PurinesPurinesA 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 pyrimidinesPyrimidinesA 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 phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes groups, form the important components of nucleotidesNucleotidesThe 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. PurinesPurinesA 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 adenineAdenineA purine base and a fundamental unit of adenine nucleotides.Nucleic Acids and guanineGuanineNucleic Acids, while pyrimidinesPyrimidinesA 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 thymineThymineOne of four constituent bases of DNA.Nucleic Acids (in DNADNAA 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), uracilUracilOne of four nucleotide bases in the nucleic acid RNA.Nucleic Acids (in RNARNAA 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 cytosineCytosineA pyrimidine base that is a fundamental unit of nucleic acids.Nucleic Acids. Purine nucleotide synthesisSynthesisPolymerase Chain Reaction (PCR) follows a series of reactions using carbon donors, amino acidsAmino acidsOrganic 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., glutamineGlutamineA 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, aspartateAspartateOne 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 bicarbonateBicarbonateInorganic 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 adenosineAdenosineA 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 synthesisSynthesisPolymerase Chain Reaction (PCR) is regulated in the 1st 2 steps. SynthesisSynthesisPolymerase Chain Reaction (PCR) of pyrimidine nucleotidesNucleotidesThe 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 thymineThymineOne of four constituent bases of DNA.Nucleic Acids, a part of deoxyribonucleotidesDeoxyribonucleotidesA 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 riboseRiboseA pentose active in biological systems usually in its d-form.Nucleic Acids moiety. Degradation of nucleotidesNucleotidesThe 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 acidUric acidAn 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 purinesPurinesA 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 pyrimidinesPyrimidinesA 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 acidsAmino acidsOrganic 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.
UracilUracilOne of four nucleotide bases in the nucleic acid RNA.Nucleic Acids (U)
CytosineCytosineA pyrimidine base that is a fundamental unit of nucleic acids.Nucleic Acids (C)
Other minor basesBasesUsually 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
NucleosidesNucleosidesPurine or pyrimidine bases attached to a ribose or deoxyribose.Nucleic Acids: 2 components:
A nitrogenous base:
AdenineAdenineA purine base and a fundamental unit of adenine nucleotides.Nucleic Acids, guanineGuanineNucleic Acids, thymineThymineOne of four constituent bases of DNA.Nucleic Acids, and cytosineCytosineA pyrimidine base that is a fundamental unit of nucleic acids.Nucleic Acids in DNADNAA 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
AdenineAdenineA purine base and a fundamental unit of adenine nucleotides.Nucleic Acids, guanineGuanineNucleic Acids, uracilUracilOne of four nucleotide bases in the nucleic acid RNA.Nucleic Acids, and cytosineCytosineA pyrimidine base that is a fundamental unit of nucleic acids.Nucleic Acids in RNARNAA 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:
RiboseRiboseA pentose active in biological systems usually in its d-form.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., adenosineAdenosineA 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).
NucleotidesNucleotidesThe 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
PhosphatePhosphateInorganic salts of phosphoric acid.Electrolytes groups (varying number)
These molecules form the DNADNAA 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., adenosineAdenosineA 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)
EsterificationEsterificationThe 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 phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes groups forms the corresponding nucleoside diphosphates and triphosphates (e.g., adenosineAdenosineA 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), adenosineAdenosineA 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 nucleotidesNucleotidesThe 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 acidRibonucleic acidA 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 (RNARNAA 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)).
Structure of purines adenine and guanine
Image: “123” by Kevin Ahern. License: Public Domain, cropped by Lecturio.
Pyrimidine nucleotides and their structures
Image: “123” by Kevin Ahern. License: Public Domain, cropped by Lecturio.
Components that build a nucleotide
Image: “123” by Kevin Ahern. License: Public Domain, cropped by Lecturio.
