2. metab purin- pirimidin

7/21/2019 2. Metab Purin- Pirimidin

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Purin, Pirimidin

dan AsamNukleat

RETNO SINTOWATI


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Purin, Pirimidin, Asam nukleat

I. Pendahuluan

II. Basa Purin dan Basa Pirimidin

III. Nukleosida

IV. Nukleotida

V. Asam Nukleat


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I. Pendahuluan

Nukleoprotein

protein majemukterdapat dalam inti selpenyusun material inti seltersusun atas $

protein$ histon % protamin

gugus non proteinsemua sel hidup mengandung nukleoprotein

KromatinKonstituen penting dalam sel" tersusun atas

nukleoproteinkelainan pembentukan nukleoprotein

perubahan dlm pertumbuhan %reproduksi sel

sebab kromatin pembelahan sel


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Nukleoprotein

Enzim proteolitik Protein sederhana Asam nukleat

trtm$ histon & protamin 'RNase / DNase)

polinukleotidapolinukleotidase

(fosfoesterse)mononukleotida

purin/pirimidin nukleotidase(fosfatas

nukleosida asam (os(at

'fosforilase)basa purin%basa pirimidin gula 'ribosa%deoksi ribosa)


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Adenosin *uanosin

adenosin deaminase purin nukleosidafosforilase

N+, Inosin *uanin purin nukleosida fosforilase

+ipo#antin Xantin oksidase -antin /0 asam uraturin

Xantin oksidase


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Penyelamatan Purin

Untuk pembentukan nukleotida bbrp jaringan

manusiatgt pd purin %purin ribonukleosida eksogen

Ada 2 jalan penelamatan !

1. 2os(oribosilasi purin bebas dgn en3im yang

membutuhkan P4PP sbg donor ribosa (os(at

0. 2os(orilasi nukleosida purin pd gugus 56hidroksioleh en3im adenosin kinase

"onto# !

,. Adenin menjadi A7P dg en3im adenin(os(oribosa trans(erase

8. +ipo#antin dan *uanin menjadi I7P dan *7Pdengan en3im hipo#antinguanin (os(oribosa

trans(erase


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Nukleosida pirimidin

!itidin 9eoksisitidin

deaminasiUridin deaminasi

9eoksiuridin9eoksitimidin

fosforilse

Urasil dan :imin de$radasi

alanin N+%&;/2 de$radasi As. amino isobutirat

N+%&;/2

urine

Banyak tdp pd penderita tumor yang dikhemoterapi


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.Pirimidin

Basa PurinBasa heterosiklis " molekul planar " aromatiksebag. besar tdp. dlm sel dlm. bentuk asam

nukleat

disintesis seara de novo" dg sumber $N'dari as. Aspartat";dr ;/2respirasi"Ndari glisin";*dari N+"N'metenil2+%,N-dan N.dari nitrogen amida der. *lutamin dan;2dari N(ormil tetrahidroksi (olat

9iberi nomor mulai atom N'kearah kebalikanjarum jam


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asaPirimidinnama lebih panjang dari purin ttp hy

mgd < atom yang heterosiklis" sedangpurin

nama pendek mgd = atom heterosiklis

!itosin '!)$ tdp dlm semua asam nukleat"keuali 9NA >irus ttt

:imin ':) $ trtm tdp dlm as nukleat

yg mgd gula deoksiribosa '9NA)?

sedikit tdp dlm t4NAUrasil 'U)$ tdp dalam 4NA


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Nitrogenous BasesPlanar" aromati" and heteroyli

9eri>ed (rom purine or pyrimidine

Numbering o( bases is @unprimed


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Nulei Aid BasesPurines Pyrimidines


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!ugarsPentoses '5; sugars)

Numbering o( sugars is @primed


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!ugars 94ibose and 069eo#yribose

