Purines Pyrimidines Nucleosides Nucleotides

Purines and pyrimidines are nitrogen-containing hete-rocycles, cyclic compounds whose rings contain both carbon and other elements (hetero atoms). Note that the smaller pyrimidine has the longer name and the larger purine the shorter name and that their six-atom rings are numbered in opposite directions (Figure 33-1). The planar character of purines and pyrimidines facilitates their close association, or "stacking," which stabilizes double-stranded DNA (Chapter 36). The oxo and amino groups of purines and pyrimidines exhibit keto-enol and amine-imine tautomerism (Figure 33-2), but physiologic conditions strongly favor the amino and oxo forms.

Purine

Pyrimidine

Figure 33-1. Purine and pyrimidine. The atoms are numbered according to the international system.

Nucleosides & Nucleotides

Nucleosides are derivatives of purines and pyrimidines that have a sugar linked to a ring nitrogen. Numerals with a prime (eg, 2' or 3') distinguish atoms of the sugar from those of the heterocyclic base. The sugar in ribonucleosides is d-ribose, and in deoxyribonucleo-sides it is 2-deoxy-d-ribose. The sugar is linked to the heterocyclic base via a P-N-glycosidic bond, almost always to N-1 of a pyrimidine or to N-9 of a purine (Figure 33-3).

Figure 33-2. Tautomerism of the oxo and amino functional groups of purines and pyrimidines.

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'-" is usually omitted when naming them. UMP and dAMP thus represent nucleotides with a phosphoryl group on C-5 of the pentose. Additional phosphoryl groups linked by acid anhydride bonds to the phos-phoryl group of a mononucleotide form nucleoside diphosphates and triphosphates (Figure 33-4).

Steric hindrance by the base restricts rotation about the P-N-glycosidic bond of nucleosides and nu-

Adenine

1

11

II

O

O-

II O

Adenine

> Ribose

HO OH

Adenosine 5'-monophosphate (AMP)

> Ribose

HO OH

Adenosine 5'-monophosphate (AMP)

Adenosine 5'-diphosphate (ADP)

Adenosine 5'-triphosphate (ATP)

Figure 33-4. ATP, its diphosphate, and its monophosphate.

cleotides. Both therefore exist as syn or anti conformers (Figure 33-5). While both conformers occur in nature, anti conformers predominate. Table 33-1 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, dGTP) (Figure 33-6).

Nucleic Acids Also Contain Additional Bases

Small quantities of additional purines and pyrimidines occur in DNA and RNAs. Examples include 5-methyl-cytosine of bacterial and human DNA, 5-hydroxy-methylcytosine of bacterial and viral nucleic acids, and mono- and di-N-methylated adenine and guanine of

OH OH

Anti

Anti

OH OH

OH OH

Figure 33-5. The syn and anti conformers of adenosine differ with respect to orientation about the N-gly-cosidic bond.

Table 33-1. Bases, nucleosides, and nucleotides.

Base Formula

Base X = H

Nucleoside X = Ribose or Deoxyribose

Nucleotide, Where X = Ribose Phosphate

1

X

Adenine A

Adenosine A

Adenosine monophosphate AMP

O

N

Guanine G

Guanosine G

Guanosine monophosphate GMP

1

X

Cytosine C

Cytidine C

Cytidine monophosphate CMP

X

Uracil U

Uridine U

Uridine monophosphate UMP

O

O^N^

Thymine T

Thymidine T

Thymidine monophosphate TMP

dX

OH OH

OH H

OH OH OH H

AMP dAMP

ch2oh

5-Hydroxymethylcytosine ch2oh

5-Methylcytosine

H3C^/CH3

5-Hydroxymethylcytosine

Dimethylaminoadenine

Dimethylaminoadenine

7-Methylguanine

7-Methylguanine

Figure 33-7. Four uncommon naturally occurring pyrimidines and purines.

mammalian messenger RNAs (Figure 33-7). These atypical bases function in oligonucleotide recognition and in regulating the half-lives of RNAs. Free nucleotides include hypoxanthine, xanthine, and uric acid (see Figure 34-8), intermediates in the catabolism of adenine and guanine. Methylated heterocyclic bases of plants include the xanthine derivatives caffeine of coffee, theophylline of tea, and theobromine of cocoa (Figure 33-8).

