BIOLOGICAL FUNCTIONS OF NUCLEOTIDES
· Precursors of DNA and RNA.
· Activated intermediates in many biosyntheses: e.g UDP-glucose ® glycogen, CDP-diacylglycerol ® phosphoglycerides, S-adenosylmathionine as methyl donor, etc.
· Nucleotside triphosphates, especially ATP, as the universal currency of energy in biological systems.
· Adenine nucleotides are components of the coenzymes, NAD(P)+, FAD, and CoA.
· Metabolic regulators: (a) c-AMP is the mediator of hormonal actions; (b) ATP-dependent protein phosphorylation - activates phosphorylase and inactivates glycogen synthase; (c) adenylation of a Tyr of bacterial glutamine synthetase - more sensitive to feedback inhibition and less active; (d) allosteric regulator - glycogen phosphorylase activated by ATP and inactivated by AMP.
NOMENCLATURE AND MOLECULAR STRUCTURES
See Table 3-1
SYNTHESIS OF PURINE RIBONUCLEOTIDES
General Synthetic Strategy
1. Fisrt, build up attachment on the a-D-ribose.
2. Next, cyclize the attachment to form the purine ring.
· Important initial findings from the identification of the labeling pattern of uric acid isolated from pigeons fed with various isotopically labeled compounds.
· Divergent organisms (such as E. coli, yeast, pigeon, human) have virtually identical pathways for the biosynthesis of purine nucleotides.
· The initially synthesized purine derivative is inosine monophosphate (IMP).
· See figure on p. 788 for the biosynthetic origins of purine ring atoms.
The Pathway for the Biosynthesis of IMP
· See Fig. 22-1.
Synthesis of AMP and GMP from IMP
· See Fig. 22-3.
· The synthesis of GMP from IMP requires ATP, whereas the synthesis of AMP from IMP requires GTP. This is a way to prevent any excessive synthesis of either AMP or GMP.
· GMP is a feedback inhibitor against IMP dehydrogenase.
· AMP is a feedback inhibitor against adenylosuccinate synthetase.
Interconversion of Nucleoside Mono-, Di- and Triphosphate
1. Nucleoside Monophosphate Kinase:
NMP + ATP D NDP + ADP
2. Nucleoside Diphosphate Kinase:
NDP + ATP D NTP + ADP
Do not discriminate between ribose and deoxyribose.
3. Adenylate Kinase:
AMP + ATP D 2 ADP
REGULATION OF PURINE BIOSYNTHESIS
· See Fig. 22-4.
· Ribose phosphate pyrophosphokinase sensitive to inhibition by GDP and ADP.
· Amidophosphoribosyl transferase sensitive to activation by 5-phosphoribosyl pyrophosphate (PRPP), and inhibition by XMP, GMP, GDP, GTP, AMP, ADP, and ATP.
· IMP dehydrogenase sensitive to inhibition by GMP.
· Adenylosuccinate synthetase sensitive to inhibition by AMP.
· The synthesis of GMP requires ATP.
· The synthesis of AMP requires GTP.
· In animals, all purine nucleotide and deoxynucleotides → Uric acid.
· Involves oxidation: Hypoxanthine → Xanthine → Uric acid by Xanthine Oxidase. (Fig. 22-17)
Fate of Uric Acid
· In humans and other primates: uric acid excreted in urine.
· Birds, terrestrial reptiles, and many insects: Also excrete uric acid, often at high levels. These organisms do not excrete urea. Moreover, they convert excess amino acid nitrogen to uric acid via purine biosynthesis.
· A disease: elevated levels of uric acid in body fluid → deposition of crystals of sodium urate → painful arthritic inflammation.
· Could result from a number of metabolic insufficiencies, most of which are not well characterized.
· One well understood case: hypoxanthine-guanine phosphoribosyltransferase deficiency → PRPP accumulation ® increased synthesis of purine nucleotides → increased uric acid formation.
Hypoxanthine + phosphoribosyl-pyrophosphate → IMP + PPi
Allopurinol (a “Competitive” reversible inhibitor for xanthine oxidase) for treatment.