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Nucleic Acids

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Nucleic Acids Nucleic acids Nucleic acids consist from nucleotides which are the monomers or the building units for the nucleic acids. Nucleotides also serve as carriers of activated intermediates in the synthesis of some carbohydrates, lipids, and proteins, and are structural components of several essential coenzymes, for example, coenzyme A, FAD, NAD+, and NADP+. NUCLEOTIDE STRUCTURE Nucleotides are composed of a nitrogenous base, a pentose monosaccharide, and one, two, or three phosphate groups. The nitrogen-containing bases belong to two families of compounds: the purines and the pyrimidines. A. Purine and pyrimidine structures Both DNA and RNA contain the same purine bases: adenine (A) and guanine (G). Both DNA and RNA contain the pyrimidine cytosine (C), but they differ in their second pyrimidine base: DNA contains thymine (T), whereas RNA contains uracil (U). T and U differ by only one methyl group, which is present on T but absent on U Note: Unusual bases are occasionally found in some species of DNA and RNA, for example, in some viral DNA, and in transfer RNA. The presence of an unusual base in a nucleotide sequence may aid in its recognition by specific enzymes, or protect it from being degraded by nucleases. Note: The conjugated double bonds of purine and pyrimidine bases absorb ultraviolet light. The mutagenic effect of ultraviolet light results from its absorption by nucleotides in DNA with accompanying chemical changes. While spectra are pH dependent, at pH 7 all the common nucleotides absorb light at a wavelength close to 260 nm. The concentration of nucleotides and nucleic acids thus often are expressed in term of absorbance at 260 nm. B. Pentose: There are two types of pentose in the nucleotides; the first one is ribose which is found in nucleotides derived from RNA, while the second is deoxy ribose which is found in the nucleotides derived from DNA. Nucleosides The addition of a pentose sugar to a base produces a nucleoside. If the sugar is ribose, a ribonucleoside is produced; if the sugar is 2-deoxyribose, a deoxyribonucleoside is produced. The ribonucleosides of A, G, C, and U are named adenosine, guanosine, cytidine, and uridine, respectively. The deoxyribonucleoside of A, G, C, and T have the added prefix, "deoxy-", for example deoxyadenosine. The sugar is linked to the heterocyclic base via a B-N-glycosidic bond to N1 of pyrimidine or to N9 of purine. Notes: *nitrogen base + ribose = nucleoside (like: adenosine and guanosine) *nucleoside + phosphoryl group = mononucleotide. *mononucleoside + add. Phosphoryl groups = nucleoside di or tri phosphate. Metabolism of purine and pyrimidine nucleotides Introduction The biosynthesis of purine and pyrimidine is regulated by feedback mechanism that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch_Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. Human tissues each synthesize purines and pyrimidines therefore the ingested nucleic acids are degraded in the intestinal tract to mononucleotides, which may be absorbed or converted to purine and pyrimidine bases. The purine bases are then oxidized into uric acid which may be absorbed and excreted in the urine. Synthesis of purine nucleotides Introduction Purine and pyrimidine nucleotides are synthesized at a rate consistent with physiologic need. The nucleotides are synthesized by two different pathways, the first one is de novo pathway which synthesizes purine and pyrimidine cycle from low molecular weight precursors by sequence reactions, these precursors (ribose, phosphate, many amino acids, CO2, and ammonia) incorporate to form nucleotides. The cells are capable to use the free bases or nucleosides which are made from nucleic acids destruction in the synthesis of nucleotides, this pathway is the second and is called salvage pathway. The de novo pathway is the most common in the most cells, but in the cells which lack to the enzymes that are participate in the de novo pathway, the salvage pathway will be responsible for nucleotides formation. The atoms of the purine ring are contributed by a number of compounds, including amino acids (aspartic acid, glycine, and glutamine), C02, and N10- formyltetrahydrofolate.The purine ring is constructed by a series of reactions that add the donated carbons and nitrogens to a preformed ribose 5-phosphate. A. Synthesis of 5-phosphoribosy 1-1-pyrophosphate (PRPP) PRPP is an "activated pentose" that participates in the synthesis of purines and pyrimidines. Synthesis of PRPP from ATP and ribose 5-phosphate is catalyzed by PRPP synthetase (ribose