METABOLISME NUKLEOTIDA

Evi Umayah Ulfa

Nucleotides

• Monomers for nucleic acid polymers

• Nucleoside Triphosphates are important energy carriers (ATP, GTP)

• Important components of coenzymes

– FAD, NAD+ and Coenzyme A

NUCLEOTIDE SYNTHESIS: DE NOVO AND SALVAGE PATHWAYS

De novo pathway

• Synthesis from low molecular weight precursors (Liver)

Salvage pathway

• Synthesis from nucleosides or bases that become available through the diet or from degradation of nucleic acids (Peripheral tissues)

DE NOVO PURINE SYNTHESIS

Source of Nitrogen

• 2 from Glutamine

• 1 from Aspartate

• 1 from Glycine

Source of Carbon

• 2 from Glycine

• 2 from N10-Formyl tetrahydrofolate

• 1 from CO2

Ribose 5 Phosphate

PRPP

5-Phosphoribosylamine

IMP

Adenylosuccinate XMP

AMP

ADP

ATP

GMP

GDP

GTP

PRPP synthetase

Amido tranferase

Adenylosuccinate

synthetase

IMP dehydrogenase

PURINES ARE NOT MADE AS FREE BASES – BUT AS NUCLEOTIDES

PPi DISPLACEMENT BY NH2

INOSINE 5’- MONOPHOSPHATE (IMP)

GLUTAMINE

GLYCINE + ATP

N10-FORMYL THF

GLUTAMINE + ATP

CO2

ASPARTATE + ATP

N10-FORMYL THF

5’-PRPP

ADDITION OF GLYCINE

FORMYL GROUP TRANSFER

NH2 GROUP TRANSFER

ATP RING CLOSURE

COO- ADDITION

ASPARTATE ADDITION

FUMARATE LOSS

FORMYL GROUP TRANSFER

RING CLOSURE

1

2

3

4

5

6

7

8

9

10

Purine Degradation

GMP

Excess bases are converted to Urate, releasedto the circulation and excreted through the Kidney

Diseases of Purine Metabolism:

Most common: Gout• Caused by excessive Urate• Urate has low solubility, high concentrations

precipitate faster than they can be cleared in Kidney• Leads to painful deposits in joints

• Underexcretion of uric acid• Diet rich in purines/alcohol; deficient in dairy products• Increased purine degradation• Increased PRPP Synthetase activity

overproduction of PRPP = increased purine synthesis = increased purine degradation = increased uric acid production

• Decreased/partial HGPRT activity1) Deficiency of HGPRT = increased HX and G2) Deficiency of HGPRT = accumulation of PRPP =

increased purine synthesis = increased uric acidlevels

3) Deficiency of HGPRT = decreased IMP and GMP = decreased inhibitors for purine synthesis

GOUT - Causes

As with Purines, there are both de novo and salvage pathways

PIRIMIDINE SYNTHESIS

De Novo PirimidineSynthesis

• Synthesis of the pyrimidine bases.

• CPSII = carbamoylphosphate synthetase II.

• RR=ribonucleotidereductase

• FH2 and FH4 forms of folate.

AspartateTranscarbamylase

Salvage of Pirimidine Base

• pyrimidinenucleoside phosphorylase converts the pyrimidinebases to their respective nucleosides

• specific nucleoside kinases react with the nucleosides, forming nucleotides

Other products derived from Purines/Pyrimidines

Nucleotide sugarse.g. UDP-Glucose or GDP MannoseCoenzyme A (Adenine)NAD (Adenine)NADP (AdenineFAD (Adenine)Vitamin B12 (Adenine)Biopterin (Guanine)