Purine and Pyrimidine Metabolism

Overview

Basic terms

Nitrogenous base:

• Purine:
  • Adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids (A)
  • Guanine Guanine Nucleic Acids (G)
• Pyrimidine:
  • Thymine Thymine One of four constituent bases of DNA. Nucleic Acids (T)
  • Uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids (U) 
  • Cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids (C)
• Other minor bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance:
  • Hypoxanthine
  • Xanthine

Nucleosides Nucleosides Purine or pyrimidine bases attached to a ribose or deoxyribose. Nucleic Acids: 2 components:

• A nitrogenous base: 
  • Adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids, guanine Guanine Nucleic Acids, thymine Thymine One of four constituent bases of DNA. Nucleic Acids, and cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • Adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids, guanine Guanine Nucleic Acids, uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids, and cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids in RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure
• Pentose sugar:
  • Ribose Ribose A pentose active in biological systems usually in its d-form. Nucleic Acids 
  • Deoxyribose Deoxyribose Nucleic Acids

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 Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs, guanosine, cytidine, thymidine, uridine, inosine).

Nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids: 3 main components:

• Nitrogenous base 
• Pentose sugar
• Phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes groups (varying number)

These molecules form the DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure backbone (e.g., adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs monophosphate, guanosine monophosphate, cytidine monophosphate)

> 1 phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes groups:

Esterification Esterification The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an Acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. Lipid Metabolism of the phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes groups forms the corresponding nucleoside diphosphates and triphosphates (e.g., adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate (ATP), adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs diphosphate (ADP)).

Nucleic acid: 

Polymer of nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids (e.g., ribonucleic acid Ribonucleic acid A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure ( RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure)).

Mnemonics

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

Biomedical importance

The main functions of nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids:

• Form the building blocks of nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance
• Act as cosubstrates and coenzymes Coenzymes Small molecules that are required for the catalytic function of enzymes. Many vitamins are coenzymes. Basics of Enzymes in biochemical reactions
• Involved in cell signaling pathways and also act as intracellular second messengers Second messengers Signaling pathways are complex systems in which a single extracellular signal can elicit multiple intracellular events, some of which may also be triggered by other signaling pathways or may themselves trigger other intracellular events. “Second messengers” is a term used to refer to a diverse group of small molecules or ions that transmit the extracellular signal initiated by a ligand binding to a cell surface receptor to effector proteins inside the cell. 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 Polymerase Chain Reaction (PCR)) 

Synthesis of Purines

Building the structure (de novo synthesis Synthesis Polymerase Chain Reaction (PCR))

• Nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids are formed from simple molecules: amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids (e.g., glutamine Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids), carbon donors (e.g., formyl tetrahydrofolate Tetrahydrofolate Sulfonamides and Trimethoprim), and bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes. 
• Purine nucleotide synthesis Synthesis Polymerase Chain Reaction (PCR) is a multireaction process beginning with the conversion of ribose-5-phosphate Ribose-5-phosphate Pentose Phosphate Pathway to 5-phosphoribosyl-1-pyrophosphate (PRPP).
• The major site of synthesis Synthesis Polymerase Chain Reaction (PCR) 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: Anatomy (intracytoplasmic).

Step 1

Synthesis Synthesis Polymerase Chain Reaction (PCR) of PRPP

• PRPP is the substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes for purine synthesis Synthesis Polymerase Chain Reaction (PCR).
• Ribose-5-phosphate Ribose-5-phosphate Pentose Phosphate Pathway is converted to PRPP, with phosphates coming from ATP (reaction of which produces AMP).
• Enzyme: PRPP synthetase/ ribose Ribose A pentose active in biological systems usually in its d-form. Nucleic Acids phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes pyrophosphokinase
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability: PRPP overactivity: X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) disorder associated with overproduction of nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids, manifesting with ↑ uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis and neurodevelopmental anomalies

Step 2

Formation of 5-phosphoribosylamine (PRA)

• PRPP + glutamine Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids → 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 Glycine A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. Synthesis of Nonessential Amino Acids is added to PRA to form GAR.
• Glycine Glycine A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. Synthesis of Nonessential Amino Acids contributes C4, C5, and N7.
• Enzyme: GAR synthetase (GARS)/phosphoribosylamine glycine Glycine A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. Synthesis of Nonessential Amino Acids 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 Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate (ATP)-dependent reaction, glutamine Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids donates the N3, forming FGAM.
• Enzyme: FGAM synthetase/phosphoribosyl formyl glycinamide synthase

Step 6

Formation of the purine imidazole ring Imidazole Ring Nitroimidazoles

• 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 Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes
• C6 of purine is contributed by bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes. 
• Enzyme: AIR carboxylase

