Nucleic Acids in Chemistry and Biology

3.4 Biosynthesis of Nucleotides

Nucleotides play a key role as the precursors of DNA and RNA, as activated intermediates in many biosyn-
thetic processes and as metabolic regulators. One particular nucleotide, adenosine 5-triphosphate (ATP),
is an important energy source. For example, an average human turns over 40 kg of ATP per day and can require
0.5 kg min^1 during exercise. The biosynthesis of nucleotides involves both constructive (anabolic) and
destructive (catabolic) pathways. In the following sections, we will concentrate on only the general prin-
ciples of nucleotide and nucleic acid metabolism and then show how certain steps are prime targets for
biosynthetic interference, especially for the design of anti-cancer and anti-viral agents.

3.4.1 Biosynthesis of Purine Nucleotides120,121

3.4.1.1 De novo Pathways. The key intermediate in the biosynthesis of both pyrimidines and purines

is -D-5-phosphoribosyl 1-pyrophosphate (PRPP), which is formed from -D-5-ribose 5-phosphate by a

116 Chapter 3

O

O

HO OH

P Ade

O

O

Y O

HO OH

O Ade

HO OH

Ade P O

O

O

Y

P

X

P

O

OOO O

P

O

OY

(i), (ii)

Figure 3.69 Syntheses of Ap 4 A and some analogues. Reagents: (i) (PhO) 2 POCl, pyridine; and (ii) O 3 PXPO 34 
(XO, CH 2 , CF 2 , NH etc.; YO or S)

O

O

O O

N

NH

N

N

O

P

O

X

O

O P

O

S

Me

NH 2

H OMe

OMe

(i), (ii)

+pAUG m

(^7) G(5'-)pppAUG
Figure 3.70 Synthesis of the ‘cap’ structure of mRNA. Reagents: (i) Ag, imidazole, DMF; and (ii) H 3 O
P O Ado
S
O
O
P
OO
O P O Ado
S
O
Ø
P
OO
O
P
O
O
P O
O
O
O P O Ado
S
Ø
O
P O Ado
S
O
Ø
Sp Rp
Sp
(i)
(ii)
(iii)
Figure 3.68 Syntheses of (Rp)-[a^17 O] ATP and (Sp) AMP. Reagents: (i) Br 2 , H 217 O; (ii) snake venom phosphodi-
esterase, H 218 O (retention); and (iii) pyruvate kinase, Mg^2 , K, phosphoenol pyruvate
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