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Purine and Pyrimidine Metabolism

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 and 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 heterocyclic aromatic compounds, which, along with sugar and phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes groups, form the important components 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. 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 include adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids and guanine Guanine Nucleic Acids, while 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 include thymine Thymine One of four constituent bases of DNA. 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), uracil Uracil One of four nucleotide bases in the nucleic acid RNA. 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), and cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids. Purine nucleotide synthesis Synthesis Polymerase Chain Reaction (PCR) follows a series of reactions using carbon donors, 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, 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), 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. The de novo pathway generates inosine monophosphate (IMP), which is the precursor of 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 (AMP) and guanosine monophosphate (GMP). Purine synthesis Synthesis Polymerase Chain Reaction (PCR) is regulated in the 1st 2 steps. Synthesis Synthesis Polymerase Chain Reaction (PCR) 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 also follows different reactions, producing uridine monophosphate (UMP), which is converted to uridine triphosphate (UTP) and cytidine triphosphate (CTP). For thymine Thymine One of four constituent bases of DNA. Nucleic Acids, a part of deoxyribonucleotides Deoxyribonucleotides A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. DNA Types and Structure, ribonucleoside reductase is required to reduce the ribose Ribose A pentose active in biological systems usually in its d-form. Nucleic Acids moiety. Degradation 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 result in xanthine then 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 production in 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, while 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 produce the 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, β-alanine, and β-aminobutyrate.

Last updated: Apr 27, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Basic terms

Nitrogenous base:

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: 

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 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 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).
Atom sources for purine synthesis

Atom sources for purine synthesis Synthesis Polymerase Chain Reaction (PCR)
THF: tetrahydrofolate Tetrahydrofolate Sulfonamides and Trimethoprim

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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
Synthesis of phosphoribosyl pyrophosphate

Synthesis Synthesis Polymerase Chain Reaction (PCR) of phosphoribosyl pyrophosphate (PRPP):
Ribose-5-phosphate Ribose-5-phosphate Pentose Phosphate Pathway (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 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/N5-CAIR synthase

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/N5-carboxy aminoimidazole ribonucleotide mutase

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)

Step 11

Cyclization to form IMP

  • Inosine monophosphate is formed by the enzymatic closure of the larger ring of FAICAR with the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of water.
  • Inosine monophosphate is the precursor of AMP and GMP.
  • Enzyme: IMP cyclohydrolase
Table: Summary of de novo purine synthesis Synthesis Polymerase Chain Reaction (PCR)
Step Reaction Added atom Enzyme Product Product A molecule created by the enzymatic reaction. Basics of Enzymes
1 Ribose-5-phosphate Ribose-5-phosphate Pentose Phosphate Pathway → PRPP Phosphates (from ATP) PRPP synthetase PRPP
2 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 → 5-phosphoribosylamine N9 (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) Amidophosphoribosyltransferase PRA
3 PRA conversion to GAR C4, C5, N7 (from 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) 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 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) FGAM synthetase FGAM
6 Ring closure, forming AIR AIR synthetase AIR
7 Carboxylation of AIR C6 (from 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) AIR carboxylase AICAR
8 Formation of SAICAR N1 (from 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) SAICAR synthetase SAICAR
9 Fumarate Fumarate Citric Acid Cycle 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 Tetrahydrofolate Sulfonamides and Trimethoprim

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 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 and Types 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).
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 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:
Conversion of imp to gmp and then to gtp

Conversion of IMP to GMP and then to GTP:
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+: nicotinamide adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids dinucleotide (oxidized)
NADH: nicotinamide adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids dinucleotide (reduced)
NDPK: nucleoside diphosphate kinase
PPi: pyrophosphate

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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
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 Phosphate Inorganic salts of phosphoric acid. Electrolytes

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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
Regulators of purine metabolism

Regulators of purine metabolism

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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 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 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 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 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)
Salvage pathway that recycles nucleotides for utilization

The salvage pathway that recycles 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 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: 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.
Degradation of guanine

Degradation of guanine Guanine Nucleic Acids

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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 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
Degradation of adenine

Degradation of adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids

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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 Product A molecule created by the enzymatic reaction. Basics of Enzymes, 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 Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat.
  • 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.
Degradation of guanine and hypoxanthine into uric acid

Degradation of guanine Guanine Nucleic Acids and hypoxanthine into 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

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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
Sources of the carbon and nitrogen atoms in pyrimidine synthesis

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 in pyrimidine synthesis Synthesis Polymerase Chain Reaction (PCR)

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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)
The rate-limiting step of pyrimidine synthesis

Rate-limiting step of pyrimidine synthesis Synthesis Polymerase Chain Reaction (PCR):
Reaction converts carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes to 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, catalyzed by aspartyl transcarbamoylase (ATCase). Subsequent reactions eventually lead to the end product Product A molecule created by the enzymatic reaction. Basics of Enzymes, 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 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)

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.

Table: Summary of de novo pyrimidine synthesis Synthesis Polymerase Chain Reaction (PCR)
Step Enzyme Product Product A molecule created by the enzymatic reaction. Basics of Enzymes
1 Carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes synthetase II Carbamoyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes
2 Aspartyl transcarbamoylase* 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
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 Synthesis Polymerase Chain Reaction (PCR), 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 Phosphate Inorganic salts of phosphoric acid. Electrolytes 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 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
Synthesis of utp and ctp (triphosphates)

Synthesis Synthesis Polymerase Chain Reaction (PCR) of UTP and CTP (triphosphates)

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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).
  • 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)

Formation of thymine in the form of dttp

Formation of thymine Thymine One of four constituent bases of DNA. Nucleic Acids 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 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 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 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 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, 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 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 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
NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway: nicotinamide adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids dinucleotide phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes

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Disorders of Nucleotide Metabolism

Table: Disorders of purine metabolism
Disorder Defective enzyme Nature of defect Manifestations
Hyperuricemia Hyperuricemia Excessive uric acid or urate in blood as defined by its solubility in plasma at 37 degrees c; greater than 0. 42 mmol per liter (7. 0 mg/dl) in men or 0. 36 mmol per liter (6. 0 mg/dl) in women. Gout/ 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 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 Inflamed and painful joints
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 ↓ HGPRT Lack of enzyme → defective purine salvage pathway
  • Delayed puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty
  • Self-mutilation
  • Developmental delay
  • Impaired renal function
SCID SCID 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 (SCID) ↓ ADA Lack of enzyme → ↓ immune cells
  • Repeated infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, 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. Skin: Structure and Functions, 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
  • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
Xanthinuria ↓ Xanthine oxidase Oxidase Neisseria 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 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
APRT: adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids phosphoribosyltransferase
HGPRT: hypoxanthine guanine Guanine Nucleic Acids phosphoribosyltransferase
PRPP: phosphoribosyl pyrophosphate
SCID SCID 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 (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 (SCID)
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 and Types
Drug-induced 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 OMP decarboxylase
  • Caused by allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs 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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