Lecture 6 (3B) - Purines Biosynthesis Flashcards
Nucleotides act as precursors of
nucleotides
DNA or RNA
Nucleotides and energy
critical components of metabolism - ATP
Nucleotides form structural parts of
coenzymes - CoA
Nucleotides as regulators and signal molecules
cAMP
Nucleotides and associated defects
inheritable diseases
Nucleotides - targets for
anti-microbials and anti-cancer agents
Nucleotide roles
- precursors of nucleic acids - DNA or RNA
- crtical components of energy metabolism - ATP
- structural parts of coenzymes - CoA
- regultors and signal molecules - cAMP
- associated defects → inheritable diseases
- targets for anti-microbials and anti-cancer agents
Purines
Adenine
Guanine
2 rings
Biosynthesis of purines
2 methods
- de novo - forms inosine monophosphate
- salvage pathway - reclaimed from hydrolytic degradation of nucleic acids and nucleotides
de novo synthesis
first there are
primer reactions
- necessary before actual process
- add (ortho) phosphate - activates bond then nucleophilic attack
de novo synthesis
Primer 1
activation of
α-D-ribose-5-phosphate
de novo synthesis
Primer 1
adds diphosphate to
C1 of ribose ring
de novo synthesis
Primer 1
requires
ATP
ATP → AMP + diphosphate (to C1)
- retains α-configuration on ribose
- forms 5-phosphoribosyl-α-pyrophosphate (PRPP)
de novo synthesis
Primer 1
forms
5-phosphoribosyl-α-pyrophosphate
de novo synthesis
Primer 1
PRPP
important precursor
- pyrimidines
- histidine
- tryptophan
enzyme: ribose-pyrophosphokinase
(key enzyme)
de novo synthesis
Primer 1
key enzyme
ribose-pyrophosphokinase
de novo synthesis
the process
created from successive steps of activation followed by displacement by ammonia or a nucleophile
de novo synthesis
Primer 2
N9 atom
de novo synthesis
Primer 2
adds N9 to
C1 of ribose ring
de novo synthesis
Primer 2
requires
glutamine and water
- N9 from glutamine amide side chain
- glutamine → glutamate
- inverts to β-configration on ribose
- forms 5-phosphoribosyl-1-amine
de novo synthesis
Primer 2
glutamine → glutamate
- N9 from glutamine amide side chain
- inverts to β configuration on ribose
- forms 5-phosphoribozyl-1-amine
de novo synthesis
Primer 2
important…
flux generating step
- allows increase of purine production
de novo synthesis
Primer 2
enzyme
glutamine phosphoribosyl amidotransferase
The first COMMITTED step in purine biosynthesis
Primer 1
formation of 5-phosphoribosyl-1-amine
by glutamine phosphoribosyl amidotransferase
After priming, 9 further steps to
create the purine ring
- all require activation (phosphate addition) and nucleophilic attack (often by ammonia) to displace the addition
- add on to activate, take off to make energetically favorable
de novo synthesis
numbered steps
- C4, C5, N7 atoms
- C8 atom
- N3 atom
- ring closure
- C6 atom
- N1 atom
- fumarate removed (energetically favorable)
- C2 atom (onto N1 to close the molecule)
- second ring closure
de novo synthesis
- C4, C5, and N7 atoms
- only step where more than 1 purine ring atom is added
- adds glycine to N9
- requires ATP: ATP → ADP + Pi
- intermediate: phsphate added to carboxyl of glycine to activate it
- activation with PO4 addition
- glycine of carboxyl group forms peptide bond with N9
- forms glycinamide ribonucleotide
de novo synthesis
- C4, C5, and N7
forms
glycinamide ribonucleotide
