PERAN NUKLEOTIDA : Membentuk DNA dan RNA Membentuk UDP-Glukose, CDP Membentuk UDP-Glukose, CDP Diacylglycerin , S-Adenosyl Methionin Membentuk energi : ATP dan GTP GTP Bagian dari enzym : NAD + ,FAD dan Co-A Regulator metabolisme : cAMP dan cGTP
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Membentuk DNA dan RNA Membentuk UDP -Glukose , CDP ...ocw.usu.ac.id/course/download/1110000095... · Katabolisme Pyrimidine : dTMP 2’-Deoxythymidine Thymine ... Microsoft PowerPoint
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� PERAN NUKLEOTIDA :
� Membentuk DNA dan RNA
� Membentuk UDP-Glukose, CDP � Membentuk UDP-Glukose, CDP Diacylglycerin , S-Adenosyl Methionin
�Hypoxanthin + PRPP �Hypoxanthin + PRPP Inosinat + PPi
�Guanin + PRPP Guanylat + PPi
�Inhibitor (feedback) : AMP, GMP dan IMP
Feedback Inhibition on Purine biosynthesis
� Synthese Pyrimidine :
� Glutamin + 2 ATP + HCO-3
2 ADP + Pi + Glutamat + 2 ADP + Pi + Glutamat + Carbamoylphosphat
� Carb. Ph.+ Aspartat
N-Carbamoylaspartat
� N-Carb.aspartat Uridylat (UMP)
�CMP dibentuk dari proses aminasi terhadap UMP
Glutamin Glutamat
UMP CMP
ATP + H2O ADP +Pi + 2H+
�Proses methylasi terhadap dUMP TMP
�Donor methyl : N5,N10
Methylentetrahydrofolat
�Pada DNA tdk tdp Uracil tetapi Thymin
�Thymin dibentuk dari methylasi terhadap Desoxyuridylat (dUMP) oleh enzim Thymidylat synthaseDesoxyuridylat (dUMP) oleh enzim Thymidylat synthase
�Donor grup Methyl : N5, N10-Methylentetrahydrofolat
�Grup Methyl yang ditransfer dalam bentuk tereduksi, dimana 2 elektron untuk proses reduksinya berasal dari Unit H4-Folat sendiri dalam bentuk Hydrid-ion (H:-)
�Ion ini menjadi bagian dari -CH3 yang ditransfer ke dTMP dan selanjutnya
�Co-A : Phosphorilasi terhadap Pantothenat Pantothenic acid
� Persamaan karakteristik ketiga reaksi tersebut (NAD, FAD dan Co-A): transfer AMP dari ATP thd grup Phosphat dari zat intermediate yang diphosphorilasi.intermediate yang diphosphorilasi.
� Pyrophosphat yang terbentuk dihydrolisa menjadi Orthophosphat.
� Hal yang sering berulang dalam reaksi Biokimia : Reaksi biosynthese sering terjadi melalui hydrolysa Pyrophosphat yang dibebaskan.
Ribose-5 Phosphat PRPP
Phosphoribosyl-amin IMPPhosphoribosyl-amin IMP
Adenylosuccinat AMP
IMP
Xanthylat GMP
� Feedback inhibition dari synthese Purin-nucleotide kontrol dari biosynthese Purin.
� Synthese Purin-nucleotide dapat dihambat secara feedback pd bbrp tmpt.
� 1. Enzim 5 Phosphoribosyl-1-Pyrophosphat-synthetase yang diinhibisi oleh AMP, GMP, IMP mengatur konsentrasi PRPP.
� 2. Reaksi “kunci” untuk dimulainya proses biosynthese Purin (transfer dari gugus amido dari rantai samping gugus amido dari rantai samping Glutamin) oleh enzim Glutamin-PRPP-Amidotransferase dihambat oleh Purin-ribonucleotide.
� Endproduct dari reaksi ini (AMP dan GMP) menghambat secara synergis.
� 3. AMP menghambat synthese Adenylosuccinat dari Inosinat, sedang GMP menghambat perobahan dari Inosinat menjadi Xanthylat.Inosinat menjadi Xanthylat.
� 4. GTP merupakan substrat dari synthese AMP dan ATP merupakan substrat dari synthese GMP.
� Hubungan timbal balik substrat ini (Reciproke) memelihara produksi yang seimbang dari Adenin- dan Guanin-ribonucleotide.
� Nucleotide intraselluler selalu dibentuk dan didegradasi secara kontinu.
