第 23章
核苷酸代谢
一、核苷酸降解代谢
1,Uric acid is the excreted end product of purine
catabolism in humans and many other animals
? For adenosine,the amino group is hydrolyzed
before the ribose group is removed,
? For guanosine,the amino group is hydrolyzed
after the ribose group is removed,
? Xanthine oxidase,having multiple cofactors
(including an FAD,a Mo complex,four different
Fe-S clusters),catalyzes the O2-dependent
conversion of hypoxanthine to xanthine and
xanthine to uric acid,
? Uric acid can be further converted to allantoin,
allantoate,urea or NH4+ in various animals,
? The deficiency of adenosine deaminase causes
the severe immunodeficiency disease in humans
(it is likely the accumulated adenosine is
converted to dATP,which inhibits the formation
of all dNDPs by ribonucleotide reductase),
? Overproduction of uric acid was revealed to
cause gout (痛风 ),
? Allopurinol,an inhibitor of xanthine oxidase,is
used to treat gout,
(黄嘌呤 )
(尿酸 )
(尿囊素 ）
(尿囊酸 )
Dephosphorylation
Dephosphorylation
Deamination
Deamination
Deribosylation Deribosylation
Oxidation
Oxidation
Allopurinol was designed to be a competitive inhibitor
of xanthine oxidase to treat gout by Elion and Hitchings,
who shared the Nobel Prize in 1988 for their discoveries
of important principles for drug treatment
2,Pyrimidines are broken down via
reduction
? The degradation of thymine produces
mathylmalonyl-CoA,which can be converted to
succinyl-CoA (a citric acid cycle intermediate) by
the catalysis of of uracil and cytidine produces
malonyl-CoA,which is one precursor for fatty acid
biosynthesis,
? To a limited extent,catabolism of pyrimidine
nucleotides contributes to the energy metabolism
of the cell,
Propionyl-CoA Succinyl-CoA
Degradation products of
pyrimdines can enter the
citric acid cycle
二、核苷酸的生物合成
1,Nucleotides are synthesized via
either the de novo pathways or the
salvage pathways
? In the de novo pathway simple precursors,
including amino acids,PRPP,NH4+,CO2,
and one-carbon units (carried on H4 folate)
are used,
? In the salvage pathway the free bases and
nucleosides released from nucleic acid
breakdown are used,
? The free bases (A,G,C,U,T) are not
intermediates during the de novo synthesis,the
purine ring is assembled on ribose phosphate to
make AMP and GMP; the pyrimidine ring is first
synthesized as orotate（ 乳清酸 ）,which is then
attached to ribose phosphate before being
converted to UTP and CTP (dTMP is made from
dUMP),
? The deoxyribonucleotides (dNDPs) are
synthesized by reduction of ribonucleotides
(NDPs),
2,Radioisotope tracer(放射同位素示踪 )
experiments revealed the origins of the
atoms in the purine and pyrimidine rings
? Buchanan and Greenberg revealed this by
feeding a variety of isotopically labeled
compounds to pigeons (1940s),
? The atoms of the purine rings were found to be
derived from formate,CO2,Gly,Asp,and Gln,
? The atoms of the pyrimidine rings were found to
be derived from Asp,Gln and HCO3-,
Radioisotope tracer experiments revealed
the origins of the ring atoms of purines
Gln amide
HCO3-
C
The atoms of the pyrimidine rings were revealed to
Be derived from HCO3-,Gln and Asp,
3,De novo purine nucleotide synthesis
begins with the transferring of an
amino group from Gln to PRPP
? PRPP is synthesized from ribose 5-P,
? In the first (committing) step of purine nucleotide
synthesis,the PPi part on PRPP (at C-1) is
replaced by the side chain amino group of Gln,
forming 5-phosphoribosylamine,
? A glycine (2C +1N),a N10-formyl H4 folate (1C),a
Gln (1N),a HCO3-(1C) Asp (1N),and another N10-
formyl H4 folate (1C) then brings the rest atoms
for the purine ring,
? The first intermediate having a complete
purine ring is IMP (次黄嘌呤核苷酸 ),
? IMP is converted to AMP by accepting an
amino group from Asp,and converted to
GMP by a NAD+-dependent
dehydrogenation reaction (at C-2) and an
amino group transfer from Gln (catalyzed
by an amidotransferase),
? The production of AMP from IMP requires
GTP,and the production of GMP from IMP
requires ATP,
