kuliah pur pir1
DESCRIPTION
Basic BiochemestryTRANSCRIPT
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METABOLISME PURIN DAN PIRIMIDIN
NUKLEOTIDA
BudiSusatia
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Kegunaan Biomedis
• Sebagai sumber energi (ATP dll)
• Bagian dari koenzim
• Sebagai regulator dan 2nd messenger
(cAMP dan cGMP)
• Sebagai penyusun RNA dan DNA
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Semua sel dalam tubuh dapat mensin-tesa purin dan pirimidin. Asam nukleat dari makanan akan di-katabolisme menjadi asam urat (purin)dan β-alanin atau β-amino isobutirat(pirimidin) dan CO2, NH3. Tidak ada purin atau pirimidin dari makanan yang digabung dgn asam nukleat jaringan.
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Purin
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Pirimidin
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NUKLEOSIDA
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Nukleosida yang lain
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Nukleotida
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Nukleotida yang lain
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BasaNukleosidaNukleotida
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PolinukleotidaTerikat dgn 3’-5’ fosfodiesterDNA double stranded anti paralel
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De novo sintesa Purin nukleotida
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Basa purin disintesa dalam bentuk nukleotida
Ribosa 5-fosfat dengan ATP akan membentuk 5-fosforibosil 1-pirofosfat (PRPP)
Enzim yg mengkatalisa : PRPP sintase Terjadi dalam banyak jaringan PRPP berfungsi : juga dlm sintesa pirimidin,
“salvage pathways”, NAD dan NADP Dipengaruhi oleh : Di dan Tri fosfat, 2,3 DP Gliserat
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Pembentukan IMP
1.PRPP + glutamin 5-fosforibosilamin (PRA) (glutamin-PRPP amidotransferase).
2.Gugus amino asilasi oleh glisin glisinamid ribonukleotida (GAR) (GAR sintase)3.Gugus formil dari 10-formiltetrahidrofolat pada N-7 menjadi Formilglisinamid ribonukleotida (FGAR) ( GAR transformilase)4.Amida diubah menjadi amidin, memerlukan ATP, glutamin sebagai sumber N formilglisinamidin ribonukleotida (FGAM) (FGAM sintase)
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5.Penutupan cincin (5), memerlukan ATP aminoimidazol ribonukleotida (AIR) (AIR sintase)
6.Pengikatan CO2 pada C-5, yang akan membentuk C-6, karboksiimidazol ribonukleotida (CAIR) (AIR karboksilase). Tidak memerlukan biotin. CO2 mula-mula diikatkan pada N-3, kemudian dipindah terikat pada C-5. Perlu ATP7 dan 8. Aspartat berkondensasi dengan karboksilat yang baru terbentuk menjadi suatu amida, aminoimidazol suksinilokarboksamida ribonukletida (SAICAR) (SAICAR sintase). Fumarat dipecah oleh enzim adenilosuksinat liase dan menghasilkan amino-imidazol karboksamida ribonukleotida (AICAR)
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9.Menyerupai tahap ketiga, 10-formiltetrahidrofolat menyerahkan gugus formil (-CH=O) pada gugus amino (N-3) dari aminoimidazol karboksamida ribonukleotida. (AICAR transformilase)10.Nitrogen dari amida berkondensasi dengan gugus formil, dan menutup cincin (6 sudut) purin. (IMP siklohidrolase)
Mulai tahap ke 1 hingga ke 10 memerlukan5 ATP, selain itu pembentukan PRPP juga memerlukan ATP. (Untuk mengubah glutamatMenjadi glutamin juga perlu ATP)
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PRPP + Gln PRA GAR
FGARFGAMAIR
CAIR SAICAR AICAR
FAICARIMP
1 2 3
456
7 89
10
2, 4, 5, 6, dan 7perlu ATP
Ringkasan de novo sintesa purin nukleotida
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Pembentukan AMP dan GMPIMP dapat diubah menjadi AMP atau GMPGMP. IMP dioksidasi menjadi XMP
(xanthosine) memerlukan NAD+
(IMP dehidrogenase)O pada 2 diganti N (glutamin). Perlu ATP (GMP sintetase)AMP.IMP dpt N (aspartat) mengganti O pd
pos. 6. (adenilosuksinat sintase)Perlu GTP. Fumarat lepas. (adenilosuksinat liase)
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Mekanisme kontrol pada de novo sintesa purin nukleotida
Fase pertama : thd amidotransferase
(oleh inhibitor-inhibitor dan atau PRPP)Pengaturan kadar ATP dan GTP
(ATP diperlukan dlm sintesa GMP
GTP diperlukan dlm sintesa AMP)Ada beberapa “feedback inhibition”
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FeedbackInhibition in
Purine NucleotideBiosynthesis
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Katabolisme dan “salvage” purin nukleotida
• Dalam usus : asam nukleat oleh ribonuklease atau deoksiribonuklease polinukleotida nukleotida (fosfodiesterase) nukleosida (nukleosidase) :
basa pur / pir + ribosa (lumen usus) basa pur / pir + Ribose 1-fosfat (dR 1-P) (dlm sel: nukleosid fosforilase) Basa Pur / Pir dipecah (usus, hepar) “salvage” nukleotidaR 1-P (dR 1-P) R 5-P (dR 5-P)R 5-P PRPP MHP Shunt
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Allopurinol menghambatXanthine oksidase danXanthine dehidrogenase
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Santin (Xanthine) oksidase : pd mammalia adalah enzim ekstra selluler.Mungkin suatu perubahan bentuk dari santin (xanthine) dehidrogenase (enzim intra selluler)
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Daur “salvage” (daur penyelamatandaur ulang):
AdeninGuaninHiposantin
Nukleotida
Adenin + PRPP AMP + PPi
Hiposantin + PRPP IMP + PPiGuanin + PRPP GMP + PPi
Adeninfosforibosiltransferase (APRT)
Hiposantin-guanin fosforibosiltransferase (HGPRT)
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Purin nukleotida fosforilase (arah kebalikan) dapat juga melakukan “salvage” (tidak signifikan).
