BIOC/DENT/PHCY 230 LECTURE 6

Lecture 6: Nitrogen Metabolism III Amino acids as a source of nitrogen for biosynthesis of specialised compounds and nucleotides

 Unde rstand why ami no ac ids are precursors for specialis ed compound s and nuc leotides.

 Be famil iar wit h the notable features of

de novo

bio synthes is of purines and pyrimidines.

 Be aware of the bene fits of nuc leotide salvage pathway s.

 Note the ve ry different end produc ts of pur ine and pyr imi dine degr adation.

 Know that the product from pur ine degradation is uric acid and why it can cause medical problems .

 Expl ain so me of the bene fit s to medicine of unde rstand ing nitrogen metaboli sm.

Nucleotides

  found in DNA and RNA used for energy (ATP and GTP)  building blocks for coenzymes (NADH)

Building blocks for nucleotides

Two classes of bases

Two types of ribose

Synthesis of nucleotides

 nucleotide bases can be recycled or synthesised de novo  purine bases are synthesised on ribose  pyrimidine bases are synthesised independent of ribose

Synthesis of PRPP

  PRPP contributes ribose phosphate to nucleotides formation catalysed by PRPP synthetase AMP PRPP synthetase is allosterically inhibited by AMP, ADP and GDP.

De novo purine synthesis

Glutamine donates an amide to initiate purine synthesis A whole glycine is added to the nitrogen

The coenzyme tetrahydrofolate donates a formyl group Glutamine donates a second amide

Imidazole ring is closed in an energy dependent reaction

Aspartate is added in an energy dependent reaction This is analogous to the urea cycle

Ring closure Tetrahydrofolate donates a second formyl group

Origins of purine base

IMP can be converted to GMP and AMP

De novo pyrimidine synthesis

The pyrimidine base is synthesised before being attached to ribose

ring closure and oxidation

Ribose is now added via PRPP

UMP can be used to synthesise CTP

Origins of pyrimidine base

Comparison of purine and pyrimidine biosynthesis

Base synthesis Amino acids Other molecules ATP purines on ribose gln(2), asp, gly formate(2) HCO 3 5

(AMP,GMP)

pyrimidines free asp CMP gln carbamoyl phosphate 2

(UMP)

3

Ribonucleotides are used as precursors for deoxyribonucleotides

ATP GTP CTP UTP dATP dGTP dCTP dUTP Ribonucleotide reductase

Thymidine nucleotides are derived from dUMP

Tetrahydrofolate donates a methyl group

Degradation of pyrimidine nucleotides CTP UTP

b

-alanine, NH 3 , CO 2

Degradation of purine nucleotides

Free ammonia is also produced in muscle

 during severe muscle activity ATP 2ADP ADP + P i ATP + AMP AMP

AMP deaminase

IMP + NH 4 +

Degradation of purine nucleotides

GOUT

 uric acid is quite insoluble  excess uric acid can crystallise in joints  gout can be treated with allopurinol  allopurinol is a competitive inhibitor of xanthine oxidase

The take home message

 nucleotides have a number of functions  they can be synthesised de novo if required  some steps are analogous with the urea cycle  amino acids provide many of the components  synthesis is regulated by the concentrations of various nucleotides  synthesis is energetically expensive  the degradation of excess purines can cause gout