PRPP is synthesized from ribose 5-P in a
Reaction catalyzed by PRPP synthetase,
The purine ring is built up one or a few atoms at
a time on ribose 5-P
Steps 1,3,and 5 are
catalyzed by one
multifunctional protein
in some eukaryotic cells,
IMP is first
formed and
is then converted
to AMP and
GMP,
Steps 7 and 8 are
catalyzed by one
protein in some
eukaryotic cells
Steps 10 and 11 are
catalyzed by one protein
in some eukaryotic cells
IMP is converted to AMP by accepting an amino
group from Asp (GTP is needed to activate Asp) and to
GMP by accepting an amino group from Gln (ATP is
needed to activate XMP)
4,The biosynthesis of AMP and GMP is
regulated by feedback inhibition
PRPP synthetase and glutamine-PRPP
amidotransferase are both inhibited by the
end products IMP,AMP and GMP (AMP and
GMP act synergistically),
AMP inhibits adenylosuccinate synthetase
and GMP inhibits IMP dehydrogenase,
AMP and GMP synthesis is balanced by the
following mechanism,GTP is needed for
AMP synthesis and ATP for GMP synthesis,
The de novo synthesis
of AMP and GMP
is regulated mainly
by sequential feedback
Inhibition,
5,The de novo biosynthesis of
pyrimidines begin with the formation
of carbamoyl phosphate
? Carbamoyl phosphate is formed from Gln,HCO3-,
and ATP in a reaction catalyzed by the carbamoyl
phosphate synthetase II（ 氨甲酰磷酸合成酶 II ）,
? In the committing step of pyrimidine biosynthesis,
carbamoyl phosphate condenses with Asp to form
N-carbamoylaspartate in a reaction catalyzed by
aspartate transcarbamoylase (ATCase 天冬氨酸转
氨甲酰酶 ),
? A ring closing reaction generates L-
dihydroorotate,which is then oxidized to
form orotate (乳清酸 ) in a reaction catalyzed
by dihydroorotate dehydrogenase,
? Orotate is then linked to PRPP to form
orotidylate,which is then converted to UMP
by a decarboxylation reaction,
? CTP is derived from UTP by accepting an
amino group from Gln or NH4+,
? In eukaryotic cells,carbamoyl phosphate
synthetase II,aspartate transcarbamoylase,
dihydroorotase,and are part of a
trifunctional proteins called CAD,
? When PALA,an ATCase inhibitor was
added to cultured mammalian cells,
concentrations of all three enzymes are
increased dramatically for cells resistant to
PALA,
Gln
HCO3-+ATP
NH4+
Carbamoyl phosphate
Intermediates in
bacterial carbamoyl
phosphate synthetase
is channeled,
6,Pyrimidine nucleotide biosynthesis
is regulated at the aspartate
transcarbamoylase (ATCase)
? ATCase is inhibited by CTP,the end
product of the de novo pyrimidine
nucleotide biosynthesis pathway,
? CTP binds at the regulatory subunits,
which changes the conformation of the
catalytic subunits,inactivating them,
? ATP is able to prevent the changes
induced by CTP,
ATCase contains separate catalytic and
regulatory subunits
Catalytic
Subunits (binding Asp and carbamoyl phosphate)
Regulatory subunits (binding CTP or ATP)
7,Base specific NMP kinases together
with a nonspecific NDP kinase converts
NMPs to NTPs
? Nucleotides participate in biosynthesis (of
RNA and DNA) in the forms of NTPs,
? Each specific nucleoside monophosphate
(NMP) kinase converts the corresponding
NMP/dNMPs to NDP/dNDPs using ATP,
? The nonspecific nucleoside diphosphate
(NDP) kinase converts all NDP/dNDPs to
NTP/dNTPs using ATP or other NTPs,
8,Deoxyribonucleotides are made
from ribonucleotides at the NDP level
? This occurs by direct reduction at the 2`-
carbon,
? Ribonucleotide reductase catalyzes all such
conversions,
? The electrons are provided by NADPH and
is transferred to the ribonucleotide
reductase via two possible paths (via either
thioredoxin or glutaredoxin),
NDPs are converted
to dNDPs with the
catalysis of
ribonucleotide
reductase,with
electrons ultimately
coming from
NADPH
Electrons are transferred from NADPH to the ribonucleotides
Via thioredoxin
(硫氧还蛋白 ）
Via glutaredoxin
(谷氧还蛋白 ）
Ribonucleotide
reductase is a
tetramer of two
different subunits
The R2 dimer of
ribonucleotide reductase,
with a Tyr radical and a
Fe3+-Fe3+ binuclear center,
Tyr radical
Fe3+-Fe3+
A proposed
mechanism for
converting a
