lorry here are two types of nucleic acids, namely deoxyribonucleic acid (DNA) and ribonucleic acid RNA). Primarily, nucleic acids serve as repositories and transmitters of genetic information, Brief history DNA was discovered in 1869 by Johann Friedrich Miescher, a Swiss researcher. The demonstration that DNA contained genetic information was first made in 1944, by Avery, Macleod and MacCary. Functions of nucleic acids DNA is the chemical basis of heredity and nay be regaided as the reserve bank of genetic information. DNA is exclusively responsible for ‘maintaining the identity of different species of organisms over millions of years. Further, every aspect of cellular function is under the control of DNA. The DNA is organized into genes, the {undamental units of genetic information. The genes control the protein synthesis through the mediation of RNA, as shown below Gu +r ‘The intertelationship of these three classes of biomolecules (DNA, RNA and proteins) constitutes the central dogma of molecular biology or more ‘commonly the central dogma of lie. Components of nucleic acids ‘Nucleic acids are the polymers of nucleotides (polynucleotides) held by 3° and 5’ phosphate bridges. In other words, nucleic acids are built up by the monomeric unite—nucleotides (It may a polymer of amino Stet) Nucleotides are composed of « nitrogenous base, a pentose sugar and a phosphate. Nucleo- tides perform a wide variety of functions in the living cells, besides being the building blocks or 6970 BIOCHEMISTRY ‘monomeric units in the nucleic acid (DNA and RNA) structure. These include their role as structural components of some coenzymes of Becomplex vitamins (e.g. FAD, NAD*), in the energy reactions of cells (ATP is the energy currency), and in the contol of metabolic reactions. STRUCTURE OF NUCLEOTIDES As already stated, the nucleotide essentially consists of mucleobase, sugar and. phosphate. The term nucleoside refers to base + sugar. Thus, nucleotide is nucleoside + phosphate. Purines and pyrimidines ‘The nitrogenous bases found in nucleotides land, therefore, nucleic acids) are aromatic heterocyclic compounds. The bases are of two ‘ypes—purines and pyrimidines. Their general structures are depicted in Fig.5.1. Purines are ‘numbered in the anticlockwise direction while yes are numbered inthe clockwise ‘And this is an internationally accepted system to represent the structure of bases. Major bases in nucleic acids The structures of major purines and pyrimidines found in nucleic acids are shown in Fig.5.2. DNAand RNA contain the same purines ‘namely adenine (A) and guanine (G). Further, the pyrimidine cytosine (C) is found in both ONA and RNA. However, the nucleic acids differ with respect to the second pyrimidine base. DNA contains thymine (1) whereas RNA contains uracil (U). As is observed in the Fig.5.2, thymine and uracil difer in structure by the presence (in T) or absence (in U) of a methyl group. ‘Tautomeric forms of purines and pyrimidines The existence of a molecule in a keto (lactam) and enol (lactim) form is known as tautomerism. The heterocyclic rings of purine: and. pyri ‘groups exhibit tautomerism as simplified below. gn i hate as 2D a 4 HO S me 4 4 Adenine (A). Guanine (G) (6-aminopurine)_ (2-amino 6-oxypurine) “7 4 onan (2-oxy 4-aminopyrimidine) : Hy Wh WA A t t — acl, ca tn) acta ig. 52: Structures of maor pues (A, ) and pytmidres(C, TU) found in nucleic acids.Chapter'S : NUCLEIC ACIDS AND NUCLEOTIDES nm ee NH ont OX 9 5 Aa “Kt Kk rt i fs ‘ Ry no SO On On on 4 4 D-Ribose (D-2-Deoxyribose Lactam form Laetin form Fig. 5.5: Sisctures of sugars prosent in nude acids The purine—guanine and pyti cytosine, thymine and uracil exhibit tautomerism. The lactam and lactim forms of cytosine are represented in Fig.5.3. ‘At physiological pH, the lactam (keto) tauto- ‘meric forms are predominantly present. Minor bases found in nucleic acids : Besices the bases described above, several minor and ‘unusual bases are often found in DNA and RNA. These include 5-methyleytosine, N4-acetyl- cytosine, N®-methyladenine, N®, N&-dimethyl adenine, pseudouracil etc. It is believed that the ‘unusual bases in nucleic acids will help in the recognition of specific enzymes. ‘Other biologically important bases : The bases such a5 hypoxanthine, xanthine and uric acid (Fig.5.4) are present in the free state in the cells. The former two are the intermediates in purine synthesis while uric acid is the end product of purine degradation. Purine bases of plants : Plants contain certain ‘methylated purines which are of pharmaco- logical interest. These include caffeine (of coffee), theophylline (of tea) and theobromine {of cocoa). 