Post on 06-Jul-2018
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There are two pathways leading tonucleotides
De novo synthesis: The synthesis ofnucleotides begins with their
metabolic precursors: amino acids,ribose-5-phosphate, CO2, and one-carbon units
!alvage pathways: The synthesis ofnucleotide by recycle the free basesor nucleosides released from nucleic
acid brea"down
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2 !ynthesis of #$%
&'
'
'
'
(-5-% %(%%
)T% )$%
%(%%"inase
*ln *lu
amidotransferase5-phospho-
ribosylamine
+%(),
stepsO
(- 5.-%
+ #$% ,
inosine 5-monophosphate
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/ !ynthesis of )$% and *$%
#$%
0$%
&2O
)T%*ln *lu
)denylsuccinate 1)$%!13
)$%! lyase
4umarate
*$% synthetase
')D &2O
&'
'
'
'
'&
(-5.-%
&'
'&
'
'
O
(-5.-%
C&&OOC C&2 COO&
O
&'
'&
'
'
O
(-5.-%
)$%
&'
'
'
'
'&2
(-5.-%
*$%
&'
'
'
'&2'
O
(-5.-%
*T%)sp
')D& &
)$%!synthetase
#$%dehydrogenase
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6 27 De novo synthesis• !ite: in cytosol of liver , small
intestine and thymus
• Characteristics:
a %urines are synthesi8ed using 5-phosphoribose as the startingmaterial step by step
b %(%% is active donor of (-5-%
c )$% and *$% are synthesi8edfurther at the base of #$%
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7 9lement sources of purine bases
'
C
'
C
CC
'
C
'
CO2
Onecarbonunit
Gln
Gly
Asp
1
23
4
5 7
89
6
Onecarbonunit
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(egulation of de novo synthesis of
purine nucleotides
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The course of salvage pathway :
adenosine )$%
)T% )D%
adenylate "inase
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%entose
1´
2´3´
4´
5´O&
OC&2O&
O& O&
-D-ribose
O&O
C&2O&
O&
-D-2-deoyribose
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6 2 ; 4ormation of
deoyribonucleotide• 4ormation of deoyribonucleotide
involves the reduction of the sugarmoiety of ribonucleosidediphosphates +)D%, *D%, CD% or
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!
!
&2O$g2
')D%& &')D%
!&!&thioredoin
ribonucleotide reductase
'D%1'=), *, C,
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(egulation of ribonucleotide reductase
CDP dCDP dCTP
ATP
UDP dUDP dTTP
GDP dGDP dGTP
ADP dADP dATP
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!ummary of purine biosynthesis
d)T%
d*T%
AMP
GMP
ADP
GDP
dADP
dGDP
#$%)T%
*T%
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6 2 5 )ntimetabolites of purine
nucleotides • )ntimetabolites of purine
nucleotides are structural analogs of
purine, amino acids and folic acid They can interfere, inhibit or bloc"synthesis pathway of purine
nucleotides and further bloc"synthesis of ('), D'), andproteins
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7 %urine analogs
• ?-$ercaptopurine +?-$% is a analogof hypoanthine
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?-$% ?-$% nucleotide
de novo synthesis
salvage pathway
&*%(T
amidotrans!ras!
