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 Features

· 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.

PURINE DEGRADATION

· 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.

Gout

· 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

(Guanine) (GMP)

·

Allopurinol (a “Competitive” reversible inhibitor for xanthine oxidase) for treatment.