NDP to a dNDP
by ribonucleotide
reductase,the
radical property
of the enzyme is
transiently
transferred to the
substrate; the
presence of the
radical at C-3
stabilizes the
carbon cation
formed at C-2,
Both the substrate specificity and
the overall enzymatic activity of
ribonucleotide reductase is
regulated to balance the
biosynthesis of all nucleotides,
9,dTMP is synthesized by methylation
of dUMP
? dUTP is first formed from either dUDP (via
phosphorylation) or dCTP (via deamination),
? dUMP is then formed from dUTP in a reaction
catalyzed by dUTPase (keeping dUTP at a low
level to prevent its incorporation into DNA),
? dUMP is then converted to dTMP by the catalysis
of thymidylate synthase（ 胸腺嘧啶核苷酸合酶 ）,
with a methylene group transferred from and
reduced by N5,N10-methylene H4 folate (being
donors of both one-carbon unit and electrons!),
? The dihydrofolate is reduced to H4 folate by
NADPH in a reaction catalyzed by dihydrofolate
reductase (DHFR),
? The N5,N10-methylene H4 folate is regenerated
from Ser and tetrahydrofolate in a reaction
catalyzed by serine hydroxymethyltransferase,
? The reactions catalyzed by ribonucleotide
reductase and thymidylate synthase are
probably key for the transition from an RNA
world to one in which DNA stores genetic
information,
dTMP is derived from dUMP via a methylation
reaction using N5,N10-methylene H4 folate as
donors of both one-carbon unit and electrons,
dUMP is converted to
dTMP in a N5,N10-
methylene H4 folate-
dependent reaction
catalyzed by
thymidylate synthase,
三、嘌呤和嘧啶碱基的再利用（ 核苷
酸合成的节约途径 ）
Purine and pyrimidine bases can be reconverted into
nucleotides via the salvage pathway
? Adenine phosphoribosyltransferase catalyzes the
synthesis of AMP from adenine and PRPP,
? Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
catalyzes the synthesis of GMP and IMP,
? The lack of HGPRT will cause Lesch-Nyhan syndrome,
? Pyrimidine bases are recycled in a similar way in
microorganisms,but pyrimidine bases does not seem to
be salvaged in significant amounts in mammals,
The purine bases can be converted
to purine nucleotides via the
salvage pathways
四, Many cancer chemotherapeutic（ 化
学疗法 ） drugs target enzymes in the
nucleotide biosynthetic pathways
? Analogs of Gln,like azaserine and acivicin,
inhibits many amidotransferases used in
nucleotide (and amino acid) biosynthesis,
? Fluorouracil,after being converted to FdUMP by
the salvage pathway,can inhibit the thymidylate
synthase after two steps of conversion,thus
inhibit the dTMP synthesis,
? Methotrexate,a folate analog,inhibits the
dihydrofolate reductase,thus the dTMP synthesis,
Azaserine and acivicin
inhibits amidotransferases,
thus inhibit the biosynthesis
of nucleotides and amino
acids,
FdUMP (from fluorouracil)
and methotrexate inhibits
thymidylate synthase and
DHFR respectively,
FdUMP is an suicide inhibitor of
thymidylate synthase
? Summary
? Purine nucleotides are synthesized from PRPP,Gln,
Gly,N10-formyl H4 folate,Gln,HCO3-,Asp through
the de novo pathway,
? Pyrimidine nucleotides are synthesized using
HCO3-,Gln,Asp,and PRPP,
? De novo synthesis of nucleotides are regulated via
feedback inhibition (no covalent modifications yet
revealed),
? Deoxyribonucleotides are derived from
ribonucleotides at the NDP level,with the catalysis
of ribonucleotide reductase,which contains a
chain of electron carriers,uses free radicals,and
being regulated for both substrate specificity and
overall enzymatic activities,
? The dTMP molecule is derived from dUMP by
thymidylate synthase,an enzyme using N5,N10-
methylene-tetrahydrofolate as the donor of both
one-carbon unit and electrons,
? Degradation of purines and pyrimidines produces
uric acid and citric acid cycle intermediate/fatty
acid synthesis precursor,respectively,
? Purine and pyrimidine bases can be reused via
the salvage pathway,
? Many cancer chemotherapeutic drugs (e.g.,
azaserine,acivicin,fluorouracil,and methotrexate)
inhibits enzymes in the nucleotide biosynthetic
pathways,
