Purine and Pyrimidine Synthesis Flashcards
Amino acids are precursors of:
- proteins
- hormones
- coenzymes
- nucleotides
- alkaloids
- cell wall polymers
- porphyrins
- antibiotics
- pigments
- neurotransmitters
Nucleotides roles in cellular metabolism:
- energy currency in metabolic transactions
- essential chemical links in the response of cells to hormones and other extracellular stimuli
- structural components of an array of enzyme cofactors and metabolic intermediates
- constituents of nucleic acids: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)
Nucleotides have three components:
- a nitrogenous base (pyrimdine or purine)
- A pentose
- 1+ phosphates
Nucleoside
nucleotide without a phosphate group
Nucleotide Bonds
- N-β-glycosyl bond = covalently joins the 1′ carbon of the pentose to the base (at N-1 of pyrimidines and N-9 of purines)
- formed by removal of the elements of water
- the phosphate is esterified to the 5′ carbon
Nucleotide Nitrogenous Bases:
- major purine bases:
- adenine (A) = in DNA and RNA
- guanine (G) = in DNA and RNA
- major pyrimidine bases:
- cytosine (C) = in DNA and RNA
- thymine (T) = only in DNA
- uracil (U) = only in RNA
Label
Nucleotide Pentoses
two kinds of pentoses:
form:
- 2′-deoxy-d-ribose = in DNA
- D-ribose = in RNA
Both are int their β-furanose (closed five-membered ring) form
structural units of RNA
ribonucleotides
also called ribonucleoside 5’-monophosphates
structural units of DNA
deoxyribonucleotides
also called deoxyribonucleoside 5′-monophosphates, deoxynucleotides, and deoxynucleoside triphosphates
label
*methylated foms - most common in DNA
Nucleotides with Phosphate Groups in Different Positions
- ribonucleoside 2′,3′-cyclic monophosphates = isolatable intermediates
- ribonucleoside 3′-monophosphates = end products of RNA hydrolysis
- adenosine 3′,5′-cyclic monophosphate (cAMP)
- guanosine 3′,5′-cyclic monophosphate (cGMP)
Solubility of Nucleotides
- hydrophobic and relatively insoluble in pH 7.0 water
- leads to stacking interactions (van der Waals and dipole-dipole)
- charged and more soluble at acidic or alkaline pH values
Two Pathways Lead to Nucleotides
- de novo pathways = begin with metabolic precursors: amino acids, ribose 5-phosphate, CO2, and NH3
- bases are synthesized while attached to ribose
- pyrimidine ring is synthesized as orotate
- Glu provides most amino groups
- Gly is the precursor for purines
- Asp is the precursor for pyrimidines
- salvage pathways = recycle the free bases and nucleosides released from nucleic acid breakdown
Origin of Ring Atoms in Purines
adenine and guanine are synthesized as AMP and GMP.
De Novo purine nucleotide synthesis begins with
PRPP
in the first committed step, an amino group donated by glutamine is attached at C-1 of PRPP to form 5-phosphoribosylamine
in the second step, three atoms are added from glycine
requires ATP
in the eleventh step, a second ring closure occurs to form:
inosinate (IMP)
IMP is the first intermediate with a complete purine ring
Addition of the Amino Groups of AMP and GMP
- conversion of inosinate to adenylate requires an amino group from aspartate
- requires GTP
- conversion of inosinate to guanylate requires an amino group from glutamine
- requires ATP
Biosynthesis of AMP and GMP from IMP
Nucleotide synthesis regulation overview
Tight regulation is needed to maintain balanced supplies of amino acids resources and nucleotide products.
The metabolic flux through most of these pathways is far less than for carbohydrate or lipid biosynthetic pathways;
most amino acids and nucleotides are not stored, but are synthesized as they are needed.
Purine Nucleotide Biosynthesis is Regulated by
Feedback Inhibition
four major feedback mechanisms cooperate in regulating:
the overall rate of de novo purine nucleotide synthesis
the relative rates of formation of AMP and GMP
Pyrimidine Nucleotides are Made from
Aspartate, PRPP, and Carbamoyl Phosphate
pyrimidine synthesis proceeds by first making the pyrimidine ring (in the form of orotate)
ribose 5-phosphate is attached after pyrimidine ring formation
aspartate and carbamoyl phosphate provide the atoms for the ring structure
catalyzes the first committed step in pyrimidine nucleotides
highly regulated in bacteria
aspartate transcarbamoylase
catalyzes the removal of water from N-carbamoylaspartate to close the pyrimidine ring
dihydroorotase
in eukaryotes, the first three enzymes are part of
a single trifunctional protein (CAD)
is decarboxylated to uridylate, which is phosphorylated to UTP
orotidylate
catalyzes the formation of CTP from UTP by way of an acyl phosphate intermediate
requires ATP
cytidylate synthetase
Pyrimidine Nucleotide Biosynthesis Is Regulated by
Feedback Inhibition
aspartate transcarbamoylase (ATCase)
- catalyzes the first reaction in the sequence
- inhibited by end-product CTP
- accelerated by ATP
phosphorylates AMP to ADP
adenylate kinase
ADP is phosphorylated to ATP by
glycolytic enzymes or through oxidative phosphorylation
use ATP to form other nucleoside diphosphates
nucleoside monophosphate kinases
convert nucleoside diphosphates to triphosphate
nucleoside diphosphate kinases
NTPD + NDPA ⇌ NDPD + NTPA
where A is the phosphate acceptor and D is the donor
