PERAN NUKLEOTIDA : Membentuk DNA dan RNA 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

INHIBITOR NUKLEOTIDA : Methotrexate (Analog asam

folat) menghambat pembentukan Desoxythymidylat (pembentuk DNA)

Azidothymidine (AZT) inhibitor proses reverse transcription

NUKLEOSIDA : Purine atau Pyrimidine yang terikat dengan Pentosa

NUKLEOTIDA : Ester Phosphat dari Nukleosida

Basa Purine utama : Adenine dan GuanineYang lain : Hypoxanthine dan Xanthine (zat intermediate dari metabolisme Adenine dan Guanine)

Basa Pyrimidine : Cytosine, Thymine, Uracil

Basa : Ribonukleosida : Ribonukleotida :Adenine (A) Adenosine Adenylat (AMP)Guanine (G) Guanosine Guanylat (GMP)Uracil (U) Uridine Uridylat (UMP) Cytosine (C) Cytidine Cytidylat

(CMP)

NC

C

CCN

N

NH

CH

NH2|

H

NC

C

CCN

N

NH

CH

O||

H

H2N

NC

C

CCNH

O

NH2|

H

H NC

C

CCNH

O

H

H

O|| CH3

NC

C

CCNH

O

O||

HH

H

adenineadenine guanineguanine

cytosinecytosine thyminethymine uraciluracil

Cincin Purine : Glycin, Glutamin, Aspartat Cincin Pyrimidine : Aspartat, Carbamoyl phosphat (Glutamin + HCO3)

Ribosephosphat yang menyusun Purine atau Pyrimidine berasal dari 5- Phosphoribosyl-1-Pyrophosphat (PRPP)

PRPP berasal dari ATP + Ribose 5- phosp.

Ribose 5 Phosphat berasal dari HMP shunt (PPC)

Purine dibentuk dari Asam Amino

Synthese Purine (de novo) : Glutamin Glutamat

PRPP 5 Phosphoribosyl-1Amin Enzym : Amido-Phosphoribosyl

transferase

Adenylosuccinat

ATP

10 Reaksi Inosinat (IMP)

Xanthylat GTP

Synthese Purine (Salvage Pathways) : PRPP Purin-ribonukleotida

Purine PPi Enzym : Adenin-Phosphoribosyl-

transferase Adenin + PRPP Adenylat + PPi

Enzym : Hypoxanthin-Guanin-Phosphoribosyl-transferase (HGPRT)

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 + Carbamoylphosphat

Carb. Ph.+ Aspartat N-Carbamoylaspartat N-Carb.aspartat Uridylat

(UMP)

CMP dibentuk dari proses aminasi terhadap UMP

Glutamin GlutamatUMP CMPATP + 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 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

H4-Folat Dihydrofolat. NAD+ : Tryptophan Nicotinat

(Niacin) + PRPP Nicotinatribonukleotida

FAD : Riboflavin + 2 ATP 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.

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 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 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.

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.

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 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 Urat di sendi-sendi Gout

Therapy : Allopurinol (analog Hypoxanthin), bekerja sebagi substrat dan kemudian inhibitor terhadap Xanthin-oxidase

Asam Urat : anti oxidant

Adenosine deaminase deficiency Immunodeficiency

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.

Katabolisme Pyrimidine : dTMP 2’-Deoxythymidine Thymine

Dihydrothymine β-Ureidoisobutyrate -Aminoisobutyrate

Transaminasi Methylmalonatsemialdehyd

Methylmalonyl-CoA Succinyl-CoA Cytidine dan dCMP Uracil

Dihydrouracil β-Alanine. β-Alanine Acetyl-CoA

Digestion of dietary Nucleic acids

Enzim Nuclease (DNAase dan RNAase) : Nucleic acids Oligonucleotides

Enzim Phosphodiesterase : Oligonucleotides Mononucleotides

Enzim Nucleotidase : Nucleotides Nucleosides (Phosphat dipisahkan)

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 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 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, 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 drugs interfere 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 acidCertain 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 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 dan Methotrexate, yaitu analog Dihydrofolat)

Toxis terhadap : Stemcell (BM), Epithel GIT dan Follikel rambut.