Metabolism Of Purin Pirimidin 4s1j1s

METABOLISM OF PURIN & PIRIMIDIN

Metabolism of Nucleotides

N

N

N

N

N H

N

Nucleoside and Nucleotide Nucleoside =

Nitrogenous base ribose

Nucleotide =

Nitrogenous base ribose phosphate

Purines vs Pyrimidines

Degradation of nucleic acid Nucleoprotein

In stomach

Gastric acid and pepsin

Nucleic acid

In small intestine

Protein

Endonucleases: RNase and DNase

Nucleotide

Nucleotidase Phosphate

Nucleoside

Nucleosidase

Base

Ribose

Significances of nucleotides 1. Precursors for DNA and RNA synthesis

2. Essential carriers of chemical energy, especially ATP 3. Components of the cofactors NAD+, FAD, and coenzyme A

4. Formation of activated intermediates such as UDP-glucose and CDP-diacylglycerol. 5. cAMP and cGMP, are also cellular second messengers.

Synthesis of Purine Nucleotides

There are two pathways leading to nucleotides • De novo synthesis: The synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose-5-phosphate, CO2, and one-carbon units.

• Salvage pathways: The synthesis of nucleotide by recycle the free bases or nucleosides released from nucleic acid breakdown.

§ 2.1 De novo synthesis • Site: – in cytosol of liver, small intestine and thymus

• Characteristics: a. Purines are synthesized using 5phosphoribose(R-5-P) as the starting material step by step. b. PRPP(5-phosphoribosyl-1-pyrophosphate) is active donor of R-5-P. c. AMP and GMP are synthesized further at the base of IMP(Inosine-5'-Monophosphate).

1. Element sources of purine bases

N10-Formyltetrahydrofolate

N10-Formyltetrahydrofolate

First, synthesis Inosine-5'-Monophosphate, IMP

2. Synthesis of Inosine Monophosphate (IMP) • Basic pathway for biosynthesis of purine ribonucleotides • Starts from ribose-5-phosphate(R-5-P) • Requires 11 steps overall • occurs primarily in the liver

3. Conversion of IMP to AMP and GMP Note: GTP is used for AMP synthesis.

Note: ATP is used for GMP synthesis.

IMP is the precursor for both AMP and GMP.

4. ADP, ATP, GDP and GTP biosynthesis kinase

kinase

AMP

ATP

ADP

ADP

ATP

ATP

kinase

ADP

kinase GTP

GDP

GMP

ATP

ADP

ATP

ADP

5. Regulation of de novo synthesis The significance of regulation: (1) Meet the need of the body, without wasting. (2) AMP and GMP control their respective synthesis from IMP by a mechanism, [GTP]=[ATP]

§ 2.2 Salvage pathway • Purine bases created by degradation of RNA or DNA and intermediate of purine synthesis can be directly converted to the corresponding nucleotides. • The significance of salvage pathway : – Save the fuel. – Some tissues and organs such as brain and bone marrow are only capable of synthesizing nucleotides by salvage pathway.

• Two phosphoribosyl transferases are involved: – APRT (adenine phosphoribosyl transferase) for adenine. – HGPRT (hypoxanthine guanine phosphoribosyl transferase) for guanine or hypoxanthine.

Purine Salvage Pathway . adenine phosphoribosyl transferase

Adenine

PRPP

AMP

PPi O N

O N

2-O

N

N N Hypoxanthine O N N

hypoxanthine-guanine phosphoribosyl transferase (HGPRT)

PRPP N

N

Guanine

NH2

3POH2C

O

N

N

N

HO OH IMP O

PPi

N 2-O

3POH2C

O

N

N N

NH2

HO OH GMP

.

Absence of activity of HGPRT leads to Lesch-Nyhan syndrome.

§ 2. 3 Formation of deoxyribonucleotide • Formation of deoxyribonucleotide involves the reduction of the sugar moiety of

ribonucleoside diphosphates (ADP, GDP, CDP or UDP).

• Deoxyribonucleotide synthesis at the nucleoside diphosphate(NDP) level.

