2. Metab Purin- Pirimidin
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Transcript of 2. Metab Purin- Pirimidin
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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