VII - Nucleotides Flashcards
Monomer units or buiding blocks of nucleic acids
nucleotides
Form part of many co-enzymes, serve as donors of phosphoryl groups, second messengers, allosteric regulators, synthetic analogs
nucleotides
Nitrogen-containing heterocycles, cyclic compounds whose rings contain both carbon and other elements, their planar characteristics facilitates stacking
purines & pyrimidines
Pyrimidines
Cytosine, Uracil, Thymine
Purines
Adenine, Guanine
Sugar + Purine/Pyrimidine
nucleoside
Link between sugar & purine/pyrimidine
β-N-Glucosidic Bond
Nucleoside with a phosphoryl group esterified to a hydroxyl group of a sugar
nucleotide
Most common form of nucleotides, phosphoryl group attached to the C-5 of pentose
5’-nucleotides
5’-phosphoryl group forms a phosphodiester bond with the 3’-OH of another nucleotide, phoshodiesterases catalyze the hydrolysis of phosphodiester bonds, slow spontaneous hydrolysis
polynucleotide
DNA is ___ stable than RNA.
more (DNA > RNA)
Polynucleotides are _____ macromolecules.
directional
Nucleotide Synthesis: sugar first
Purine Synthesis
The purine ring is constructed by adding carbons and nitrogens to a
preformed ribose 5-phosphate
Purine Synthesis: Substrates
Aspartic Acid, Glutamine, Carbon Dioxide, Glycine, N10-formyltetrahydrofolate / N5,N10-methenyltetrahydrofolate
Nucleotide Synthesis: ring first
Pyrimidine Synthesis
Pyrimidine Synthesis: Substrates
Aspartic Acid, Glutamine, Carbon Dioxide
Steps in De Novo Purine Synthesis
Synthesis of 5-phosphoribosyl-1-pyrophoshate (PRPP), 5’-phosphoribosylamine, Inosine Monophosphate, Conversion of IMP to AMP/GMP
De Novo Purine Synthesis: activated pentose that participates in the synthesis of purines and pyrimidines and in the salvage of purine bases
5-phosphoribosyl-1-pyrophoshate (PRPP)
Synthesis of 5-phosphoribosyl-1-pyrophoshate (PRPP): Substrates
ATP, Ribose 5-phosphate
Synthesis of 5-phosphoribosyl-1-pyrophoshate (PRPP): Enzyme
PRPP Synthetase
Synthesis of 5-phosphoribosyl-1-pyrophoshate (PRPP): Activator
inorganic phosphate (Pi)
Synthesis of 5-phosphoribosyl-1-pyrophoshate (PRPP): Inhibitor
purine nucleotides
Committed step in purine nucleotide biosynthesis
Synthesis of 5’-phosphoribosylamine
De Novo Purine Synthesis: Rate-Limiting Enzyme
Glutamyl PRPP Amidotransferase
Glutamyl PRPP Amidotransferase: Inhibitors
5’-nucleotides, AMP, GMP, IMP
Product from hypoxanthine, parent purine nucleotide
Inosine Monophosphate (IMP)
De Novo Purine Synthesis: Requires a two-step energy-requiring pathway
Conversion of IMP to AMP/GMP
AMP synthesis requires
GTP
GMP synthesis requires
ATP
Purines that result from the normal turnover of cellular nucleic acids or that are obtained from the diet and not degraded, can be reconverted into nucleoside triphosphates and used by the body
Purine Salvage
Purine Salvage: Irrevesible Enzymes
Adenine Phosphoribosyltransferase (APRT), Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT)
Carbamoyl Phosphate Synthetase: mitochondria
CPS I
Carbamoyl Phosphate Synthetase: Urea Cycle
CPS I
Carbamoyl Phosphate Synthetase: nitrogen from ammonia
CPS I
Carbamoyl Phosphate Synthetase: activated by N-acetylglutamate
CPS I
Carbamoyl Phosphate Synthetase: cytosol
CPS II
Carbamoyl Phosphate Synthetase: Pyrimidine Synthesis
CPS II
Carbamoyl Phosphate Synthetase: nitrogen from γ-amide group of glutamine
CPS II
Carbamoyl Phosphate Synthetase: inhibited by UTP, activated by ATP
CPS II