Step 8

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

• The addition of aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids forms an amide bond with C6 to form SAICAR.
• N1 of purine is contributed by aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids. 
• Enzyme: SAICAR synthetase

Step 9

Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of fumarate Fumarate Citric Acid Cycle

• 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is formed by the cleaving off the fumarate Fumarate Citric Acid Cycle 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 Tetrahydrofolate Sulfonamides and Trimethoprim to form FAICAR.
• C2 of the purine ring is contributed by N10-formyl tetrahydrofolate Tetrahydrofolate Sulfonamides and Trimethoprim.
• 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

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 Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids, 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 Synthesis Polymerase Chain Reaction (PCR).
• 2 important consequences of folic acid deficiency Folic Acid Deficiency A nutritional condition produced by a deficiency of folic acid in the diet. Many plant and animal tissues contain folic acid, abundant in green leafy vegetables, yeast, liver, and mushrooms but destroyed by long-term cooking. Alcohol interferes with its intermediate metabolism and absorption. Folic acid deficiency may develop in long-term anticonvulsant therapy or with use of oral contraceptives. This deficiency causes anemia, macrocytic anemia, and megaloblastic anemia. It is indistinguishable from vitamin B 12 deficiency in peripheral blood and bone marrow findings, but the neurologic lesions seen in B 12 deficiency do not occur. Megaloblastic Anemia 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 deficiency Folate deficiency A nutritional condition produced by a deficiency of folic acid in the diet. Many plant and animal tissues contain folic acid, abundant in green leafy vegetables, yeast, liver, and mushrooms but destroyed by long-term cooking. Alcohol interferes with its intermediate metabolism and absorption. Folic acid deficiency may develop in long-term anticonvulsant therapy or with use of oral contraceptives. This deficiency causes anemia, macrocytic anemia, and megaloblastic anemia. It is indistinguishable from vitamin B12 deficiency in peripheral blood and bone marrow findings, but the neurologic lesions seen in B12 deficiency do not occur. Megaloblastic Anemia).

Adenine and Guanine Formation

Inosine monophosphate is converted to adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids and guanine Guanine Nucleic Acids as AMP and GMP. Formed from GMP, guanosine triphosphate (GTP) provides the energy to convert IMP to AMP.

Synthesis Synthesis Polymerase Chain Reaction (PCR) of guanosine monophosphate

• Step 1: dehydrogenation of IMP
  • Dehydrogenation of IMP forms xanthosine monophosphate (XMP).
  • H⁺ ions are released (and accepted by NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺).
  • Enzyme: IMP dehydrogenase
• Step 2: amidation of XMP
  • Amidation of XMP (amide from glutamine Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids) and hydrolysis Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water. Proteins and Peptides of ATP occur, yielding GMP. 
  • Enzyme: GMP synthetase
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability:
  • Mycophenolate Mycophenolate Immunosuppressants, an immunosuppressant, inhibits IMP dehydrogenase (IMPDH), reducing proliferation of immune cells.

Synthesis Synthesis Polymerase Chain Reaction (PCR) of AMP

• Step 1: Donation of the amino group by aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids
  • The amino group of aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids (links to IMP) + GTP hydrolysis Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water. Proteins and Peptides → adenylosuccinate
  • Enzyme: adenylosuccinate synthetase
• Step 2: Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of fumarate Fumarate Citric Acid Cycle to form AMP
  • Adenylosuccinate is enzymatically converted to AMP by the removal of fumarate Fumarate Citric Acid Cycle. 
  • Enzyme: adenylosuccinase/adenylosuccinate lyase

Regulation of synthesis Synthesis Polymerase Chain Reaction (PCR)

Synthesis Synthesis Polymerase Chain Reaction (PCR) of IMP, ATP and GTP is regulated to control the amount of purine nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids 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 Synthesis Polymerase Chain Reaction (PCR)) is inhibited by AMP.
• The enzyme IMP dehydrogenase (in GMP synthesis Synthesis Polymerase Chain Reaction (PCR)) is inhibited by GMP.
• External factors affecting purine synthesis Synthesis Polymerase Chain Reaction (PCR) include purine analogs Purine Analogs Antimetabolite Chemotherapy:
  • Thiopurines (inhibit de novo purine synthesis Synthesis Polymerase Chain Reaction (PCR))
    • 6-Mercaptopurine 6-Mercaptopurine An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. Antimetabolite Chemotherapy ( 6-MP 6-MP An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. Antimetabolite Chemotherapy): antineoplastic and immunosuppressive agent
    • 6-Thioguanine 6-Thioguanine An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. Antimetabolite Chemotherapy
    • Azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants (immunosuppressant): undergoes nonenzymatic reduction into 6-MP 6-MP An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. Antimetabolite Chemotherapy 
  • Fludarabine Fludarabine Antimetabolite Chemotherapy
  • Cladribine Cladribine An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. Antimetabolite Chemotherapy

