Nucleotide Metabolism

Summary of nucleotide metabolism #00df68 #ff00fe

Ribose-5-phosphate —> ATP, glutamine, aspartate, glycine —> Purine and Pyrimidine nucleotides

• Purine nucleotides (A + G, double) can be broken down into uric acid and ribose-1-phosphate

• Pyrimidine nucleotides (T + C, single) can be broken down into malonyl-CoA and ribose-1-phosphate

What is the difference between nucleoside and nucleotides?

• Nucleosides = no phosphate

• Nucleotide = has phosphate

Synthesis of Purine Nucleotides

What are the 2 ways of biosynthesis and where does it occur?

• De Novo Pathway: Formation of purine nucleotides from simple acyclic precursors (from scratch) #01d08b

  • Occurs: Liver

• Salvage (reserve) Pathway: Formation of purine nucleotides from recycled purines that have been decomposed

  • Occurs: Tissues outside liver #02d0cd

BOTH ON IPAD

SAME CONCEPT FOR PYRIMIDINE NUCLEOTIDES

How is purine synthesis regulated?

• PRPP synthease inhibited by high levels of ADP and GDP

• Glutamine Phosphoribosyl Amidotransferase inhibited by AMP, GMP and IMP

  • Prevents the formation of 5-phosphoribosyl-1-amine

• Adenylosuccinate synthase (enzyme for AMP synthesis, IMP —> adenylosuccinate intermediate —> AMP) inhibited by AMP

• IMP dehydrogenase (enzyme for GMP synthesis, IMP —> XMP —> GMP) inhibited by GMP

What is an inhibitor of xanthine to prevent production of uric acid

Allopurinol acts as a competitive inhibitor

• Which at active site is converted to oxypurinol which is the competitive inhibitor

What is hyperuricemia? #ffbb00

The condition where there is an abnormally high level of uric acid in blood

How can hyperuricemia be gained (secondary)?

• Radiation injury

• Blood disease

• Tumors

• Kidney disease

What is gout?

An inherited disease accompanied with hyperuricemia and crystalisation of uric acid

• Causing the formation of salts in joints, cartilage and kidneys

• Symptoms:

  • Joints inflammation, acute pain

  • Renal stones

  • Tophuses (accumulation of uric acid salts in cartilages under skin)

Lesch-Nyhan Syndrome

• What

• Caused by

• Present in

• Characterised by

• Symptoms

What: Inherited disorder that affects purine metabolism

Caused by: Deficiency of HGPRT enzyme

• Leading to inability to reconvert guanine or hypoxanthine to GMP

Present in: Males (X linked)

Characterised by: Increase serum uric acid levels and absence of HGPRT

Symptoms:

• Gout

• Severe mental and physical problems

• Self mutilatitng behaviors

Pyrimidines can be converted to?

CoA derivatives for catabolism

Salvage Synthesis of Pyrimidine Nucleotides from Pyrimidine Bases

• Uracil —> UMP

• Cytosine —> CMP

• Thymine —> TMP

#ff00fe

Uracil —> UMP: #7200ff

• Sugar phosphate group is added to uracil when it reacts with PRPP using UPRT enzyme

• Uracil + PRPP (w/ UPRT) —> UMP + PPi

Cytosine —> CMP: #ff0086

• Sugar phosphate group is added to cytosine when it reacts with PRPP using CPRT enzyme

• Cytosine + PRPP (w/ CPRT) —> CMP + PPi

Thymine —> TMP:

• Thymine first converted to thymidine (nucleoside) by thymidine phosphorylase

• Then converted to TMP by thymidine kinase

Salvage Synthesis of Pyrimidines

• What if there are free nucleosides (uridine, cytidine)?

They can be directly phosphorylated to nucleotides

How is pyrimidine synthesis regulated?

Enzyme carbamoly phosphate synthease II is

• Inhibited by UTP

• Activated by PRPP

Orotaciduria

• What

• Caused by

• Symptoms

• Treatment

What: Inherited disorder of pyrimidine synthesis

Caused by: Deficiency of orotate-phosphoribosyltransferase and decaroxylase enzyme

Symptoms:

• Excess of orotic acid

• Mental and physical retardation

• Megaloblastic anemia

Treatment: Consumption of uridin for whole life