Steps in De Novo Pyrimidine Synthesis
Synthesis of Carbamoyl Phosphate, Orotic Acid, Pyrimidine Nucleotide, UTP & CTP, dTMP from dUMP
De Novo Pyrimidine Synthesis: Rate-Limiting Step
Synthesis of Carbamoyl Phosphate
De Novo Pyrimidine Synthesis: Rate-Limiting Enzyme
Carbamoyl Phosphate Synthetase II
Carbamoyl Phosphate Synthetase II: Inhibitor
UTP
Carbamoyl Phosphate Synthetase II: Activators
ATP, PRPP
The only enzyme for synthesis of orotic acid inside the mitochondria
Dihydroorotate Dehydrogenase
Parent pyrimidine nucleotide
Orotidine Monophosphate (OMP)
OMP is converted to Uridine Monophosphate (UMP) by
OMP Decarboxylase
Synthesizes UTP and CTP
CTP Synthetase
Synthesizes dTMP from dUMP using N5,N10-methenyltetrahydrofolate as the source of the methyl group
Thymidylate Synthase
Salvageable Pyrimidines
Uridine, Cytidine (uridine-cytidine kinase), Deoxycytidine (deoxycitidine kinase), Thymidine (thymidine kinase)
Nucleoside diphosphates are synthesized from the corresponding nucleoside monphosphates using
Base-Specific Nucleoside Monophosphate Kinases
Source of the transferred phosphate in the synthesis of diphosphates and triphosphates
ATP
Deoxyribonucleotide Synthesis: Enzyme
Ribonucleotide Reductase
Multisubunit enzyme specific for the reduction of nucleoside diphosphates to their deoxy forms
Ribonucleotide Reductase
Regenerates the reduced form of ribonucleotide reductase
Thioredoxin
Reconverts thioredoxin to its reduced form
NADPH
Degradation of dietary nucleic acids occurs in
small intestines
Hydrolyze nucleotides to nucleosides and free bases
pancreatic enzymes
Dietary purines are generally converted to
uric acid
The _____ ring can be opened and degraded to highly soluble structures.
pyrimidine
Pyrimidine Degradation: roducts
β-alanine (precursor for acetyl CoA), β-aminoisobutyrate (precursor for succinyl-CoA)
Structural analogs of PABA that competitively inhibit bacterial synthesis of folic acid
Sulfonamides
Co-enzyme for purine synthesis
Tetrahydrofolate (THF)
Inhibit the reduction of dihydrofolate to tetrahydrofolate catalyzed by dihydrofolate reductase
Methotrexate, Trimethoprim
hyperuricemia with recurrent attacks of acute arthritis caused by deposition of uric acid crystals
Gouty Arthritis
Gouty Arthritis: no known cause
Primary
Gouty Arthritis: ↑ cell turnover, ↑ UA production, ↓ UA excretion
Secondary
Gouty Arthritis: Acute Phase Management
NSAIDs, steroids, colchicine
Gouty Arthritis: Intercritical Phase Management
allopurinol (overproducers), probenecid (underexcretors)
X-linked recessive deficiency in HGPRT that causes a rise in intracelular PRPP, hyperuricemia, mental retardation, self-mutilation
Lesch-Nyhan Syndrome
Purine overproduction and hyperuricemia secondary to enhanced generation of PRPP precursor of 5-phosphate
Von Gierke’s Disease
Leads to severe combined immunodeficiency (T and B lymphocytes), high dATP which inhibits ribonucleotide reductase and inhibits formation of deoxyribonucleotides
Adenosine Deaminase Deficiency (SCID)
Metabolically converted to 5-FdUMP which becomes permanently bound to the inactivated thymidylate synthase
5 Fluorouracil
Low activities of orotidine phosphate decarboxylase and orotate phosphoribosyltransferase, abnormal growth, megaloblastic anemia, excretion of large amounts of orotate in the urine
Orotic Aciduria
Orotic Aciduria: Treatment
diet rich in uridine results in the improvement of the anemia and decreased excretion of orotate