Mnemonics
NucleoSide: base + Sugar
NucleoTide: base + sugar + phosphaTe
Biomedical importance
The main functions of nucleotidesNucleotidesThe 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 acidsAcidsChemical 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 coenzymesCoenzymesSmall 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 messengersSecond messengersSignaling 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 acidAmino acidAmino 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 membraneCell MembraneA 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 MembranesynthesisSynthesisPolymerase Chain Reaction (PCR))
NucleotidesNucleotidesThe 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 acidsAmino acidsOrganic 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., glutamineGlutamineA 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 tetrahydrofolateTetrahydrofolateSulfonamides and Trimethoprim), and bicarbonateBicarbonateInorganic 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 major site of synthesisSynthesisPolymerase Chain Reaction (PCR) is the liverLiverThe 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 THF: tetrahydrofolate
Enzyme: PRPP synthetase/riboseRiboseA pentose active in biological systems usually in its d-form.Nucleic AcidsphosphatePhosphateInorganic salts of phosphoric acid.Electrolytes pyrophosphokinase
Clinical correlationCorrelationDetermination 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-linkedX-linkedGenetic 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 nucleotidesNucleotidesThe 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 acidUric acidAn 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 (PRPP): Ribose-5-phosphate (R5P) is converted to PRPP. The phosphates come from ATP and then produce AMP. The enzyme for the conversion is PRPP synthetase.
Image by Lecturio.
Step 2
Formation of 5-phosphoribosylamine (PRA)
PRPP + glutamineGlutamineA 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.
GlycineGlycineA 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.
GlycineGlycineA 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 glycineGlycineA 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 adenosineAdenosineA 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, glutamineGlutamineA 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.
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 bicarbonateBicarbonateInorganic 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 bicarbonateBicarbonateInorganic 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 aspartateAspartateOne 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 aspartateAspartateOne 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.
PRPP + glutamineGlutamineA 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 glutamineGlutamineA 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 glycineGlycineA 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 glutamineGlutamineA 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 bicarbonateBicarbonateInorganic 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 aspartateAspartateOne 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)
Role of folateFolateFolate 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, glutamineGlutamineA 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 folateFolateFolate 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 synthesisSynthesisPolymerase Chain Reaction (PCR).
2 important consequences of folic acid deficiencyFolic Acid DeficiencyA 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 anemiaMegaloblastic anemiaMegaloblastic 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 deficiencyFolate deficiencyA 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).
Inosine monophosphate is converted to adenineAdenineA purine base and a fundamental unit of adenine nucleotides.Nucleic Acids and guanineGuanineNucleic Acids as AMP and GMP. Formed from GMP, guanosine triphosphate (GTP) provides the energy to convert IMP to AMP.
Dehydrogenation of IMP forms xanthosine monophosphate (XMP).
H+ ions are released (and accepted by NADNAD+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 glutamineGlutamineA 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 hydrolysisHydrolysisThe 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 correlationCorrelationDetermination 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:
MycophenolateMycophenolateImmunosuppressants, an immunosuppressant, inhibits IMP dehydrogenase (IMPDH), reducing proliferation of immune cells.
Conversion of IMP to GMP and then to GTP:
NAD+: nicotinamide adenine dinucleotide (oxidized)
NADH: nicotinamide adenine dinucleotide (reduced)
NDPK: nucleoside diphosphate kinase
PPi: pyrophosphate
Step 1: Donation of the amino group by aspartateAspartateOne 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 aspartateAspartateOne 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 hydrolysisHydrolysisThe process of cleaving a chemical compound by the addition of a molecule of water.Proteins and Peptides → adenylosuccinate
Enzyme: adenylosuccinate synthetase
Step 2: EliminationEliminationThe initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of fumarateFumarateCitric Acid Cycle to form AMP
Adenylosuccinate is enzymatically converted to AMP by the removal of fumarateFumarateCitric Acid Cycle.
Enzyme: adenylosuccinase/adenylosuccinate lyase
Conversion of IMP to AMP and then to ATP:
NDPK: nucleoside diphosphate kinase
Pi: inorganic phosphate
SynthesisSynthesisPolymerase Chain Reaction (PCR) of IMP, ATP and GTP is regulated to control the amount of purine nucleotidesNucleotidesThe 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:
6-Mercaptopurine6-MercaptopurineAn 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-MP6-MPAn 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-Thioguanine6-ThioguanineAn antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia.Antimetabolite Chemotherapy
AzathioprineAzathioprineAn 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-MP6-MPAn 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
CladribineCladribineAn antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia.Antimetabolite Chemotherapy
Generation of nucleotidesNucleotidesThe 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 acidsAcidsChemical 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 purinesPurinesA 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 nucleotidesNucleotidesThe 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:
AdenineAdenineA purine base and a fundamental unit of adenine nucleotides.Nucleic Acids phosphoribosyltransferase (APRT)
Clinical correlationCorrelationDetermination 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 syndromeLesch-Nyhan syndromeAn 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 recessiveX-Linked RecessiveDuchenne Muscular Dystrophy disorder caused by defect in HGPRT (unable to salvage purine basesBasesUsually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines.Acid-Base Balance → ↑ uric acidUric acidAn 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)
The salvage pathway that recycles nucleotides for utilization
Image by Lecturio.