§ 2. 4 Antimetabolites of purine nucleotides • Antimetabolites of purine nucleotides are structural analogs of purine, amino acids and folic acid. • They can interfere, inhibit or block synthesis pathway of purine nucleotides and further block synthesis of DNA, RNA, and proteins. • Widely used to control cancer.

Degradation of Purine Nucleotides

NH2

Adenosine N Deaminase

C N

C

O C HN

C

N CH

CH HC

C

HC

N

N

C N

O

N Ribose-P

Ribose-P IMP

AMP

C HN

CH HC

C

C

N

HN C

C O

C N H

N H Hypoxanthine

O

C HN

C

N

Xanthine Oxidase O

C

N H

Uric Acid (2,6,8-trioxypurine)

C

N

O

CH C O

C N H

N

N H

Xanthine The end product of purine metabolism

GMP

Uric acid • Uric acid is the excreted end product of purine catabolism in primates, birds, and some other animals. • The rate of uric acid excretion by the normal adult human is about 0.6 g/24 h, arising in part from ingested purines and in part from the turnover of the purine nucleotides of nucleic acids. • The normal concentration of uric acid in the serum of adults is in the range of 3-7 mg/dl.

Synthesis of Pyrimidine Nucleotides

§ 4.1 De novo synthesis • shorter pathway than for purines • Pyrimidine ring is made first, then attached to riboseP (unlike purine biosynthesis) • only 2 precursors (aspartate and glutamine, plus HCO3-) contribute to the 6-membered ring • requires 6 steps (instead of 11 for purine) • the product is UMP (uridine monophosphate)

1. Element source of pyrimidine base

C Gln

N3

4

5C

Asp CO 2

C2

1

N

6C

Step 1: synthesis of carbamoyl phosphate

•Carbamoyl phosphate synthetase(S) exists in 2 types: •S-I, a mitochondrial enzyme, is dedicated to the urea cycle and arginine biosynthesis. •S-II, a cytosolic enzyme, used here. It is the committed step in animals.

Step 2: synthesis of carbamoyl aspartate ATCase: aspartate transcarbamoylase

•Carbamoyl phosphate is an “activated” compound, so no energy input is needed at this step.

Step 3: ring closure to form dihydroorotate

Step 4: oxidation of dihydroorotate to orotate

CoQ QH2

(a pyrimidine)

Step 5: acquisition of ribose phosphate moiety

Step 6: decarboxylation of OMP

The big picture

3. UTP and CTP biosynthesis kinase

kinase UMP

UDP

ATP

ADP

UTP

ATP

ADP

4. Formation of dTMP The immediate precursor of thymidylate (dTMP) is dUMP. The formation of dUMP either by deamination of dCMP or by hydrolyzation of dUDP. The former is the main route. UDP

dUDP

dCMP

dCDP

dUMP

N5,N10-methylenetetrahydrofolic Acid dTMP synthetase

dTMP

ATP

dTDP

ADP

ATP

dTTP

ADP

§ 4. 2 Salvage pathway uridine-cytidine kinase uridine cytidine + ATP deoxythymidine + ATP deoxycytidine + ATP

uracil thymine + PRPP orotic acid

thymidine kinase deoxycytidine kinase pyrimidine phosphate ribosyltransferase

UMP + ADP CMP dTMP + ADP dCMP + ADP

UMP dTMP + PPi OMP

§ 4. 3 Antimetabolites of pyrimidine nucleotides • Antimetabolites of pyrimidine nucleotides are similar with them of purine nucleotides.

Degradation of Pyrimidine Nucleotides

O

NH2 N O

H2O

N H cytosine

NH3

O

HN O

uracil

HN N H

O

HOOC

O

N H

N H

CH2

NH2 CH CH3 O

N H

H2O H2N CH2 CH2 COOH

thymine

HOOC

NH2 CH2

¦Â-ureidopropionate

CH3

CH2 ¦Â-ureidoisobutyrate H2O

CO2 + NH3

H2N CH2 CH COOH

¦Â-alanine

Highly soluble products

CH3 ¦Â-aminoisobutyrate