#$%
)$% and *$%
-
-
-
-
-
• ?-$% nucleotide is a analog of #$%
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2 )mino acid analogs
• )8aserine +)! is a analog of *ln
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/ 4olic acid analogs
• )minopterin +)% and $ethotreate +$T0
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folate 4&2 4&;
')D%& &
')D%')D%& &
')D%
4&2 reductase 4&2 reductase
)% or $T0
- -
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!ection / Catabolism
of %urine 'ucleotides
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nucleotide
nucleotidase&
2O
%i
nucleosidenucleoside
phosphorylase
%i (-7-%
purine
(-5-%
%(%%
pentose phosphatepathway
salvage pathway
o:idation
uric acid
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'
&C'
C
CC
'
C&
'
'&2
(ibose-%
)$%
&'
&C'
C
CC
'
C&
'
O
(ibose-%
#$%&'
&C
'
C
CC
'&
C&
'
O
&'
C'&
C
CC
'&
C&
'
O
O
&'
C'&
C
CC
'&
C
'
O
O
O
*$%
&ypoanthine
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•
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•The disease gout, is a disease of the Boints, usually in males, caused by anelevated concentration of uric acid inthe blood and tissues The Boints
become inflamed, painful, and arthritic,owing to the abnormal deposition ofcrystals of sodium urate The "idneys
are also affected, because ecess uricacid is deposited in the "idney tubules
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&'
&C
'
C
CC
'
&
C&
'O
&ypoanthine
&'
&C
'
C
CC
'
&
'
&C
O
)llopurinol
)llopurinol a suicide inhibitor used to treat *out
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!ection ; !ynthesis of
%yrimidine 'ucleotides
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6 ;7 De novo synthesis
Characteristics:• The en8ymes mostly lie in cytosol, but
some en8ymes eist in mitochondria
• The pyrimidine ring is first synthesi8ed,then combines with %(%%
•
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'
'&7
/2
;5
?
>ase: %yrimidine
Cytosine +C
'
'&
'&2
O
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7 9lement source of pyrimidine
base
'
C'
C
CC
1
2
34
5
6
)spCO2
Gln
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2 !ynthesis of
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C%!Ⅰ C%!Ⅱ
location Mit( live
r) Cytosol (all
the cell)
source ofnitrogen
NH3 Gln
allosteric
agent AGA none
function urea
synthesis pyrimiine
!iosynthesis
Difference of carbamoyl phosphate synthetase andⅠ Ⅱ
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&'
'
O
O
&'
'
O
OCOO&
&'
'&
O
O COO&
&'
C '&
C
C&2C
O
O COO&&
'&2
C'&
C
C&2C
O
O COO&&
&O'&2C
&2'C
C&2COO
COO&&
&OO %
carbamoylphosphate
carbamoylaspartate
&2O
dihydroorotase
dihydroorotate')D5
')D&&5
orotic acid
%(%%
%%i
orotidinemonophosphate 1O$%13
CO2
O$%decarbo:ylase
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/ !ynthesis of CT%
)midation at the nucleoside triphosphatelevel
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; 4ormation of dT$%
The immediate precursor ofthymidylate +dT$% is d
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dT$% synthesis at the nucleoside
monophosphate level
d
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5 (egulation of de novo synthesis
carbamoyl phosphate
carbamoyl aspartate
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CTP
!ummary of pyrimidine biosynthesis
UDP UTP
CDP
dUDP
dCDP
dUMP
dCMP
dTMP
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6 ; 2 !alvage pathway
)T%
)T%
)T%
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6 ; / )ntimetabolites of
pyrimidine nucleotides • )ntimetabolites of pyrimidine
nucleotides are similar with them ofpurine nucleotides
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7 %yrimidine analogs
• 5-fluorouracil +5-4
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5-4<5-4d
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2 )mino acid analogs
• )8aserine +)! is a analog of *ln
,inhibits the synthesis of CT%
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/ 4olic acid analogs
• $ethotreate +$T0 inhibits the synthesisof dT$%
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; 'ucleoside analogs
• )rabinosyl cytosine +ara-c inhibitsthe synthesis of dCD%
'
'
'&2
O
ara-c
O
&
O& &
&
C&2O&
& O&
'
'
'&2
O
cytosine
O
&
O& O&
&
C&2O&
& &
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!ection 5 Catabolism of
%yrimidine 'ucleotides
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&2O&2O
&2' C&2 C&2 COO& &2' C&2 C& COO&
C&/
'
'&
O
'&2&2O '&/
&'
'&
O
O
C&2
C&2'&2
'&
O
&OOC
&'
'&
O
O
C&/
C&2
C&'&2
'&
O
&OOCC&/
cytosine uracilthymine
FG-ureidopropionate
FG-ureido-isobutyrate
CO2 '&/