*Lacks a 2-OH group


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Nuleosides4esult (rom linking one o( the sugars with a

purine or pyrimidine base through an Nglyosidi linkage

Purines bond to the ;16 arbon o( the sugar attheir N= atoms

Pyrimidines bond to the ;16 arbon o( the sugarat their N1 atoms


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Nuleosides


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Phosphate *roups7ono" di or triphosphates

Phosphates an be bonded to either ;, or ;5atoms o( the sugar


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Nuleotides4esult (rom linking one or more

phosphates with a nuleoside onto the 56end o( the moleule through

esteriation


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0001 Nukleosida dan nukleotidaNukleosida$

tdr daribasa dribosa gula ribosaterikat

padaN.basa purin dan pada N'basa

pirimidin 'keuali U pd ;+ ikatan ;;)dan semuanya mrpk ikatan Nglikosidik

Nukleosida yang diman(aatkan untuk

menghambat pertumbuhan sel$ 5Cuorourasil 56iodo06

deoksiuridin


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Nukleotida7rpk unit struktural as nukleat" mrpk komponen seluler

yg mudah dpt diketahui krn menyerap kuat sinar UV" der.

basa purin absorbsinya lebih kuat dari der. basa pirimidin:ersusun$ basa purin% basa pirimidin

gula 'ribosa atau 0deoksiribosa)"

asam (os(at

Pengikatan (os(at$ 4NA pd at ;-dari gulanya

9NA pd at ;+dari gulanya

asa Nukleosida Nukleotida3in$katan

RNADNA

Adenin Adenosin Asam adenilat A

dA

4uanin 4uanosin Asam $uanilat 4

d43itosin 3itidin Asam 3itidilat "


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7anjutan nukleotida

bentuk nukleotida lebih mudah larut dalam air dp nukleosidadan basa bebasnya

8un$si nukleotida1. Berperan dlm metabolisme energi

;ontoh$ A:P bentuk energi kimia yang diperlukan untuk sel" dihasilkan dari (os(orilasi

oksidati( atau (os(orilasi tingktsubstrat

terlibat dalam kontraksi otot

transport akti(

mempertahankan gradien%ion

membantu sbg donor (os(at untuksin

tesis nukleosida 56tri(os(at

substrat untuk reaksi yg dikatalisis

oleh 4NA dan 9NA polimerase


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7anjutan fun$si nukleotida

0. 7onomer unit asam nukleat$ 9NA dan 4NA

,. 7ediator siologik$ nukleosida dan nukleotidamembantu sbg kuni mediator siologik prosesmetabolik$

adenosin penting dlm kontrol aliran darahkoroner

A9P criticaldlm agregasi platelet dankoagulasi

darah

A7P & *7P$ bekerja sbg second messenger

*:P$ diperlukan untuk apping m4NA

8. Preursor (untion$ *:P adalah prekursorpemben

tukan ko(aktor" tetrahidrobiopterin" untuk reaksihidroksilasi dan generasi oksida nitrat


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7anjutan fun$si nukleotida


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7anjutan sintesis nukleotida

I7P A7P energinya dari *:P

I7P *7P energinya dari A:P Apabila terjadi de(ek dlm reaksi

metabolik menyebabkan kehilanganpengaturan sintesis nukleotida purin

o>er produksi purin asam uratmeningkat

Artritis gout

Pem9entukan deoksi ri9onukleotida

pada keadaan sel tidak proli(erasirendah

pada saat replikasi sintesis 9NA sintesis

deoksiribonukleotida meningkat untuk

u


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. u(Polinukleotid)

dibentuk dari ikatan (os(odiester ygterikat pada ;,6 dan ;56 monomer ygberdekatan

ada mol. yg berakhir 56 dan ,6

masingmasing mol. memp. strukturprimernya" ontoh 56,6p *p *p Ap :p;p A

Ada 0 maam asam nukleat besar$ 9NA& 4NA


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Nu:leotida!3nt#esis danDe$radasi


