Page 199 - Color Atlas of Biochemistry

190 Metabolism

Nucleotide biosynthesis side diphosphates. This reduction is a com-
plex process in which several proteins are
De novo synthesis of purines and pyrimidines involved. The reducing equivalents needed
+
yields the monophosphates IMP and UMP, come from NADPH+H . However, they are
respectively (see p. 188). All other nucleotides not transferred directly from the coenzyme
and deoxynucleotides are synthesized from to the substrate, but first pass through a redox
these two precursors. An overview of the series that has several steps (1).
pathways involved is presented here; further In the first step, thioredoxin reductase re-
details are givenonp. 417. Nucleotide syn- duces a small redox protein, thioredoxin,via
thesis by recycling of bases (the salvage path- enzyme-bound FAD. This involves cleavage of
way) is discussed on p. 186. a disulfide bond in thioredoxin. The resulting
SH groups in turn reduce a catalytically active
disulfide bond in nucleoside diphosphate
A. Nucleotide synthesis: overview
reductase (“ribonucleotide reductase”). The
The synthesis of purine nucleotides (1)starts free SH groups formed in this way are the
from IMP. The base it contains, hypoxanthine, actual electron donors for the reduction of
is converted in two steps each into adenine or ribonucleotide diphosphates.
guanine. The nucleoside monophosphates In eukaryotes, ribonucleotide reductase is a
AMP and GMP that are formed are then phos- tetramer consisting of two R1 and two R2
phorylated by nucleoside phosphate kinases to subunits. In addition to the disulfide bond
yield the diphosphates ADP and GDP,and mentioned, a tyrosine radical in the enzyme
these are finally phosphorylated into the also participates in the reaction (2). It initially
triphosphates ATP and GTP.The nucleoside produces a substrate radical (3). This cleaves a
triphosphates serve as components for RNA, water molecule and thereby becomes radical
or function as coenzymes (see p. 106). Con- cation. Finally, the deoxyribose residue is pro-
version of the ribonucleotides into deoxyribo- duced by reduction, and the tyrosine radical is
nucleotides occurs at the level of the diphos- regenerated.
phates and is catalyzed by nucleoside diphos- The regulation of ribonucleotide reductase
phate reductase (B). is complex. The substrate-specificity and ac-
The biosynthetic pathways for the pyrimi- tivity of the enzyme are controlled by two
dine nucleotides (2)are more complicated. allosteric binding sites (a and b) in the R1
The first product, UMP, is phosphorylated first subunits. ATP and dATP increase or reduce
to the diphosphate and then to the the activity of the reductase by binding at
triphosphate, UTP. CTP synthase then converts site a. Other nucleotides interact with site b,
UTP into CTP. Since pyrimidine nucleotides and thereby alter the enzyme’s specificity.
are also reduced to deoxyribonucleotides at
the diphosphate level, CTP first has to be hy-
drolyzed by a phosphatase to yield CDP before
dCDP and dCTP can be produced.
The DNA component deoxythymidine tri-
phosphate (dTTP)is synthesized from UDP in
several steps. The base thymine, which only
occurs in DNA (see p. 80), is formed by meth-
ylation of dUMP at the nucleoside monophos-
phate level. Thymidylate synthase and its
helper enzyme dihydrofolate reductase are
important target enzymes for cytostatic drugs
(see p. 402).

B. Ribonucleotide reduction
2 -Deoxyribose, a component of DNA, is not
synthesized as a free sugar, but arises at the
diphosphate level by reduction of ribonucleo-

Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.