Salvage Pathway of Purines

Building the structure

• Generation of nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids from the breakdown of nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance
• Free purines Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. Nucleic Acids are converted back to their respective nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids through salvage pathways. 
• PRPP is an essential component in this pathway. 
• The 2 main enzymes involved are:
  1. Adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids phosphoribosyltransferase (APRT)
  2. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

Reactions

• The brief summary of the salvage pathway is:
  • Adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids + PRPP ⇋ AMP + PPi (enzyme: APRT)
  • Guanine Guanine Nucleic Acids + PRPP ⇋ GMP + PPi (enzyme: HGPRT)
  • Hypoxanthine + PRPP ⇋ IMP + PPi (enzyme: HGPRT)
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability: Lesch-Nyhan syndrome Lesch-Nyhan syndrome An inherited disorder transmitted as a sex-linked trait and caused by a deficiency of an enzyme of purine metabolism; hypoxanthine phosphoribosyltransferase. Elevation of uric acid in the serum leads to the development of renal calculi and gouty arthritis. Purine Salvage Deficiencies: X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy disorder caused by defect in HGPRT (unable to salvage purine bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance → ↑ uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis)

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: Histology and the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, the salvage pathway is important owing to the absence of de novo purine synthesis Synthesis Polymerase Chain Reaction (PCR).
• The pathway economizes intracellular energy expenditure Energy expenditure Energy expenditure is the sum of internal heat produced and external work. Energy Homeostasis. 

Catabolism of Purine Nucleotides

Nucleic acid ( RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure/ DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure) is broken down by nucleases Nucleases Pancreatic Parameters to nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids. To degrade purine nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids, the phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes and ribose Ribose A pentose active in biological systems usually in its d-form. Nucleic Acids are removed first, with further reactions leading to xanthine and then to uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis.

Guanosine monophosphate

• Conversion of nucleotide to nucleoside (GMP to guanosine) by the enzyme nucleotidase, resulting in phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes removal
• Guanosine is further broken down:
  • Reaction leads to guanine Guanine Nucleic Acids and ribose-1-phosphate. 
  • Enzyme: purine nucleoside phosphorylase
• Deamination Deamination The removal of an amino group (NH2) from a chemical compound. Catabolism of Amino Acids of guanine Guanine Nucleic Acids leads to the formation of xanthine.

AMP

• Conversion from nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance ( RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure/ DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure to AMP to bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance) can have different pathways, using different deaminases.
• 1st pathway:
  • AMP → adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs: catalyzed by the enzyme purine nucleotidase, with removal of the phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes
  • Adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs converted to inosine by adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs deaminase (ADA)
  • Inosine is degraded by purine nucleoside phosphorylase (PNP) to hypoxanthine and ribose-1-phosphate.
  • Hypoxanthine is oxidized to xanthine by xanthine oxidase Oxidase Neisseria.
• 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 Oxidase Neisseria.
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability:
  • ADA deficiency: leads to ↑ deoxy-ATP, deoxy-GTP (toxic to immune cells such as T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions)
  • PNP deficiency PNP deficiency Severe Combined Immunodeficiency (SCID): leads to ↑ deoxy-ATP, deoxy-GTP (toxic to immune cells such as T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions) and also associated with developmental delay

Xanthine

• Both adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs and guanosine are converted to xanthine.
  • Adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs → inosine → hypoxanthine → xanthine
  • Guanosine → guanine Guanine Nucleic Acids → xanthine
• Xanthine oxidase Oxidase Neisseria:
  • Catalyzes hypoxanthine to xanthine and xanthine to uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis reactions
  • The end product, uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis, is excreted in the urine.
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability: allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs, an inhibitor of xanthine oxidase Oxidase Neisseria, 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.