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Nuleotide 7etabolism

PU4INE 4IB/NU;FE/:I9E!$ (ormed denovoi.e." purines are not initially synthesi3ed as (ree

bases2irst purine deri>ati>e (ormed is Inosine 7ono

phosphate 'I7P) 6#e purine 9ase is #po;ant#ine A


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Purine Nuleotides*et broken down into Uri Aid 'a purine)

Buhanan 'mid 1=GGs) showed wherepurine ring omponents ame (rom$

N1: Aspartate Amine

C2, C8: Formate

N3, N: !"utamine

C#, C$, N%: !"&cineC': (icar)onate on


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Form&"-+HFForm&"-+HF

N

N

C

C

C

CC

N

NH

H

H

H

H

H

!"utamine !"utamine

Aspartate

CO2!"&cine


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HN

N

C

C

C

C

C

N

NH

H

H

H

H

H

urine

N

N

C

C

C

C

H

H

H

H

&rimiine

H

H

!"&cine

!"utamine .2/

Aspartate

N10-Form&"-+HF .2/

CO2

!"utamine

Aspartate

CO2

.C$H%N#/ .C#H'N2/

P i N l tid 3 t# i

O


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Purine Nu:leotide 3nt#esis

OH

H

H

CH2

OH OH

H HO

O2-

O3

--i)ose-$-ospate .$/

O

H

H

CH2

OH OH

H HO

O2-

O3

$-ospori)os&"--p&ropospate ./

O

O

O

O

O

O

A+

A4

i)ose

ospate

&ropospokinase

H

NH2

H

CH2

OH OH

H HO

O2-

O3

-$-ospori)os&"amine .A/

Amiopospori)os&"+rans5erase

!"utamine6 H2O

!"utamate

6 i

H

NH

H

CH2

OH OH

H HO

O2-

O3

CO

H2C NH2

!"&cinamie i)otie .!A/

!A 7&ntetase

!"&cine6 A+,

A1,

6 ,i

H2C

C

NH

O

CH

HN

O

i)ose-$-ospate

Form&"g"&cinamie ri)otie .F!A/

H2C

C

NH

O

CH

H

N

HN

i)ose-$-,ospate

Form&"g"&cinamiine ri)otie .F!A4/

+HFN10

-Form&"-+HF

!A2 +rans5orm&"ase

A+ 6

!"utamine6

H2O

A 6

!"utamate 6 iF!A4

7&ntetase

HC

CN

CH

N

H2N

i)ose-$-ospate

#

$

$-Aminoimiao"e i)otie .A/

A+

A 6 i

A7&ntetase

C

CN

CH

N

H2N

OOC

i)ose-$-ospate

#

$

Car)o9&amioimiao"e i)otie .CA/

A+

6HCO3

A 6 iA

Car )o9&"ase

Aspartate

6 A+A

6 i

7ACA 7&ntetase

Aen&"osuccinateL&ase

Fumarate

C

CN

CH

N

NH

i)ose-$-ospate

#

$

$-Formaminoimiao"e-#-car)o9amie

ri)otie .FACA/

CH2N

O

C

H

O

C

CN

CH

N

H2N

i)ose-$-ospate

#

$

$-Aminoimiao"e-#-car)o9amie

ri)otie .ACA/

CH2N

O

C

CN

CH

N

H2N

CN

H

HC

COO

CH2

COO

i)ose-$-ospate

#

$

$-Aminoimiao"e-#-.N-succin&"ocar)o9amie/

ri)otie .7ACA/

+HF

ACA+rans5orm&"ase

N10

-Form&"-

+HF

nosine 4onopospate .4/

HN

HC

N

C

C

C

N

CH

N

O

#

$

HH

CH2

OH OH

H HO

O2-

O3

4

C&c"o&ro"ase

H2O


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Ribose-P

HCN

C

CC

N

N

CH

N

NH2

Ribose-P

CN

C

CC

HN

N

CHN

O

HO

Ribose-P

CN

C

C

C

HN

N

CH

N

O

H2N

Ribose-P

HCN

C

CC

HN

N

CH

N

O GTP

Aspartate

GDP + Pi

Fumarate

ATPGlutamine

ADP + PiGlutamate

H2O + NAD+

NADH +H+

A4

!4

4 is conerte to A4 or !4

4

;4


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Re$ulator "ontrol of PurineNu:leotide iosnt#esis*:P is in>ol>ed in A7P synthesis and A:P is

