2nd metabolism of nucleotides

8/18/2019 2nd Metabolism of Nucleotides

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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 '&/

2nd metabolism of nucleotides

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