Nucleic Acid Metabolism Flashcards
What are nucleotides?
Structural units of nucleic acids Ubiquitous in nature -ATP highest conc. among nucleotides in cells -Ribonucleotides (mM range) -Deoxyribon. (uM range) Composed of -inorganic P -5 C sugars (D-ribose or deoxyribose) -Nitrogenous bases (purines/pyrimidines)
Natural products that are purine derivatives
Caffeine (coffee, tea)
Theophylline (tea)
Theobromine (cocoa)
What is a nucleoside? (base-sugar)
purine or pyrimidine linked to sugar by a beta-N-glycosidic bond
-more soluble than its corresponding free base
Uric Acid is a purine
primary N excretory product in birds and reptiles is URIC acid, not urea
Precursors for purine biosynthesis
Glutamine is sensitive to allosteric feedback
to AMP since glutamine is necessary for AMP synthesis
Initially synthesized purine is..
IMP (inosine monophosphate
Synthesis of IMP begins with …
Ribose-5-phosphate (from PPP)
IMP is the precursor for
AMP, GMP
Requirements for AMP, GMP synthesis
AMP synthesis requires Asp, GTP
GMP synthesis requires Glutamine, ATP
cross-requirement of ATP for GMP syn and GTP for AMP synthesis is no coincidence
-ensures balanced synthesis of AMP and GMP
Reciprocal regulation
important in balancing purine synthesis
GTP generated from IMP is used to activate ATP synthesis
ATP is reciprocally regulating GTP synthesis
Purine nucleotide biosynthesis is regulated at several steps
IMP is regulated at 1st 2 rxn: PRPP synthesis and 5-Phosphoribosylamine.
Ribose phosphate pyrophosphokinase is inhibited by both ADP and GDP (Synergy)
Amidophosphoriribosyl transferase, enz catalyzed 1st commited step of pathway is also subject to feedback inhibition
-This rxn is also activated by PRPP (feedforward activation)
-Reciprocity in AMP and GMP synthesis
Salvage pathway for purines
-Breakdown of RNA in cells generates free purines
AMP —(nucleotidase)—>A + Pi
-in mammals, purines are mostly salvaged by 2 diff enzymes (adenine phosphoribosyl transferase (APRT)) mediates AMP formation using PRPP
Adenine+PRPP–(APRT)–>AMP+PPi
-Hypoxanthine-guanine phosphoribosyl transferase
Guanine+PRPP–>GMP+PPi
-Lesch-Nyhan Syndrome: HGPRT deficiency-sex-linked congenital defect affecting males- excessive uric acid in patients (mental retardation, aggressive, self-destructive behaviour)
Pyrimidine biosynthesis
-UMP is synthesized as a pyrimidine base to which R5P gets added
-CTP and UTP are derived from UMP
-Major control steps for pyrimidine nucleotide synthesis
(1st pdt: carbamoyl P)
end pdt: UMP
Comparison of pyrimidine synthesis regulation in E.cli and animals
ATP allosterically stimulates ATCase
- UTP, CTP inhibitors
- In animals, CPS-II inhibited by UDP. UTP
- activated by ATP, PRPP
- PRPP inhibited by AMP, GMP
Disorders in metabolism
Orotic aciduria, inherited human disease characterized by excretion of orotic acid in urine
Deficiency of orotic acid conversion enzymes- protate phosphoribosyl transferase and OMP decarboxylase