� Melalui enzim Nucleotidase dihydrolysa menjadi Nucleoside.menjadi Nucleoside.
� AMP dihydrolisa oleh enzim 5’-nucleotidase Adenosine dan oleh Adenosine deaminase
Inosine
� Purine -nucleoside-phosphorilase akan merobah Inosine, Guanosine dan Xanthosine menjadi Hypoxanthine, Guanine dan Xanthine dan juga Ribose1 Phosphat.
� Ribosephosphat mutase merobahnya menjadi Ribose 5 Phosphat Synthese PRPP
Hypoxanthine Xanthine oleh enzim � Hypoxanthine Xanthine oleh enzim Xanthine oxidase (Mo,FAD dan Fe-S) dan selanjutnya oleh enzim Xanthine Oxidase menjadi Uric acid.
� Guanine Xanthine (deaminasi oleh enzim Guanine deaminase.
� Asam Urat dalam serum penumpukan kristal Natrium Uratdi sendi-sendi Gout di sendi-sendi Gout
� Therapy : Allopurinol (analog Hypoxanthin), bekerja sebagi substrat dan kemudian inhibitorterhadap Xanthin-oxidase
� Asam Urat : anti oxidant
� Adenosine deaminase deficiency
Immunodeficiency
� Konsentrasi dATP yang tinggi � Konsentrasi dATP yang tinggi menghambat Ribonucleotide reductase
sinthesa DNA dihambat
� Gangguan fungsi T- dan B-cells
� Purine nucleoside phosphorylase def.
level purine nucleotida meningkat dan sinthesa Uric acid menurun.
� Enzim Nucleosidase : Free bases and Ribose or Deoxyribose which are then absorbed
� Dietary purine and pyrimidine bases degraded within enterocytes.
Gouty arthritis
� The inflammation caused by urate crystals deposition attracts white blood cells, which engulf the crystals
Urate crystals disrupt the lysosomal � Urate crystals disrupt the lysosomal membranes in the white blood cells
� Result : the leakage of lysosomal enzymes into the tissues
� Visible structure called “tophi” (urate crystal stones) may form near joints and cause deformities
Gouty arthritis
� There are two forms of Gout : Primary and Secondary
� Primary : genetic defects in purine metabolism � Primary : genetic defects in purine metabolism
� Several variants of Ribose 5-phosphate pyrophosphokinase are not effectively regulated by allosteric inhibitors e.g., Pi, GDP or ADP
� Consequently PRPP consentration rise, causing the increased synthesis of purine nucleotides.
� This leads to increased uric acid synthesis
Gouty arthritis
� HGPRT deficiency causes Hyperuricemia because of decreased Salvage of purine bases.
� In Glucose 6-phosphatase deficiency, � In Glucose 6-phosphatase deficiency, hypoglycemia develops in affected individuals because they cannot produce blood glucose from glucose 6-phosphate.
� High liver concentrations of Glucose 6-phosphate stimulate the synthesis of Ribose 5-phosphate and PRPP
Gouty arthritis
� Secondary : Leukemia patients overproduce uric acid either because of massive cell destruction or the chemotherapy treatment.
� Hyperuricemia also results when certain drugsinterfere with the renal secretion of uric acid.
� Lead poisoning also develop gout because of renal damage.
� Saturnine Gout : Port wines (Lead salts were added to give very effective preservatives) and Rum (stored in containers lined with lead)
� Lesch Nyhan Syndrome :
�Deficiency of HGPRT
�Excessive production of uric acid�Excessive production of uric acid
�Certain neurological symptoms (self-mutilation, aggressive, involuntary movement and mental retardation)
�Affected children appear normal at birth but begin to deteriorate at about 3 to 4 months of age
� Lesch Nyhan Syndrome :
�The severe symptoms of hereditary HGPRT deficiency indicate that the purine salvage pathway deficiency indicate that the purine salvage pathway is vitally important.
�Purine nucleotide synthesis inhibitors for treating cancer indicate that both pathways must be inhibited for significant tumor growth suppression
�Therapy Cancer : block terhadap enzym Thymidylat synthase (Fluorouracil)
�Enzym Dihydrofolat reduktase (Aminopterin �Enzym Dihydrofolat reduktase (Aminopterin dan Methotrexate, yaitu analog Dihydrofolat)
�Toxis terhadap : Stemcell (BM), Epithel GIT dan Follikel rambut.