in>ol>ed in *7P synthesis 'reiproal ontrol o(prodution)

P4PP is a biosynthetially @entral moleule

'whyH)A9P%*9P le>els negati>e (eedbak on 4ibose Phosphate

Pyrophosphokinase

Amidophosphoribosyl trans(erase is ati>ated by P4PPle>els

AP4: ati>ity has negati>e (eedbak at two sites A:P" A9P" A7P bound at one site *:P"*9P AN9 *7P bound at the other site

4ate o( A7P prodution inreases with inreasing

onentrations o( *:P? rate o( *7P prodution


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4egulatory ;ontrol o( Purine

BiosynthesisAt le>el o( I7P prodution$

Independent ontrol

!ynergisti ontrol

2eed(orward ati>ation by P4PP

Below le>el o( I7P prodution4eiproal ontrol

:otal amounts o( purine nuleotidesontrolled

4elati>e amounts o( A:P" *:P ontrolled


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Purine ;atabolism and !al>ageAll purine degradation leads to uri aid 'but it

might not stop there)Ingested nulei aids are degraded by panreati

nuleases" and intestinal phosphodiesterases inthe intestine*roupspei nuleotidases and nonspei

phosphatases degrade nuleotides intonuleosides9iret absorption o( nuleosides2urther degradation

Nuleoside +0/ base ribose 'nuleosidase)

Nuleoside Pibase r1phosphate 'n.

phosphorylase)

N=6E!


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Intraellular Purine ;atabolismNuleotides broken into nuleosides by

ation o( 56nuleotidase 'hydrolysisreations)

Purine nuleoside phosphorylase 'PNP)Inosine +ypo#anthine

-anthosine-anthine

*uanosine*uanine4ibose1phosphate splits oJ

;an be isomeri3ed to ribose5phosphate

Adenosine is deaminated to Inosine 'A9A $

Adeosine deaminase)


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Intraellular Purine ;atabolism-anthine is the point o( on>ergene (or

the metabolism o( the purine bases

-anthine Uri aid-anthine o#idase ataly3es two reations

Purine ribonuleotide degradation pathway issame (or purine deo#yribonuleotides


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Aenosine egraation


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-anthosine 9egradation

i)ose sugar gets rec&c"e .i)ose-1-ospate-$- /

< can )e incorporate into .e55icienc&/ H&po9antine is conerte to ;antine )& Xanthine Oxidase !uanine is conerte to ;antine )& !uanine eaminase ;antine gets conerte to Uric Acid)& Xanthine Oxidase


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*7P A7P

*uanosin I7P

Inosin

*uanin +ipo#antin

L

-antin

L

Asam urat M U4IN

Ltmp kerja #antin o#idase" dihambat oleh Alopurinol


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Uri Aid E#retion+umans e#reted into urine as insolublerystals

Birds" terrestrial reptiles" some insets e#rete insoluble rystals in paste (orm'hewan urikotelik)E#ess amino N on>erted to uri aid

/thers (urther modiation $

Uri Aid Allantoin Allantoi Aid Urea Ammonia

Ekskresi asam urat total man 8GG


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Purine !al>age

'Jalur penyelamatan purin)Adenine phosphoribosyl trans(erase 'AP4:)

Adenine P4PP A7P PPi

+ypo#anthine*uanine phosphoribosyltrans(erase '+*P4:)

+ypo#anthine P4PP I7P PPi*uanine P4PP *7P PPi

'N/:E$ :+E!E A4E AFF 4EVE4!IBFE 4EA;:I/N!)