Posttranslational modification of preformed polynucleotides can generate additional bases such as pseudouridine, in which d-ribose is linked to C-5 of uracil by a carbon-to-carbon bond rather than by a P-N-glycosidic bond. The nucleotide pseudouridylic acid ¥ arises by rearrangement of UMP of a preformed tRNA. Similarly, methylation by S-adenosylmethionine of a UMP of preformed tRNA forms TMP (thymidine monophosphate), which contains ribose rather than de-oxyribose.

Figure 33-8. Caffeine, a trimethylxanthine. The di-methylxanthines theobromine and theophylline are similar but lack the methyl group at N-1 and at N-7, respectively.

Figure 33-8. Caffeine, a trimethylxanthine. The di-methylxanthines theobromine and theophylline are similar but lack the methyl group at N-1 and at N-7, respectively.

H2N^N^N

o-ch2

Nucleotides Serve Diverse Physiologic Functions

Nucleotides participate in reactions that fulfill physiologic functions as diverse as protein synthesis, nucleic acid synthesis, regulatory cascades, and signal transduction pathways.

Nucleoside Triphosphates Have High Group Transfer Potential

Acid anhydrides, unlike phosphate esters, have high group transfer potential. A0' for the hydrolysis of each of the terminal phosphates of nucleoside triphosphates is about -7 kcal/mol (-30 kJ/mol). The high group transfer potential of purine and pyrimidine nucleoside triphosphates permits them to function as group transfer reagents. Cleavage of an acid anhydride bond typically is coupled with a highly endergonic process such as covalent bond synthesis—eg, polymerization of nucleoside triphosphates to form a nucleic acid.

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; the second messenger cAMP (Figure 33-9); adenosine 3'-phosphate-5'-phosphosulfate (Figure 33-10), the sulfate donor for sulfated proteoglycans (Chapter 48) and for sulfate conjugates of drugs; and the methyl group donor S-adenosylmethionine (Figure 33-11).

Figure 33-10. Adenosine 3'-phosphate-5'-phos-phosulfate.

COO-

ch^Ch2

HO OH

Methionine Adenosine

Figure 33-11. S-Adenosylmethionine.

Table 33-2. Many coenzymes and related compounds are derivatives of adenosine monophosphate.

Adenine

R"O OR' D-Ribose

Adenine

NH3+

GTP serves as an allosteric regulator and as an energy source for protein synthesis, and cGMP (Figure 33-9) serves as a second messenger in response to nitric oxide (NO) during relaxation of smooth muscle (Chapter 48). UDP-sugar derivatives participate in sugar epimer-izations and in biosynthesis of glycogen, glucosyl disac-charides, and the oligosaccharides of glycoproteins and proteoglycans (Chapters 47 and 48). UDP-glucuronic acid forms the urinary glucuronide conjugates of bilirubin (Chapter 32) and of drugs such as aspirin. CTP participates in biosynthesis of phosphoglycerides, sphingomyelin, and other substituted sphingosines (Chapter 24). Finally, many coenzymes incorporate nucleotides as well as structures similar to purine and pyrimidine nucleotides (see Table 33-2).

Coenzyme

R

R'

R"

n

Active methionine

Methionine*

H

H

0

Amino acid adenylates

Amino acid

H

H

1

Active sulfate

SO32-

H

PO32-

1

3',5'-Cyclic AMP

H

PO32-

1

NAD*

t

H

H

2

NADP*

t

PO32-

H

2

FAD

t

H

H

2

CoASH

t

H

PO32-

2

•Replaces phosphoryl group. fR is a B vitamin derivative.

•Replaces phosphoryl group. fR is a B vitamin derivative.

nucleic acids thus often is expressed in terms of "ab-sorbance at 260 nm."

Nucleotides Are Polyfunctional Acids

Nucleosides or free purine or pyrimidine bases are uncharged at physiologic pH. By contrast, the primary phosphoryl groups (p^ about 1.0) and secondary phosphoryl groups (p^ about 6.2) of nucleotides ensure that they bear a negative charge at physiologic pH. Nucleotides can, however, act as proton donors or acceptors at pH values two or more units above or below neutrality.

Nucleotides Absorb Ultraviolet Light

The conjugated double bonds of purine and pyrimidine derivatives 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 7.0 all the common nucleotides absorb light at a wavelength close to 260 nm. The concentration of nucleotides and

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