Download lect6

BIOC/DENT/PHCY 230
LECTURE 6
Lecture 6: Nitrogen Metabolism III
Amino acids as a source of nitrogen for bios ynthesis of
specialised compounds and nucleotides
 Unde rstand why amino 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 .
Explain 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
purines
pyrimidines
Base
synthesis
on ribose
free
Amino acids
gln(2), asp,
asp
gln
gly
Other molecules
ATP
formate(2)
HCO3-
5
carbamoyl
phosphate
2
(AMP,GMP)
CMP
3
(UMP)
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
b-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
deaminase
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