Importance
In tissues like erythrocytesErythrocytesErythrocytes, 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 brainBrainThe 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 synthesisSynthesisPolymerase Chain Reaction (PCR).
The pathway economizes intracellular energy expenditureEnergy expenditureEnergy expenditure is the sum of internal heat produced and external work.Energy Homeostasis.
Catabolism of Purine Nucleotides
Nucleic acid (RNARNAA 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/DNADNAA 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 nucleasesNucleasesPancreatic Parameters to nucleotidesNucleotidesThe 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 nucleotidesNucleotidesThe 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 phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes and riboseRiboseA 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 acidUric acidAn 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 phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes removal
Conversion from nucleic acidsAcidsChemical 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 (RNARNAA 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/DNADNAA 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 basesBasesUsually 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 → adenosineAdenosineA 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 phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes
AdenosineAdenosineA 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 adenosineAdenosineA 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 oxidaseOxidaseNeisseria.
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 oxidaseOxidaseNeisseria.
Clinical correlationCorrelationDetermination 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 cellsT cellsLymphocytes 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 deficiencyPNP deficiencySevere Combined Immunodeficiency (SCID):leads to ↑ deoxy-ATP, deoxy-GTP (toxic to immune cells such as T cellsT cellsLymphocytes 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
Image by Lecturio.
Xanthine
Both adenosineAdenosineA 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.
AdenosineAdenosineA 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
Catalyzes hypoxanthine to xanthine and xanthine to uric acidUric acidAn 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 acidUric acidAn 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 correlationCorrelationDetermination 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: allopurinolAllopurinolA xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms.Gout Drugs, an inhibitor of xanthine oxidaseOxidaseNeisseria, is used for goutGoutGout 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
Pyrimidine base is synthesized first and then incorporated into the nucleotide (the ring is completed before being linked to ribose-5-phosphateRibose-5-phosphatePentose Phosphate Pathway).
Sources of the carbon and nitrogenNitrogenAn 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:
GlutamineGlutamineA 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 bicarbonateBicarbonateInorganic 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 phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes.
AspartateAspartateOne 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
The nitrogenNitrogenAn 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 glutamineGlutamineA 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 bicarbonateBicarbonateInorganic 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 phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes.
Enzyme: carbamoyl phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes synthetase II
Carbamoyl phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes reacts with aspartateAspartateOne 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 aspartateAspartateOne 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 phosphatePhosphateInorganic salts of phosphoric acid.Electrolytes.
Enzyme: aspartyl transcarbamoylase (ATCase)
Activated by ATP
Inhibited by cytidine triphosphate (CTP)
Rate-limiting step of pyrimidine synthesis:
Reaction converts carbamoyl phosphate to carbamoyl aspartate, catalyzed by aspartyl transcarbamoylase (ATCase). Subsequent reactions eventually lead to the end product, cytidine triphosphate (CTP). The ATCase is activated by ATP and inhibited by CTP.
Image by Lecturio.
Step 3
Formation of the pyrimidine ring
A molecule of water is eliminated, and carbamoyl aspartateAspartateOne 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: NADNAD+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
DecarboxylationDecarboxylationThe 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 decarboxylationDecarboxylationThe 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 enzymesEnzymesEnzymes 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.
Carbamoyl aspartateAspartateOne 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
UTP and CTP are used in the synthesisSynthesisPolymerase Chain Reaction (PCR) of RNARNAA 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:
PhosphorylationPhosphorylationThe 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)
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 glutamineGlutamineA 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.
