuridine diphosphate
dUMP: deoxyuridine monophosphate
dUTPase: deoxyuridine triphosphatase
NDPK: nucleoside diphosphate kinase
RNR: ribonucleotide reductase
UDP: uridine monophosphate

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Regulation of synthesis

  • The enzyme, carbamoyl phosphate synthetase (CPS) II in step 1: 
    • Activated by PRPP and ATP
    • Inhibited by UTP and UDP
  • The enzyme, ATCase in step 2 is allosterically inhibited by CTP.
  • The enzyme, OMP decarboxylase (step 6) is inhibited by UMP.
  • External factors include pyrimidine analogs (used as antineoplastic agents):
    • 5-fluorouracil
    • Capecitabine
    • Cytarabine
    • Gemcitabine

Salvage pathway of pyrimidine nucleotides

  • Like purines, pyrimidines are recycled from the derivative intermediates of nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids
  • Reactions convert ribonucleosides (uridine, cytidine) and deoxyribonucleosides (thymidine, deoxycytidine) to nucleotides.
  • Kinases or phosphoryltransferases catalyze phosphoryl group transfer (from ATP) to the diphosphates, producing triphosphates:
    • NDP + ATP → NTP + ADP
    • dNTP + ATP → dNTP + ADP

Catabolism of Pyrimidine Nucleotides

Animal cells break down pyrimidine nucleotides to the nitrogenous bases, with the resultant uracil and thymine degraded (via reduction) in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver

  • As in purine nucleotides, nucleic acid ( RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure/ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure) is broken down by nucleases to nucleotides.
  • Cytosine is degraded to uracil by the removal of an amino group.
  • Both uracil and thymine are then reduced to dihydrouracil and dihydrothymine, respectively, which undergo reactions to the end products:
    • Dihydrouracil → β-alanine
    • Dihydrothymine → β-aminobutyrate
    • Reaction catalyzed by: hepatic β-ureidopropionase 
    • β-aminobutyrate and β-alanine are further used in amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids metabolism.
    • The ammonium ions (NH4+) released from the breakdown are used in the urea cycle Urea Cycle The catabolism of amino acids results in the release of nitrogen in the form of ammonium. This excess nitrogen is transported to the liver and kidneys and eliminated from the body in the form of urea via the urine. The urea cycle (or ornithine cycle) takes place mainly in the liver and comprises the synthesis of urea from ammonium, CO2, aspartate, and bicarbonate. Urea Cycle.
Degradation of uracil and thymine

Degradation of uracil and thymine
NADPH: nicotinamide adenine dinucleotide phosphate

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Disorders of Nucleotide Metabolism

Table: Disorders of purine metabolism
Disorder Defective enzyme Nature of defect Manifestations
Hyperuricemia/ gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout
  • ↑ PRPP synthetase
  • ↓ HGPRT
↑ Uric acid Inflamed and painful joints
Lesch-Nyhan syndrome ↓ HGPRT Lack of enzyme → defective purine salvage pathway
  • Delayed puberty Delayed Puberty Delayed puberty (DP) is defined as the lack of testicular growth in boys past the age of 14 and the lack of thelarche in girls past the age of 13. Delayed puberty affects up to 5% of healthy boys and girls, and half of all cases are due to constitutional growth delay. Delayed Puberty
  • Self-mutilation
  • Developmental delay
  • Impaired renal function
SCID ↓ ADA Lack of enzyme → ↓ immune cells
  • Repeated infections, recurrent deep skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, or organ abscesses
  • Mucocutaneous candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis
  • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
Renal lithiasis ↓ APRT Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations → defective purine salvage pathway
  • Renal colic
  • Recurrent urinary infections
  • Nausea
  • Vomiting
Xanthinuria ↓ Xanthine oxidase Hypouricemia
  • Nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis
  • Acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury
ADA: adenosine deaminase
APRT: adenine phosphoribosyltransferase
HGPRT: hypoxanthine guanine phosphoribosyltransferase
PRPP: phosphoribosyl pyrophosphate
SCID: severe combined immunodeficiency Severe Combined Immunodeficiency Severe combined immunodeficiency (SCID), also called "bubble boy disease," is a rare genetic disorder in which the development of functional B and T cells is disturbed due to several genetic mutations that result in reduced or absent immune function. Severe Combined Immunodeficiency
Table: Disorders of pyrimidine metabolism
Disorder Defective enzyme Manifestations
Orotic aciduria Orotic aciduria Orotic aciduria is an extremely rare genetic disorder that can result in crystalluria, megaloblastic anemia, developmental delay, and failure to thrive. The disorder is caused by an enzyme deficiency in the pyrimidine synthesis pathway resulting in the accumulation of orotic acid. Orotic Aciduria
  • OPRT
  • OMP decarboxylase
  • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
  • Developmental delay
  • Megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
Drug-induced orotic aciduria OMP decarboxylase
  • Caused by allopurinol and 6-azauridine
  • Increased excretion of orotic acid
OMP: orotidine-5-monophosphate
OPRT: orotate phosphoribosyltransferase

References

  1. Moffatt, B. A., Ashihara, H. (2002). Purine and pyrimidine nucleotide synthesis and metabolism. https://doi.org/10.1199/tab.0018
  2. Pedley, A. M., Benkovic, S. J. (2017). A new view into the regulation of purine metabolism: the purinosome. Trends in Biochemical Sciences 42:141–154. https://doi.org/10.1016/j.tibs.2016.09.009
  3. Rodwell V.W. (2018). Metabolism of purine & pyrimidine nucleotides. Chapter 33 of Rodwell V.W., et al. (Ed.), Harper’s Illustrated Biochemistry, 31st ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2386&sectionid=187833691
  4. Swanson, T., et al. (2010) Nucleotide and porphyrin metabolism. In: Swanson, T., et al. (Eds.), Biochemistry, Molecular Biology and Genetics, 5th ed. Lippincott, Williams & Wilkins, pp. 203–208.

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