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Sintesa AMP dari IMP, dan “salvage” IMP melalui katabolisme AMP menghasilkan aspartat menjadi fumarat.
Siklus ini penting dalam otot. Aktivitas otot meningkat, perlu ATP, TCA Cycle perlu lebih aktif, perlu senyawa antara (anggota siklus).
Otot kekurangan enzim-enzim anaplerotik.
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Dalam otot
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Masalah klinik metabolisme purin• Gout : Hiperurikemia, NaUrat mengendap dalam
cairan sinovial inflamasi, artritis. Lesch-Nyhan sindrom: gejala gout, mal- fungsi syaraf (retardasi mental), pada yg parah
“self-mutilation”. Meninggal sebelum mencapai usia 20 th.
Kehilangan fungsi gene HGPRT. Aktivitas enzim < 1%. Sex-linked. Ekskresi urat > 6x. Sintesa
purin de novo +++ (Hiposantin dan guanin urat, PRPP de novo sintesa (bisa untuk “salvage”.
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Severe combine immunodeficiency disease( SCID)SCID kekurangan adenosin deaminase (ADA).
(adenosin inosin). Limfosit B dan T rusak.Tidak ada ADA dAdenosin dATPdATP tinggi (50x) menghambat sintesa DNA.tidak bisa poliferasi.Penderita meninggal sebelum mencapai 1 th.
Penyakit Von Gierke’s.Kekurangan glukosa 6 fosfatase G 6P ↑ HMP Shunt Ribosa 5P PRPP Purin Asam urat
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Pirimidin
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De novo sintesa Pirimidin nukleotida
• Lebih sederhana dari sintesa purin PRPP ditambahkan setelah cincin
pirimidin terbentuk.Cincin pirimidin berasal dari :
Bikarbonat ( C-2 ), Amida glutamin ( N-3 ), aspartat ( C-4, C-5, C-6 dan N-1 )
Ada 6 tahap
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Tahap pertama : Glutamin + Bikarbonat + 2ATP Karbamoil fosfat + glutamat + 2ADP + Pi Enzim , karbamoil fosfat sintase II (CPS II), Berbeda dengan CPS I pada sintesa urea.
-Memakai glutamin-Tidak perlu N-asetil glutamat
Tahap kedua : Gugus karbamoil yg aktif di- transfer ke N dari aspartat karbamoil aspartat (aspartat transkarbamoilase ATCase)Tahap ketiga : Penutupan cincin (dihidroorotase) (enzim-enzim di sitoplasma)
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Tahap keempat : dihidroorotat dioksidasi menjadi orotat (dihidroorotat dehidrogenase), dipermu- kaan luar membran dalam mitokhondria Belum banyak diketahui, suatu enzim- kompleks.Tahap kelima : Orotat + PRPP Orotidin 5’-monofosfat (OMP) + PPi (orotatfosforibosil transferase O-PRT)Tahap keenam : OMP mengalami dekarbok- silasi Uridin 5’-monofosfat (UMP) (OMP dekarbosilase)
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Pembentukan CTP
UMP + ATP UDP + ADP (uridilat kinase)UDP + ATP UTP + ADP (nukleosida difosfat kinase)UTP + ATP CTP (CTP sintase)CTP sintase dihambat oleh CTP (feeback inhibition)
CTP juga dapat menghambat “secara parsial”Aspartat transkarbamoilase (ATCase)
Kadar CTP terkontrol sesuai dengan kebutuhan
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UMP UDP(ATP ADP)
UDP UTP(ATP ADP)
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Mekanisme kontrol pada de novo sintesa pirimidin nukleotida
Pada manusia : terutama pada CPSII
Dihambat oleh : UTP (UMP)
Diaktivasi oleh : PRPP OMP dekarboksilase : dihambat oleh
UMP dan CMP (pada keadaan normal tidak penting)
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Kontrol sintesaPirimidin di E. Coli
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Salvage pathways (daur ulang) pirimidin nukleotida.