A7P"I7P"*7P do not need to beresynthesi3ed de novo !


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9i hati $ nukleotida de(os(orilasinukleosida

!ering nukleosida diputus basa bebas gula

nukleosida & basa dibawa ke jar lain

re(os(orilasi mjd nukleotida

Basa bebas diselamatkan dg mereaksikan dgP4PP nukleotida baru

En3im penghemat basa tsb +*P4:4eaksi analog juga terjadi utk pirimidin


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A ;A!E !:U9 $ */U:A 85 EA4 /F9 7AN AO/KE 24/7 !FEEP OI:+ A PAIN2UFAN9 !O/FFEN 4I*+: *4EA: :/E. /N :+E P4EVI/U! NI*+:+E +A9 EA:EN A 7EAF /2 24IE9 FIVE4 AN9 /NI/N!" A2:E4O+I;+ +E 7E: OI:+ +I! P/KE4 *4/UP AN9 94ANK A

NU7BE4 /2 BEE4!.+E !AO +I! 9/;:/4 :+A: 7/4NIN*" @*/U: A4:+4I:I!

OA! 9IA*N/!E9" AN9 !/7E :E!:! OE4E /49E4E9. +I!!E4U7 U4I; A;I9 FEVEF OA! EFEVA:E9 A: .G mg%dF 'NF QD.G mg%dF).

:+E 7AN 4E;AFFE9 :+A: +I! 2A:+E4 AN9 +I!*4AN92A:+E4" B/:+ /2 O+/7 OE4E AF;/+/FI;!" /2:EN;/7PFAINE9 /2 R/IN: PAIN AN9 !OEFFIN* IN :+EI4 2EE:.


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A ;A!E !:U9 $ */U::+E 9/;:/4 4E;/77EN9E9 :+A: :+E 7AN U!EN!AI9! 2/4 PAIN AN9 !OEFFIN*" IN;4EA!E +I!2FUI9 IN:AKE 'BU: N/: OI:+ AF;/+/F) AN9

4E!: AN9 EFEVA:E +I! 2//:. +E AF!/P4E!;4IBE9 AFF/PU4IN/F.

A 2EO 9A! FA:E4 :+E ;/N9I:I/N +A94E!/FVE9 AN9 AFF/PU4IN/F +A9 BEEN

!:/PPE9. A 4EPEA: U4I; A;I9 FEVEF OA!/B:AINE9 'D.1 mg%dF). :+E 9/;:/4 *AVE :+E7AN !/7E A9VI;E 4E*A49IN* FI2E !:FE;+AN*E!.


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*outImpaired e#retion or o>erprodutiono( uri aidUri aid rystals preipitate intojoints '*outy Arthritis)" kidneys"

ureters 'stones)Fead impairs uri aid e#retion leadpoisoning (rom pewter drinkinggoblets2all o( 4oman EmpireH

-anthine o#idase inhibitors inhibitprodution o( uri aid" and treat gout

Allopurinol treatment hypo#anthineanalog that binds to -anthine /#idaseto derease uri aid prodution


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AFF/PU4IN/F I! A -AN:+INE /-I9A!E

IN+IBI:/4

A !UB!:4A:E ANAF/* I! ;/NVE4:E9 :/ ANIN+IBI:/4" IN :+I! ;A!E A @!UI;I9EIN+IBI:/4


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Pyrimidine 4ibonuleotide

!ynthesisUridine 7onophosphate 'U7P) is synthesi3ed

rst;:P is synthesi3ed (rom U7P

Pyrimidine ring synthesis ompleted rst?then attahed to ribose5phosphate

N1, C#, C$, C': Aspartate

C2: HCO3-

N3: !"utamine amie Nitrogen

&rimiine 7&ntesis


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2 A+, 6 HCO3-6!"utamine6 H2O