phosphate pyrophosphokinase) this enzyme is activated by inorganic phosphate (P,) and inhibited by purine nucleotides (end-product inhibition). B. Synthesis of 5-phosphoribosylamine 5'-phosphoribosylamine is made from PRPP and glutamine The amide group of glutamine replaces the pyrophosphate group attached to carbon 1 of PRPP. The enzyme, glutamine phosphoribosyl pyrophosphate amidotransferase, is inhibited by the purine 5'-nucleotides AMP, GMP, and IMP—the end products of the pathway. The rate of the reaction is also controlled by the intracellular concentration of the substrates glutamine and PRPP. Synthetic inhibitors of purine synthesis Some synthetic inhibitors of purine synthesis (for example, the sulfonamides), are designed to inhibit the growth of rapidly dividing microorganisms without interfering with human cell functions. Other purine synthesis inhibitors, such as structural analogs of folic acid (for example, methotrexate), are used pharmacologically to control the spread of cancer by interfering with the synthesis of nucleotides and, therefore, of DNA and RNA. [Note: Inhibitors of human purine synthesis are extremely toxic to tissues, especially to developing structures such as in a fetus, or to cell types that normally replicate rapidly, including those of bone marrow, skin, gastrointestinal (Gl) tract, immune system, or hair follicles. As a result, individuals taking such anti-cancer drugs can experience adverse effects, including anemia, scaly skin, Gl tract disturbance, immune deficiencies, and baldness.] . Trimethoprim, another folate analog, has potent antibacterial activity because of its selective inhibition of bacterial dihydrofolate reductase. The carbons added in two reactions are contributed by derivatives of tetrahydrofolate. Purine deficiency occurs with folic acid deficiency; therefore antifolate drugs block purine nucleotides biosynthesis. Azaserine inhibits reaction 5, this compound which is made from special types of Streptomyces inhibits the enzymatic transport of amide group from glutamine by competitive inhibition because that the structure of glutamine resembles the structure of azaserine. Sulfonamide which is used as antibacterial affects indirectly in the step of the addition of formyl group to aminoimidazol because sulfonamide resemble p- aminobenzoic acid which is the building unit of folic acid therefore sulfonamide inhibits the step in which the folic acid is the responsible. The major determinant of the rate of de novo purine nucleotides biosynthesis is the concentration of PRPP. The rate of PRPP synthesis depends on the availability of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP. PRPP synthase is feedback inhibited by both purine and pyrimidine nucleotides. Conversion of IMP to AMP and GMP The conversion of IMP to either AMP or GMP uses a two-step, energy-requiring pathway (Figure 22.8). Note that the synthesis of AMP requires GTP as an energy source, whereas the synthesis of GMP requires ATP. Also, the first reaction in each pathway is inhibited by the end product of that pathway. This provides a mechanism for diverting IMP to the synthesis of the species of purine present in lesser amounts. If both AMP and GMP are present in adequate amounts, the de novo pathway of purine synthesis is turned off at the amidotransferase step. Conversion of nucleoside monophosphates to nucleoside diphosphates and triphosphates. ATP is generally the source of the transferred phosphate, because it is present in higher concentrations than the other nucleoside triphosphates. Salvage pathway for purines 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. This is referred to as the "salvage pathway" for purines. 1/ Conversion of purine bases to nucleotides: Two enzymes are involved: adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HPRT). Both enzymes use PRPP as the source of the ribose 5-phosphate group. The release of pyrophosphate makes these reactions irreversible (Figure 22.10). 2/ Lesch-Nyhan syndrome: A clinical syndrome that is associated with a virtually complete deficiency of HPRT. This deficiency results in an inability to salvage hypoxanthine or guanine, from which excessive amounts of uric acid are produced. In addition, the lack of this salvage pathway causes increased PRPP levels and decreased IMP and GMP levels. As a result, glutamine:phosphoribosylpyrophosphate amidotransferase (the committed step in purine synthesis) has excess substrate and decreased inhibitors available, and de novo purine synthesis is increased. The combination of decreased purine reutilization and increased purine synthesis results
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