0) > (ibese is found in BNA and deoxyabose in DNA; Note ‘the structural itfrence at Ce). ‘Sugars of nucleic acids The five carbon monosaccharides (pentoses) are found in the nucleic acid structure. RNA contains D-ribose while. DNA contains D-deoxyribose. Ribose and deoxyribose difer in structure at C;. Deoxyribose has one oxygen less at C; compared to ribose (Fig.5.5). Nomenclature of nucleotides. The addition of a pentose sugar to base produces a nucleoside. If the sugar is ribose, ribonucleosides are formed. Adenosine, guanosine, cytidine and uridine are the ribonucleosides of A, G, Cand U respectively. If the sugar is a deoxyribose, deoxyribo- nucleosides are produced The term mononucleotide is used when a single phosphate moiety is added to a nucleoside. Thus adenosine monophosphate (AMP) contains adenine + ribose + phosphate. The principal bases, their respective nucleosides and nuclectides found in the structure of nucleic acids are given in Table 5.1. Note that the prefix ‘4’ is used to indicate if the sugar is deoxyribose (e.g. dAMP). to 9 and. for pyrimidine as 1 to 6 (See Fig5.1). The Hyporanthine Xanthine Uric acid aon of aga ar represented wi (G-oxpurine) _(26-cioxypurine) _(2.68+rioxypurine) aN associated prime ()_for differentiation. Thus the pentose Fig. .4: Strucures of some biological important purines. carbons are 1" to 5’.72 eee 3 and nucleotides Base Ribonucleoside ‘Ribonucleotide (5’-monophosphate) ‘deine (A) Adenesine ‘Aderosne 5-nanoghosphae o adaylte AME Guatine (6) Guanesine Guanosine 5*nonophosehate or quan ue ytesne (6) tine fine monophesphae or cyte cur Uracil (U)——Uidine Uridine 5-monophosphat or wridylte une Race __Deoxyribonucteoside Deoryribonucleotide (S-monophosphate) Abbreviation ‘Adesne (A) Deoryadenssne Deoxyadenose Snonephespate or deoxyatenyte dAMP Guarine (6) __Deoryguanssine Deoxygueosine Snonephospate or deonyguanyte GMP ytesine (6) Decree Deoreyttine 5menophoophate or deonyoytlate acwr Thynine (T)__Deoxyhymidine Deooytynisine S-nonophosphate or deoaythymidate TMP BIOCHEMISTRY ‘The pentoses are bound to nitrogenous bases by B-N-ghycosidic bonds. The N9 of a purine ring represents adenosine However, for adenosine 3 ST-monophosphate. yonophosphate, the binds with Cyqyy of @ pentose sugar to form a covalent bond in the purine nucleoside. In case of pyrimidine nucleosides, the glycosidic linkage is between N! of a pyrimidine and C’y of a pentose. The hydroxyl groups of adenesine are esterified with phosphates to produce 5 or ¥-monophosphates. 5’-Hydraxyl is the most commonly esterifed, hence 5” is usually omitted while writing nucleotide names. Thus AMP abbreviation 3/-AMP is used. ‘The structures of two selected nuclectides namely AMP and TMP are depicted in Fig.5.6. Nucleoside di- and triphosphates Nucleoside monophosphates possess only ‘one phosohate moiety (AMP, TMP). The addition ‘of second or third phosphates to the nucleoside resulls in nucleoside diphosphate (e.g. ADP) or triphosphate (e.g. ATF), respectively. ‘Fig. 5.6: The structures of adenosine &-monophasphete (AMP) and thymidine §-menophssphate (TMP) (P-Addtion of secondor third ptasphate gives adenosine alphosphate (ADP) and adenosine tiphosphate (ATP) respectively)Chapter S : NUCLEIC ACIDS AND NUCLEOTIDES 73 The anionic properties of nuch nucleic acids are due to the negative charges contributed by phosphate groups. PURINE, PYRIMIDINE AND NUCLEOTIDE ANALOGS of purines, pyrimidines, _nuckosides ‘nucleotides. Some of the synthetic analogs are highly useful in clinical medicine. The structures of selected purine and pyrimidine analogs are siven in Fig.5.7. The pharmacological applications of certain analogs are listed below 1. Allopurinol is used in the treatment of hyperuricemia and gout (For details, Refer Chapter 17). 2. S-Fluorouracil, 6-mercaptopurine, Bazar guanine, 3-deoxyuridine, 5- or 6-azauridine, 5+ of 6-azacytidine and 5-idouracil are employed in the treatment of cancers. These compounds get incorporated into DNA and block cell proliferation. 3. Azathioprine (which gets degraded to S-mercaptopurine) is used 10 suppress immunological rejection during transplantation. 4. Arabinosyladenine is used for the treatment of neurological disease, viral encephalitis. 5, Arabinosyleytosine is being used in cancer therapy as it interferes with DNA replication. 6. The drugs employed in the treatment of AIDS namely zidovudine or AZT (3eazido 1,,'-dideoxythymidine) and didanosine (dideoxy- inosine) are sugar modified synthetic nucleotide analogs (For their structure and more details Refer Chapter 38) Plea ey DNA js a polymer of deoxyribonucleotides (or simply deoxynucleotides). It is composed of monomeric units namely _ deoxyadenylate (AMP), deoxyguanylate (GMP), deoxy ‘eytidylate (CMP) and deoxythymidylate (TMP) {dt may be noted here that some authors prefer to use TMP for deoxythymidylate, since it is found only in DNA). The details of the nucleotide structure are given above. ‘Schematic representation of polynucleotides ‘The monomeric deoxynucleotides in DNA are held together by 375-phosphodiester bridges (Fig.5.8). ONA (or RNA) structure is. often represented in a shortshand form. The horizontal lin tes the carbon chain of sugar with base attached to Cy. Near the middle of the horizontal line is Cy phosphate linkage while at the other end of the line is Csr phosphate linkage (ig.5.8) Chargaff’s rule of DNA composition Erwin Chargafi in late 1940s quantitatively analysed the DNA hydrolysates from different species. He observed that in all the species he studied, DNA had equal numbers of adenine and thymine residues (A = T) and equal numbers of guanine and cytosine residues (G = ©. This is known as Chargaff’s rule of molar equivalence between the purines and pyrimidines in DNA structure. The significance of Chargaft’s rule was not immediately realised. The double helical structure of DNA derives its strength from Chargaff’s rule (discussed later).