核苷酸代谢
一、核苷酸降解代谢
1,Uric acid is the excreted end product of purine
catabolism in humans and many other animals
? For adenosine,the amino group is hydrolyzed
before the ribose group is removed,
? For guanosine,the amino group is hydrolyzed
after the ribose group is removed,
? Xanthine oxidase,having multiple cofactors
(including an FAD,a Mo complex,four different
Fe-S clusters),catalyzes the O2-dependent
conversion of hypoxanthine to xanthine and
xanthine to uric acid,
? Uric acid can be further converted to allantoin,
allantoate,urea or NH4+ in various animals,
? The deficiency of adenosine deaminase causes
the severe immunodeficiency disease in humans
(it is likely the accumulated adenosine is
converted to dATP,which inhibits the formation
of all dNDPs by ribonucleotide reductase),
? Overproduction of uric acid was revealed to
cause gout (痛风 ),
? Allopurinol,an inhibitor of xanthine oxidase,is
used to treat gout,
(黄嘌呤 )
(尿酸 )
(尿囊素 ）
(尿囊酸 )
Dephosphorylation
Dephosphorylation
Deamination
Deamination
Deribosylation Deribosylation
Oxidation
Oxidation
Allopurinol was designed to be a competitive inhibitor
of xanthine oxidase to treat gout by Elion and Hitchings,
who shared the Nobel Prize in 1988 for their discoveries
of important principles for drug treatment
2,Pyrimidines are broken down via
reduction
? The degradation of thymine produces
mathylmalonyl-CoA,which can be converted to
succinyl-CoA (a citric acid cycle intermediate) by
the catalysis of of uracil and cytidine produces
malonyl-CoA,which is one precursor for fatty acid
biosynthesis,
? To a limited extent,catabolism of pyrimidine
nucleotides contributes to the energy metabolism
of the cell,
Propionyl-CoA Succinyl-CoA
Degradation products of
pyrimdines can enter the
citric acid cycle
二、核苷酸的生物合成
1,Nucleotides are synthesized via
either the de novo pathways or the
salvage pathways
? In the de novo pathway simple precursors,
including amino acids,PRPP,NH4+,CO2,
and one-carbon units (carried on H4 folate)
are used,
? In the salvage pathway the free bases and
nucleosides released from nucleic acid
breakdown are used,
? The free bases (A,G,C,U,T) are not
intermediates during the de novo synthesis,the
purine ring is assembled on ribose phosphate to
make AMP and GMP; the pyrimidine ring is first
synthesized as orotate（ 乳清酸 ）,which is then
attached to ribose phosphate before being
converted to UTP and CTP (dTMP is made from
dUMP),
? The deoxyribonucleotides (dNDPs) are
synthesized by reduction of ribonucleotides
(NDPs),
2,Radioisotope tracer(放射同位素示踪 )
experiments revealed the origins of the
atoms in the purine and pyrimidine rings
? Buchanan and Greenberg revealed this by
feeding a variety of isotopically labeled
compounds to pigeons (1940s),
? The atoms of the purine rings were found to be
derived from formate,CO2,Gly,Asp,and Gln,
? The atoms of the pyrimidine rings were found to
be derived from Asp,Gln and HCO3-,
Radioisotope tracer experiments revealed
the origins of the ring atoms of purines
Gln amide
HCO3-
C
The atoms of the pyrimidine rings were revealed to
Be derived from HCO3-,Gln and Asp,
3,De novo purine nucleotide synthesis
begins with the transferring of an
amino group from Gln to PRPP
? PRPP is synthesized from ribose 5-P,
? In the first (committing) step of purine nucleotide
synthesis,the PPi part on PRPP (at C-1) is
replaced by the side chain amino group of Gln,
forming 5-phosphoribosylamine,
? A glycine (2C +1N),a N10-formyl H4 folate (1C),a
Gln (1N),a HCO3-(1C) Asp (1N),and another N10-
formyl H4 folate (1C) then brings the rest atoms
for the purine ring,
? The first intermediate having a complete
purine ring is IMP (次黄嘌呤核苷酸 ),
? IMP is converted to AMP by accepting an
amino group from Asp,and converted to
GMP by a NAD+-dependent
dehydrogenation reaction (at C-2) and an
amino group transfer from Gln (catalyzed
by an amidotransferase),
? The production of AMP from IMP requires
GTP,and the production of GMP from IMP
requires ATP,
PRPP is synthesized from ribose 5-P in a