CO

O O3-2

NH2

Car)amo&" ospate

NH2

C

N

H

CH

CH2

C

COOO

HO

O

Car)amo&" Aspartate

HN

C

N

H

CH

CH2

C

COOO

O

i&roorotate

HN

C

N

H

C

CH

C

COOO

O

Orotate

HN

C

N

C

CH

C

COO

O

O

HH

CH2

OH OH

H H

OO

2-O3

Orotiine-$=-monopospate

.O4/

HN

C

N

CH

CH

C

O

O

HH

CH2

OH OH

H H

OO

2-O3

>riine 4onopospate

.>4,/

2 A1, 6

!"utamate 6

,i

Car)amo&"

,ospate

7&ntetase **

Aspartate

+ranscar)amo&"ase

.A+Case/

Aspartate

i

H2O

i&roorotase

?uinone

euce

?uinone1i&roorotate1e&rogenase

i

Orotate ospori)os&"

+rans5erase

CO2

O4

ecar)o9&"ase

& &


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U7P

U:P and ;:PNuleoside monophosphate kinaseataly3es trans(er o( Pito U7P to (orm

U9P? nuleoside diphosphate kinaseataly3es trans(er o( Pi(rom A:P to U9P to

(orm U:P

;:P (ormed (rom U:P >ia ;:P !ynthetasedri>en by A:P hydrolysis*lutamine pro>ides amide nitrogen (or ;8 in

animals


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4egulatory ;ontrol o(

Pyrimidine !ynthesisAnimals regulation at arbamoyl phosphatesynthetase IIU9P and U:P inhibit en3yme? A:P and P4PP

ati>ate it

U7P and ;7P ompetiti>ely inhibit /7P9earbo#ylase

SPurine synthesis inhibited by A9P and *9P at

ribose phosphate pyrophosphokinase step"ontrolling le>el o( P4PP also regulatespyrimidines


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/roti Aiduria

;aused by de(et in protein hain withen3yme ati>ities o( last two steps o(pyrimidine synthesis

Inreased e#retion o( oroti aid inurine!ymptoms$ retarded growth? se>ere

anemia/nly known inherited de(et in this

pathway 'all others would be lethal to(etus)

:reat with uridine%ytidine+/O 9/E! U4I9INE AN9 ;:I9INE

A97INI!:4A:I/N O/4K :/ :4EA: /4/:I;A;I9U4IAH

9 d i (


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9egradation o(

Pyrimidines;7P and U7P degraded to bases similarly topurines9ephosphorylation

9eamination*lyosidi bond lea>age

Urail redued in li>er" (orming alanine;on>erted to malonl>"oAfatt a:id

snt#esis (or energy metabolism

9 ib l tid


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9eo#yribonuleotide

2ormationPurine%Pyrimidine degradation are thesame (or ribonuleotides anddeo#yribonuleotides

Biosyntheti pathways are only (orribonuleotide prodution

9eo#yribonuleotides are synthesi3ed (rom

orresponding ribonuleotidesPd tingkat difosfat,gugus ribosa direduksi

mjd deoksiribosa o/ enz Ribonukleotidareduktase

e! "TP defosforilasi

"#P reduksi

d"#P


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Katabolisme pirimidin menghasilkan metabolityg dpt larut dalam air" yaitu $ ;/0" N+," Balanin"

Baminoisobutirat

Produk katab purin tidak begitu mudah larut"kelarutan ditingkatkan dg alkalinisasi.


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9a(tar Bahan 7akananKandungan purin tinggi HPurin sedang H

Purin rendah H

Bagaimana meningkatkan kelarutan asamurat dalam urin sehingga meningkat pula

ekskresinyaHBagaimana ara alkalinisasi urine H

2. metab purin- pirimidin

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