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.