Diacylglycerin, S-Adenosyl Methionin Membentuk energi : ATP dan GTP GTP Bagian dari enzym : NAD +,FAD dan Co-A Regulator metabolisme : camp dan cgtp

(5)

N C C C C N N N H CH NH₂ | H N C C C C N N N H CH O || H H₂N adenine

adenine guanineguanine

H H N C C C C N H O NH₂ | H H N C C C C N H O H H O || _CH 3 N C C C C N H O O || H H H cytosine

(6)

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

Ribosephosphat yang menyusun Purine 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

(7)

(8)

Synthese Purine (de novo) : Glutamin Glutamat PRPP 5 Phosphoribosyl-1Amin Enzym : Amido-Phosphoribosyl transferase

(9)

Adenylosuccinat ATP

10 Reaksi Inosinat (IMP)

Xanthylat GTP Xanthylat GTP

Synthese Purine (Salvage Pathways) :

PRPP Purin-ribonukleotida Purine PPi

Enzym : Adenin-Phosphoribosyl-transferase Adenin + PRPP Adenylat + PPi

(10)

Enzym : Hypoxanthin-Guanin-Phosphoribosyl-transferase (HGPRT) Hypoxanthin + PRPP Hypoxanthin + PRPP Inosinat + PPi Guanin + PRPP Guanylat + PPi

Inhibitor (feedback) : AMP, GMP

(11)

(12)

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)

(13)

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

(14)

Pada DNA tdk tdp Uracil tetapi Thymin

Thymin dibentuk dari methylasi terhadap Desoxyuridylat (dUMP) oleh enzim

Thymidylat synthase

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:-₎

(15)

Ion ini menjadi bagian dari -CH3 yang

ditransfer ke dTMP dan selanjutnya H₄-Folat Dihydrofolat.

H₄-Folat Dihydrofolat.

NAD+ : Tryptophan Nicotinat

(Niacin) + PRPP

Nicotinatribonukleotida

FAD : Riboflavin + 2 ATP

Co-A : Phosphorilasi terhadap

(16)

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.

(17)

Ribose-5 Phosphat PRPP Phosphoribosyl-amin IMP Phosphoribosyl-amin IMP Adenylosuccinat AMP IMP Xanthylat GMP

(18)

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

(19)

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

(20)

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

(21)

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.

(22)

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

(23)

(24)

Asam Urat dalam serum

penumpukan kristal Natrium Urat di sendi-sendi Gout

di sendi-sendi Gout

Therapy : Allopurinol (analog

Hypoxanthin), bekerja sebagi substrat dan kemudian inhibitor terhadap Xanthin-oxidase

(25)

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.

(26)

Katabolisme Pyrimidine : dTMP 2’-Deoxythymidine Thymine Dihydrothymine β-Ureidoisobutyrate β ββ β-Aminoisobutyrateβ ββ β-Aminoisobutyrate Transaminasi Methylmalonatsemialdehyd Methylmalonyl-CoA Succinyl-CoA

Cytidine dan dCMP Uracil Dihydrouracil β-Alanine.

(27)

(28)

Digestion of dietary Nucleic acids

Enzim Nuclease (DNAase dan RNAase) :

Nucleic acids Oligonucleotides

Enzim Phosphodiesterase : Oligonucleotides

Mononucleotides 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

(29)

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

(30)

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.

(31)

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

(32)

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)

(33)

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

(34)

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

(35)

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