Purines & Pyrimidines Are Heterocyclic Compounds Purines and pyrimidines are aromatic heterocycles, cyclic structures that contain, in addition to carbon, other (hetero) atoms such as nitrogen. Note that the smaller pyrimidine molecule has the longer name and the larger purine molecule the shorter name, and that their six-atom rings are numbered in opposite directions (Figure 1). Purines or pyrimidines with an NH2 group are weak bases (pKa values 3-4), although the proton present at low pH is associated, not as one might expect with the exocyclic amino group, but with a ring nitrogen, typically N1 of adenine, N7 of guanine, and N3 of cytosine. The planar character of purines and pyrimidines facilitates their close association, or “stacking,” that stabilizes double-stranded DNA. The oxo and amino groups of purines and pyrimidines exhibit keto–enol and amine–imine tautomerism (Figure 2), although physiologic conditions strongly favor the amino and oxo forms.

Fig1. Purine and pyrimidine. The atoms are numbered according to the international system.

Fig2. Tautomerism of the oxo and amino functional groups of purines and pyrimidines.

Nucleosides AreN-Glycosides

 Nucleosides are derivatives of purines and pyrimidines that have a sugar linked to a ring nitrogen of a purine or pyrimidine. Numerals with a prime (eg, 2′ or 3′) distinguish atoms of the sugar from those of the heterocycle. The sugar in ribonucleosides is d-ribose, and in deoxyribonucleosides is 2-deoxy-d-ribose. Both sugars are linked to the heterocycle by ana-N-glycosidic bond, almost always to the N-1 of a pyrimidine or to N-9 of a purine (Figure3).

Fig3. Ribonucleosides, drawn as thesynconformers.

Nucleotides Are Phosphorylated Nucleosides

Mononucleotides are nucleosides with a phosphoryl group esterified to a hydroxyl group of the sugar. The 3′- and 5′-nucleotides are nucleosides with a phosphoryl group on the 3′- or 5′-hydroxyl group of the sugar, respectively. Since most nucleotides are 5′-, the prefix “5′-” usually is omitted when naming them. UMP and dAMP thus represent nucleotides with a phosphoryl group on C-5 of the pentose. Additional phosphoryl groups, ligated by acid anhydride bonds to the phosphoryl group of a mononucleotide, form nucleoside diphosphates and triphosphates (Figure4).

Fig4. ATP, its diphosphate, and its monophosphate.

Heterocylic N-Glycosides Exist as SynandAntiConformers

Steric hindrance by the heterocyclic ring blocks free rotation about the β-N-glycosidic bond of nucleosides or nucleotides. Both therefore exist as noninterconvertible syn or anti con formers (Figure 5). While both syn and anti conformers occur in nature, the anti conformers predominate.

Table 1 lists the major purines and pyrimidines and their nucleoside and nucleotide derivatives. Single-letter abbreviations are used to identify adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U), whether free or present in nucleosides or nucleotides. The prefix “d” (deoxy) indicates that the sugar is 2′-deoxy-d-ribose (eg, in dATP) (Figure 6).

Fig5. The syn and anti conformers of adenosine differ with respect to orientation about the N-glycosidic bond.

Table1. Purine Bases, Ribonucleosides, and Ribonucleotides

Fig6. Structures of AMP, dAMP, UMP, and TMP.

Modification of Polynucleotides Can Generate Additional Structures

 Small quantities of additional purines and pyrimidines occur in DNA and RNAs. Examples include 5-methylcytosine of bacterial and human DNA, 5-hydroxymethylcytosine of bacterial and viral nucleic acids, and mono- and the di-N-methylated adenine and guanine of mammalian messenger RNAs (Figure 7) that function in oligonucleotide recognition and in regulating the half-lives of RNAs. Free heterocyclic bases include hypoxanthine, xanthine, and uric acid (Figure 8), intermediates in the catabolism of adenine and guanine. Methylated heterocycles of plants include the xanthine derivatives caffeine of coffee, theophylline of tea, and theobromine of cocoa (Figure 9).

Fig7. Four uncommon naturally occurring pyrimidines and purines.

Fig8. Structures of hypoxanthine, xanthine, and uric acid, drawn as the oxo tautomers.

Fig9. Caffeine, a trimethylxanthine. The dimethyl xanthines theobromine and theophylline are similar but lack the methyl group at N-1 and at N-7, respectively.

