bioc/dent/phcy 230 lecture 6. nucleotides o found in dna and rna o used for energy (atp and gtp) o...

BIOC/DENT/PHCY 230

LECTURE 6

Lecture 6: Nitrogen Metabolism II IAmino acids as a source of nitrogen for biosynthesis ofspecialised compounds and nucleotides

q Understand why amino acids are precursors for specialised compounds and

nucleotides.q Be familiar with the notable features of de novo biosynthesis of purines and

pyrimidines.q Be aware of the benefits of nucleotide salvage pathways.q Note the very different end products of purine and pyrimidine degradation.q Know that the product from purine degradation is uric acid and why it can cause

medical problems.q Explain some of the benefits to medicine of understanding nitrogen metabolism.

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 synthesisedindependent of ribose

AMP

Synthesis of PRPP

PRPP contributes ribose phosphate to nucleotides

formation catalysed by PRPP synthetase

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

Tetrahydrofolate donates a second formyl group

Ring closure

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

purines pyrimidines

Basesynthesis on ribose free

Amino acids gln(2), asp, asp

gly

Other molecules formate(2)carbamoyl

HCO3- phosphate

ATP 5 2

(AMP,GMP)

(UMP)

CMP

gln

3

Comparison of purine and pyrimidine biosynthesis

Ribonucleotides are used as precursors for deoxyribonucleotides

ATP dATP

GTP dGTP

CTP dCTP

UTP dUTP

Ribonucleotide reductase

Thymidine nucleotides are derived from dUMP

Tetrahydrofolate donates a methyl group

Degradation of pyrimidine nucleotides

CTP UTP

-alanine, NH3, CO2

Degradation of purine nucleotides

Free ammonia is also produced in muscle

during severe muscle activity

ATP ADP + Pi

2ADP ATP + AMP

AMP IMP + NH4+

AMP deamina

se

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