• Pemecahan asam nukleat (tahap awal)
sama dengan purin.Ada dua tahap:
1.Basa + ribosa 1-fosfat Nukleosida +
Pi (nukleosida fosforilase)
2.Nukleosida + ATP Nukleotida + ADP
(nukleosida kinase)
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Interkonversi Nukleotida
Basa-monofosfat + ATP Basa-difosfat + ADP (nukleosida monofosfat kinase)
AMP + ATP 2 ADP (adenilat kinase)
Monofosfat hasil de novo sintesa, yang paling banyak diperlukan adalah bentuk trifosfat.
Nukleosida difosfat kinase (spesifitas luas) BDP + ATP BTP + ADP
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Pembentukan deoksiribonukleotida
• De novo sintesa dan sebagian besar jalur “salvage” melibatkan nukleotida (kecuali timin, sedikit sekali lewat jalur “salvage”
BDP direduksi pd pos. 2’ ribosa dBDP Enzim : nukleosida difosfat reduktase tioredoksin (thioredoxin)Tioredoksin teroksidasi + NADPH HS-T-SH + NADP
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Inhibitor dATP Aktivator : ATP (nonspesifik) Aktivator spesifik : BTP atau dBTP
Kebutuhan untuk pembentukan DNA terpenuhi
Enzim : Nukleotida difosfat reduktase
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Sintesa dTMP• dTMP (dTTP) tidak dibentuk dlm sintesa
de novo; alur “salvage” tidak cukupCDP dCDP dCMP dUMP 1 2 3 dTMP dTTP 1=nukleosida difosfat reduktase 2=dCMP deaminase 3=timidilat sintetase
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Hubungan sintesa timidilat dan metabolisme tetrahidrofolat
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Katabolisme pirimidin nukleotida
Tahapan awal = purinCMP dan UMP β-alanin + CO2 + NH3
dTMP β-amino isobutirat + CO2 + NH3
Hasil katabolisme bisa masuk ke TCA Cycle
β-alanin Asetil-KoAβ-amino isobutirat Suksinil-KoAPada bakteri : β-alanin KoA
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KELAINAN METABOLISME PIRIMIDIN
Hasil akhir metabolisme pirimidin larut dalam air, tidak banyak kelainan yang disebabkannya. Ada dua penyakit bawaan
(mempengaruhi sintesa pirimidin) ↑ eksresi asam orotat (orotat aciduria). Kelainan ini disebabkan karena
kekurangan enzim yang mempunyai dua fungsi sebagai :
Orotat fosforibosil transferaseOMP dekarboksilase
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Gejala dan tanda-tanda : hambatan pertumbuhan (retarded growth) anemia berat hipokhromik sumsum tulang megaloblastik (megaloblastic bone marrow). Leukopeni juga sering dijumpai.
Kelainan ini bisa diobati dengan uridin dan atau sitidin. Uridin &/ sitidin ↑ UMP (nukleosida kinase). UMP akan menghambat CPS II, dengan demikian mengurangi pembentukan asam orotat.
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Khemoterapi Kanker, pembelahan sel tak terkontrol Khemoterapi : menghentikan pembelahan dan membunuh sel 5-fluoro deoksiuridin monofosfat ( FdUMP )
menghambat timidilat sintase (thydimidylate synthase) secara irriversibel. Tapi karena FdUMP bermuatan, senyawa ini tidak bisa masuk ke dalam sel.
Yang diberikan pada pasen adalah 5-fluoro urasil ( FUra) atau 5-fluorodeoksiuridin (FdUrd). Setelah FUra dan FdUrd massuk kedalam sel akan diubah menjadi FdUMP melalui jalur “salvage”.
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Metotreksat (methotrexate= 4-amino, 10-methyl folic acid) dan aminopterin ( 4-amino folic acid) adalah analog asam folat.Dapat menghambat dihidrofolat reduktase. menghambat sintesa de novo nukleotida purin dan dTMP. Kedua senyawa tersebut sangat toksik dan diberikan dibawah pengawasan yang ketat.
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4-amino folat
4-amino, 10metil folat