Reaction catalyzed by PRPP synthetase,
The purine ring is built up one or a few atoms at
a time on ribose 5-P
Steps 1,3,and 5 are
catalyzed by one
multifunctional protein
in some eukaryotic cells,
IMP is first
formed and
is then converted
to AMP and
GMP,
Steps 7 and 8 are
catalyzed by one
protein in some
eukaryotic cells
Steps 10 and 11 are
catalyzed by one protein
in some eukaryotic cells
IMP is converted to AMP by accepting an amino
group from Asp (GTP is needed to activate Asp) and to
GMP by accepting an amino group from Gln (ATP is
needed to activate XMP)
4,The biosynthesis of AMP and GMP is
regulated by feedback inhibition
PRPP synthetase and glutamine-PRPP
amidotransferase are both inhibited by the
end products IMP,AMP and GMP (AMP and
GMP act synergistically),
AMP inhibits adenylosuccinate synthetase
and GMP inhibits IMP dehydrogenase,
AMP and GMP synthesis is balanced by the
following mechanism,GTP is needed for
AMP synthesis and ATP for GMP synthesis,
The de novo synthesis
of AMP and GMP
is regulated mainly
by sequential feedback
Inhibition,
5,The de novo biosynthesis of
pyrimidines begin with the formation
of carbamoyl phosphate
? Carbamoyl phosphate is formed from Gln,HCO3-,
and ATP in a reaction catalyzed by the carbamoyl
phosphate synthetase II（ 氨甲酰磷酸合成酶 II ）,
? In the committing step of pyrimidine biosynthesis,
carbamoyl phosphate condenses with Asp to form
N-carbamoylaspartate in a reaction catalyzed by
aspartate transcarbamoylase (ATCase 天冬氨酸转
氨甲酰酶 ),
? A ring closing reaction generates L-
dihydroorotate,which is then oxidized to
form orotate (乳清酸 ) in a reaction catalyzed
by dihydroorotate dehydrogenase,
? Orotate is then linked to PRPP to form
orotidylate,which is then converted to UMP
by a decarboxylation reaction,
? CTP is derived from UTP by accepting an
amino group from Gln or NH4+,
? In eukaryotic cells,carbamoyl phosphate
synthetase II,aspartate transcarbamoylase,
dihydroorotase,and are part of a
trifunctional proteins called CAD,
? When PALA,an ATCase inhibitor was
added to cultured mammalian cells,
concentrations of all three enzymes are
increased dramatically for cells resistant to
PALA,
Gln
HCO3-+ATP
NH4+
Carbamoyl phosphate
Intermediates in
bacterial carbamoyl
phosphate synthetase
is channeled,
6,Pyrimidine nucleotide biosynthesis
is regulated at the aspartate
transcarbamoylase (ATCase)
? ATCase is inhibited by CTP,the end
product of the de novo pyrimidine
nucleotide biosynthesis pathway,
? CTP binds at the regulatory subunits,
which changes the conformation of the
catalytic subunits,inactivating them,
? ATP is able to prevent the changes
induced by CTP,
ATCase contains separate catalytic and
regulatory subunits
Catalytic
Subunits (binding Asp and carbamoyl phosphate)
Regulatory subunits (binding CTP or ATP)
7,Base specific NMP kinases together
with a nonspecific NDP kinase converts
NMPs to NTPs
? Nucleotides participate in biosynthesis (of
RNA and DNA) in the forms of NTPs,
? Each specific nucleoside monophosphate
(NMP) kinase converts the corresponding
NMP/dNMPs to NDP/dNDPs using ATP,
? The nonspecific nucleoside diphosphate
(NDP) kinase converts all NDP/dNDPs to
NTP/dNTPs using ATP or other NTPs,
8,Deoxyribonucleotides are made
from ribonucleotides at the NDP level
? This occurs by direct reduction at the 2`-
carbon,
? Ribonucleotide reductase catalyzes all such
conversions,
? The electrons are provided by NADPH and
is transferred to the ribonucleotide
reductase via two possible paths (via either
thioredoxin or glutaredoxin),
NDPs are converted
to dNDPs with the
catalysis of
ribonucleotide
reductase,with
electrons ultimately
coming from
NADPH
Electrons are transferred from NADPH to the ribonucleotides
Via thioredoxin
(硫氧还蛋白 ）
Via glutaredoxin
(谷氧还蛋白 ）
Ribonucleotide
reductase is a
tetramer of two
different subunits
The R2 dimer of
ribonucleotide reductase,
with a Tyr radical and a
Fe3+-Fe3+ binuclear center,
Tyr radical
Fe3+-Fe3+
A proposed
mechanism for
converting a