DNADNAA 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 RNARNAA 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 DNADNAA 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 deoxyriboseDeoxyriboseNucleic Acids, instead of riboseRiboseA pentose active in biological systems usually in its d-form.Nucleic Acids, and thymineThymineOne of four constituent bases of DNA.Nucleic Acids (5-methyluracil), instead of uracilUracilOne of four nucleotide bases in the nucleic acid RNA.Nucleic Acids.
DeoxyribonucleotidesDeoxyribonucleotidesA 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.
dNDPs in turn, are converted to deoxyribonucleoside triphosphates (dNTPs) by nucleoside diphosphate kinase (NDPK).
ThymineThymineOne of four constituent bases of DNA.Nucleic Acids is a pyrimidine present in DNADNAA 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 riboseRiboseA 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).
PhosphorylationPhosphorylationThe 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 correlationCorrelationDetermination 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-fluorouracil5-FluorouracilA 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 DNADNAA 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 StructuresynthesisSynthesisPolymerase Chain Reaction (PCR)
Formation of thymine in the form of deoxythymidine triphosphate (dTTP) dTDP: deoxythymidine diphosphate
dTMP: deoxythymidine monophosphate
dTTP: deoxythymidine triphosphate
dUDP: deoxyuridine diphosphate
dUMP: deoxyuridine monophosphate
dUTPase: deoxyuridine triphosphatase
NDPK: nucleoside diphosphate kinase
RNR: ribonucleotide reductase
UDP: uridine diphosphate
5-fluorouracil5-FluorouracilA 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
CapecitabineCapecitabineA 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
CytarabineCytarabineA 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
Salvage pathway of pyrimidine nucleotidesNucleotidesThe 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 purinesPurinesA 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, pyrimidinesPyrimidinesA 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 acidsAcidsChemical 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 nucleotidesNucleotidesThe 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.
KinasesKinasesMacrolides and Ketolides or phosphoryltransferasescatalyze phosphoryl group transfer (from ATP) to the diphosphates, producing triphosphates:
Animal cells break down pyrimidine nucleotidesNucleotidesThe 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 basesNitrogenous basesNucleic Acids, with the resultant uracilUracilOne of four nucleotide bases in the nucleic acid RNA.Nucleic Acids and thymineThymineOne of four constituent bases of DNA.Nucleic Acids degraded (via reduction) in the liverLiverThe 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 nucleotidesNucleotidesThe 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 (RNARNAA 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/DNADNAA 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 nucleasesNucleasesPancreatic Parameters to nucleotidesNucleotidesThe 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.
CytosineCytosineA pyrimidine base that is a fundamental unit of nucleic acids.Nucleic Acids isdegraded to uracilUracilOne of four nucleotide bases in the nucleic acid RNA.Nucleic Acids by the removal of an amino group.
Both uracilUracilOne of four nucleotide bases in the nucleic acid RNA.Nucleic Acids and thymineThymineOne 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 acidAmino acidAmino 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 ureaUreaA 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.
Degradation of uracil and thymine NADPH: nicotinamide adenine dinucleotide phosphate
HyperuricemiaHyperuricemiaExcessive 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/goutGoutGout 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 acidUric acidAn 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 syndromeLesch-Nyhan syndromeAn 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 pubertyDelayed PubertyDelayed puberty (DP) is defined as the lack of testicular growth in boys past the age of 14 and the lack of thelarche in girls past the age of 13. Delayed puberty affects up to 5% of healthy boys and girls, and half of all cases are due to constitutional growth delay.Delayed Puberty
Self-mutilation
Developmental delay
Impaired renal function
SCIDSCIDSevere 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 infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease, recurrent deep skinSkinThe 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 candidiasisCandidiasisCandida 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 thriveFailure to ThriveFailure 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 recessiveAutosomal recessiveAutosomal 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 InheritancemutationMutationGenetic 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 infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease
NauseaNauseaAn 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
VomitingVomitingThe forcible expulsion of the contents of the stomach through the mouth.Hypokalemia
NephrolithiasisNephrolithiasisNephrolithiasis 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 injuryAcute Kidney InjuryAcute 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
Orotic aciduriaOrotic aciduriaOrotic 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 thriveFailure to ThriveFailure 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 anemiaMegaloblastic anemiaMegaloblastic 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
Drug-induced orotic aciduriaOrotic aciduriaOrotic 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 allopurinolAllopurinolA xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms.Gout Drugs and 6-azauridine
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