Nucleotides Are Polyfunctional Acids

The primary and secondary phosphoryl groups of nucleosides have pKa values of about 1.0 and 6.2, respectively. Since purines and pyrimidines are neutral at physiologic pH, nucleotides bear a net negative charge. The pKa values of the secondary phosphoryl groups are such that they can serve either as pro ton donors or as proton acceptors at pH values approximately two or more units above or below neutrality.

Nucleotides Absorb Ultraviolet Light

The conjugated double bonds of purine and pyrimidine derivatives absorb ultraviolet light. While their spectra are pH-dependent, at pH 7.0 all the common nucleotides absorb light at wavelengths around 260 nm. The concentration of nucleotides and nucleic acids thus often is expressed in terms of “absorbance at 260 nm.” The mutagenic effect of ultraviolet light is due to its absorption by nucleotides in DNA that results in chemical modifications.

Nucleotides Serve Diverse Physiologic Functions

 In addition to their roles as precursors of nucleic acids, ATP, GTP, UTP, CTP, and their derivatives each serve unique physiologic functions discussed in other chapters. Selected examples include the role of ATP as the principal biologic transducer of free energy, and the second messenger cAMP (Figure 10). The mean intracellular concentration of ATP, the most abundant free nucleotide in mammalian cells, is about 1 mmol/L. The intracellular concentration of the information carrier cAMP (about 1 nmol/L) is six orders of magnitude below that of ATP. Other examples include adenosine 3′-phosphate-5′-phosphosulfate (Figure 11), the sulfate donor for sulfated proteoglycans and for sulfate conjugates of drugs; and the methyl group donor S-adenosylmethionine (Figure 12). GTP serves as an allosteric regulator and as an energy source for protein synthesis, and cGMP (Figure 10) serves as a second messenger in response to nitric oxide (NO) during relaxation of smooth muscle.

Fig10. cAMP, 3′,5′-cyclic AMP, and cGMP, 3′, 5′-cyclic

Fig11. Adenosine 3′-phosphate-5′-phosphosulfate.

Fig12. S-Adenosylmethionine.

UDP-sugar derivatives participate in sugar epimerizations and in biosynthesis of glycogen, glucosyl disaccharides, and the oligosaccharides of glycoproteins and proteoglycans. UDP-glucuronic acid forms the urinary glucuronide conjugates of bilirubin and of many drugs, including aspirin. CTP participates in biosynthesis of phosphoglycerides, sphingomyelin, and other substituted sphingosines. Finally, many coenzymes incorporate nucleotides as well as structures similar to purine and pyrimidine nucleotides (Table2).

Table2. Many Coenzymes and Related Compounds Are Derivatives of Adenosine Monophosphate

Nucleoside Triphosphates Have High-Group Transfer Potential

 Nucleotide triphosphates have two acid anhydride bonds and one ester bond. Relative to esters, acid anhydrides have a high group transfer potential. ΔG0′ for the hydrolysis of each of the two terminal (β and γ) phosphoryl groups of a nucleoside tri phosphate is about –7 kcal/mol (–30 kJ/mol). This high-group transfer potential not only permits purine and pyrimidine nucleoside triphosphates to function as group transfer reagents, most commonly of the γ-phosphoryl group, but also on occasion transfer of a nucleotide monophosphate moiety with an accompanying release of PPi . Cleavage of an acid anhydride bond typically is coupled with a highly endergonic process such as covalent bond synthesis, for example, the polymerization of nucleoside triphosphates to form a nucleic acid.

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"ليكانيماب".. علاج الزهايمر يطرح رسميا في السوق الألمانية

متى يجب تنظيف الأسنان في الصباح.. قبل أم بعد الإفطار؟

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5 أمور لا تفعلها أثناء تشغيل مكيف سيارتك

ضوء إدارة المحرك: أسئلة مهمة لفهم عمله ومعانيه

"واتساب" يطلق خاصية جديدة لكتابة الرسائل بالذكاء الاصطناعي

المزيد

مواضيع ذات صلة

The Deoxyribonucleosides of Uracil & Cytosine are Salvaged

Biosynthesis of Pyrimidine Nucleotides

Hepatic Purine Biosynthesis is Stringently Regulated

Inosine Monophosphate (IMP) is Synthesized From Amphibolic Intermediates

DNA & RNA are Polynucleotides

Synthetic Nucleotide Analogs are Used in Chemotherapy

Disorders of Bilirubin Metabolism

Catabolism of HEME Produces Bilirubin

Disorders of Heme Biosynthesis

Porphyrins are Colored & Fluoresce

Heme is Synthesized From Succinyl-CoA & Glycine

NON–α-AMINO ACIDS