NDP to a dNDP
by ribonucleotide
reductase,the
radical property
of the enzyme is
transiently
transferred to the
substrate; the
presence of the
radical at C-3
stabilizes the
carbon cation
formed at C-2,
Both the substrate specificity and
the overall enzymatic activity of
ribonucleotide reductase is
regulated to balance the
biosynthesis of all nucleotides,
9,dTMP is synthesized by methylation
of dUMP
? dUTP is first formed from either dUDP (via
phosphorylation) or dCTP (via deamination),
? dUMP is then formed from dUTP in a reaction
catalyzed by dUTPase (keeping dUTP at a low
level to prevent its incorporation into DNA),
? dUMP is then converted to dTMP by the catalysis
of thymidylate synthase（ 胸腺嘧啶核苷酸合酶 ）,
with a methylene group transferred from and
reduced by N5,N10-methylene H4 folate (being
donors of both one-carbon unit and electrons!),
? The dihydrofolate is reduced to H4 folate by
NADPH in a reaction catalyzed by dihydrofolate
reductase (DHFR),
? The N5,N10-methylene H4 folate is regenerated
from Ser and tetrahydrofolate in a reaction
catalyzed by serine hydroxymethyltransferase,
? The reactions catalyzed by ribonucleotide
reductase and thymidylate synthase are
probably key for the transition from an RNA
world to one in which DNA stores genetic
information,
dTMP is derived from dUMP via a methylation
reaction using N5,N10-methylene H4 folate as
donors of both one-carbon unit and electrons,
dUMP is converted to
dTMP in a N5,N10-
methylene H4 folate-
dependent reaction
catalyzed by
thymidylate synthase,
三、嘌呤和嘧啶碱基的再利用（ 核苷
酸合成的节约途径 ）
Purine and pyrimidine bases can be reconverted into
nucleotides via the salvage pathway
? Adenine phosphoribosyltransferase catalyzes the
synthesis of AMP from adenine and PRPP,
? Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
catalyzes the synthesis of GMP and IMP,
? The lack of HGPRT will cause Lesch-Nyhan syndrome,
? Pyrimidine bases are recycled in a similar way in
microorganisms,but pyrimidine bases does not seem to
be salvaged in significant amounts in mammals,
The purine bases can be converted
to purine nucleotides via the
salvage pathways
四, Many cancer chemotherapeutic（ 化
学疗法 ） drugs target enzymes in the
nucleotide biosynthetic pathways
? Analogs of Gln,like azaserine and acivicin,
inhibits many amidotransferases used in
nucleotide (and amino acid) biosynthesis,
? Fluorouracil,after being converted to FdUMP by
the salvage pathway,can inhibit the thymidylate
synthase after two steps of conversion,thus
inhibit the dTMP synthesis,
? Methotrexate,a folate analog,inhibits the
dihydrofolate reductase,thus the dTMP synthesis,
Azaserine and acivicin
inhibits amidotransferases,
thus inhibit the biosynthesis
of nucleotides and amino
acids,
FdUMP (from fluorouracil)
and methotrexate inhibits
thymidylate synthase and
DHFR respectively,
FdUMP is an suicide inhibitor of
thymidylate synthase
? Summary
? Purine nucleotides are synthesized from PRPP,Gln,
Gly,N10-formyl H4 folate,Gln,HCO3-,Asp through
the de novo pathway,
? Pyrimidine nucleotides are synthesized using
HCO3-,Gln,Asp,and PRPP,
? De novo synthesis of nucleotides are regulated via
feedback inhibition (no covalent modifications yet
revealed),
? Deoxyribonucleotides are derived from
ribonucleotides at the NDP level,with the catalysis
of ribonucleotide reductase,which contains a
chain of electron carriers,uses free radicals,and
being regulated for both substrate specificity and
overall enzymatic activities,
? The dTMP molecule is derived from dUMP by
thymidylate synthase,an enzyme using N5,N10-
methylene-tetrahydrofolate as the donor of both
one-carbon unit and electrons,
? Degradation of purines and pyrimidines produces
uric acid and citric acid cycle intermediate/fatty
acid synthesis precursor,respectively,
? Purine and pyrimidine bases can be reused via
the salvage pathway,
? Many cancer chemotherapeutic drugs (e.g.,
azaserine,acivicin,fluorouracil,and methotrexate)
inhibits enzymes in the nucleotide biosynthetic
pathways,