Pyrimidine Synthesis

Building the structure (de novo synthesis Synthesis Polymerase Chain Reaction (PCR))

• Pyrimidine base is synthesized first and then incorporated into the nucleotide (the ring is completed before being linked to ribose-5-phosphate Ribose-5-phosphate Pentose Phosphate Pathway). 
• Sources of the carbon and nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle atoms of pyrimidine:
  • Glutamine Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids and bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes contribute N3 and C2, respectively, which combine to form carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes.
  • Aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids contributes N1, C6, C5, and C4

Step 1

Synthesis Synthesis Polymerase Chain Reaction (PCR) of carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes

• This reaction occurs in the cytoplasm. 
• The nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle of glutamine Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids and carbon of bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes react to form carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes. 
• Enzyme: carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes synthetase II

Step 2

Synthesis Synthesis Polymerase Chain Reaction (PCR) of carbamoyl aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids

• Rate-limiting step 
• Carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes reacts with aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids to yield carbamoyl aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids.
• Atoms C2 and N3 are derived from carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes. 
• Enzyme: aspartyl transcarbamoylase (ATCase)
  • Activated by ATP
  • Inhibited by cytidine triphosphate (CTP)

Step 3

Formation of the pyrimidine ring

• A molecule of water is eliminated, and carbamoyl aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids 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 NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway 

Step 5

Formation of orotidine-5-monophosphate (OMP)

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

Step 6

Decarboxylation Decarboxylation The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. Catabolism of Amino Acids to form uridine monophosphate (UMP)

• Orotidine monophosphate undergoes decarboxylation Decarboxylation The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. Catabolism of Amino Acids.
• 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).

Note: The last 2 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 in this pathway, OPRT and OMP decarboxylase, are located on the same polypeptide, UMP synthase. UMP synthase catalyzes the conversion of orotic acid to UMP.

Synthesis Synthesis Polymerase Chain Reaction (PCR) of uridine triphosphate and cytidine triphosphate

UTP and CTP are used in the synthesis Synthesis Polymerase Chain Reaction (PCR) of RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure.

UTP:

• Step 1:
  • Phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing 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 Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids.
• This reaction requires ATP.
• Enzyme: CTP synthetase
  • Activated by GTP
  • Inhibited by CTP

Deoxyribonucleotides Deoxyribonucleotides A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. DNA Types and Structure and thymine Thymine One of four constituent bases of DNA. Nucleic Acids

DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure is different from RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure, as DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure has deoxyribose Deoxyribose Nucleic Acids, instead of ribose Ribose A pentose active in biological systems usually in its d-form. Nucleic Acids, and thymine Thymine One of four constituent bases of DNA. Nucleic Acids (5-methyluracil), instead of uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids.

Deoxyribonucleotides Deoxyribonucleotides A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. DNA Types and Structure 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 Thymine One of four constituent bases of DNA. Nucleic Acids is a pyrimidine present in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure; thus, the ribose Ribose A pentose active in biological systems usually in its d-form. Nucleic Acids 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 Tetrahydrofolate Sulfonamides and Trimethoprim (as the methyl donor)
• Step 5:
  • dTMP is phosphorylated to dTTP (by ATP).
  • Phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing occurs in 2 rounds.

Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability: 5-fluorouracil 5-Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy: antimetabolite agent (used in cancers) that inhibits thymidylate synthase and decreases DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)

Regulation of synthesis Synthesis Polymerase Chain Reaction (PCR)

• The enzyme, carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes 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 Pyrimidine Analogs Antimetabolite Chemotherapy (used as antineoplastic agents):
  • 5-fluorouracil 5-Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy
  • Capecitabine Capecitabine A deoxycytidine derivative and fluorouracil prodrug that is used as an antineoplastic antimetabolite in the treatment of colon cancer; breast cancer and gastric cancer. Antimetabolite Chemotherapy
  • Cytarabine Cytarabine A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the s phase of the cell cycle. It also has antiviral and immunosuppressant properties. Antimetabolite Chemotherapy
  • Gemcitabine Gemcitabine Antimetabolite Chemotherapy

Salvage pathway of pyrimidine nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids

• Like purines Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. Nucleic Acids, pyrimidines Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine; thymine; and uracil) and form the basic structure of the barbiturates. Nucleic Acids are recycled from the derivative intermediates of nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance. 
• Reactions convert ribonucleosides (uridine, cytidine) and deoxyribonucleosides (thymidine, deoxycytidine) to nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids.
• Kinases Kinases Macrolides and Ketolides or phosphoryltransferases catalyze phosphoryl group transfer (from ATP) to the diphosphates, producing triphosphates:
  • NDP + ATP → NTP + ADP
  • dNDP + ATP → dNTP + ADP

Catabolism of Pyrimidine Nucleotides

Animal cells break down pyrimidine nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids to the nitrogenous bases Nitrogenous bases Nucleic Acids, with the resultant uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids and thymine Thymine One of four constituent bases of DNA. Nucleic Acids 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: Anatomy. 

• As in purine nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids, nucleic acid ( RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure/ DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure) is broken down by nucleases Nucleases Pancreatic Parameters to nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids.
• Cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids is degraded to uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids by the removal of an amino group.
• Both uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids and thymine Thymine One of four constituent bases of DNA. Nucleic Acids 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 Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle.

Disorders of Nucleotide Metabolism