Nucleotide metabolism

What are pyrimidine nucleotides derived from?

PRPP, carbamoyl phosphate, aspartate

PRPP

5-phosphoribosyl-1-pyrophosphate

Where is pentose sugar and phosphate of pyrimidines derived from?

PRPP

PRPP synthesis

Ribose 5-phosphate + ATP → PRPP

Enzyme catalyzing PRPP synthesis

PRPP synthetase

where are pyrimidine bases derived from?

carbamoyl phosphate and aspartate

Enzymes responsible for pyrimidine de novo synthesis

CAD, DHODH, UMPS

UMP 

first pyrimidine nucleotide produced through de novo synthesis

UTP synthesis

Derived from UMP

CTP synthesis

Derived from UTP via CTP synthetase

Function of UTP and CTP

RNA synthesis

dCTP synthesis

From CTP

dTTP synthesis

From UMP

Nucleotide synthesis energetics

Highly energy-intensive (consumes ATP)

Where is the pentose sugar and phosphate for purine synthesis derived from?

PRPP

Where is the purine base derived from?

glutamine, glycine, formate, CO2, aspartate

Part 1 of purine synthesis

Synthesis of PRPP from ribose 5-phosphate

Part 2 of purine synthesis

Purine ring synthesis to form IMP

Stage 3 of purine synthesis

Derivation of AMP and GMP from IMP

Rate-limiting enzyme of purine synthesis

glutamine-PRPP amidotransferase

End-product inhibition of glutamine-PRPP amidotransferase

Inhibited by AMP, GMP, IMP

Reciprocal substrate regulation of purine synthesis

AMP requires GTP, GMP requires ATP

Salvage pathway of purine nucleotides

Cells recycle free purine bases

Purine bases

Hypoxanthine, guanosine, adenine

Salvage pathway when hypoxanthine is available

PRPP reacts with hypoxanthine to form IMP → AMP/GMP

Where does purine degradation occur?

In the liver

Purine degradation pathway

AMP/GMP → Uric acid

Fate of uric acid

excreted out of body from intestines or kidney

Hyperuricemia

High level of uric acid because of dysfunctional intestines/kidney or overproduction of purines/uric acid

Gout

Hyperuricemia → Accumulation of monosodium urate (MSU) crystals at joints

Lesch-Nyhan Syndrome (LNS)

Causes deficiency in enzyme in salvage pathway → accumulation of PRPP → uric acid accumulation