Nucleic Acids in Chemistry and Biology

biosynthesis involves the condensation of ATP with a monoalkyl phosphate, and the pyrophosphate appears
to act generally as a structural unit providing coulombic binding to appropriate enzyme residues.
Cyclic ADP ribose(Figure 3.62b) is a metabolic product formed by the cyclization of NADto close
C-1 of the second ribose onto N-1 of the adenine ring. The instability of this nucleotide appears to ori-
ginate not from its pyrophosphate diester but from the second glycosylic linkage. It has an important role
as a second messenger and is involved in calcium signalling in cells. The active forms of many hexoses are
found as pyrophosphate esters of uridine 5-diphosphate. These include UDP-glucose, UDP-galactose and
UDP-N-acetylglucosamine(Figure 3.62c) that are formed biosynthetically from UTP and hexose-1--
phosphate. The pyrophosphate ester is a good leaving group and is employed in catabolic processes involv-
ing C-1 of the hexose residue.
The P^1 ,P^4 -dinucleosidyl tetraphosphates, Ap 4 A and Ap 4 G, are found along with Ap 3 A in all cells, especially
under conditions of metabolic stress (Figure 3.63). They are produced as a result of the phosphorolysis of
aminoacyl adenylates, particularly tryptophanyl and lysyl adenylates, with ATP or GTP. Although these minor
nucleotides were discovered by Zamecnik in 1966, their purpose remains uncertain. They may have a role in
the initiation of DNA biosynthesis, and their analogues inhibit the aggregation of blood platelets. Ap 3 A is
involved in signalling for apoptosis. Somewhat related structures are found in the ‘caps’ at the 5-ends of
eukaryotic mRNAs, which have a 7-methylguanosin-5-yl residue linked to the 5-triphosphate. Both of these
species and their analogues have been targets for synthesis as a means of discovering their biological function.

3.3.2 Synthesis of Nucleoside Polyphosphate Esters

All of the naturally occurring nucleoside polyphosphates have at least one negative charge on each phosphate
residue. This is because uncharged phosphoryl residues in a string of phosphates are readily hydrolysed
spontaneously. As a result, most syntheses have avoided the formation of fully esterified intermediates,
though an early synthesis of UTP was achieved (in low yield) by the catalytic hydrogenolysis of its tetra-
benzyl ester. Generally, syntheses of monoalkyl esters fall into two classes; they involve C O bond or
P O P bond formation.
The exploitation of the alkylating properties of nucleoside 5-O-tosylates towards pyrophosphate or
tripolyphosphate anions and their methylene analogues is put to good use in the Poulter reaction.^101 This has
made direct syntheses of nucleoside 5-di- and tri-phosphates and their analogues possible (Figure 3.64).

Nucleosides and Nucleotides 113

O

HO OH

N

N

N

N

NH 2

O

HO OH

B O

P

O

O

O

P

O

P

O

OOO O

Ap 3 A n=1, B = Ade

Ap 4 A n=2, B = Ade

Ap 4 G n=2, B = Gua

n

Figure 3.63 Structures of P^1 , P^3 -Dinucleoside triphosphate and P^1 , P^4 -dinucleoside tetraphosphates

O

HO OH

N

N

N

N

NH 2

O

P

O

X

O

P

O

OO

TsO O

HO OH

N

N

N

N

NH 2

O

P

O

X

O

P

O

OO +

X = O, CH 2 , CF 2 , NH

Figure 3.64 Synthesis of ADP and its analogues by C O bond formation