Purine and Pyrimidine Metabolism Flashcards
Purine- and pyrimidine-containing nucleotides are important because these molecules are:
- The building blocks that make up the nucleic acids (DNA and RNA) which are critical for cell division and gene transcription/translation.
- The primary energy carriers in the cell in molecules such as ATP and GTP
- The foundation for many coenzymes such as CoA, FAD, NAD, NADP
- Important in intracellular signaling such as cAMP, cGMP
- Carriers for activated intermediates such as UDP-glucose which is directed to glycogen synthesis and CDP-diacylglycerol which is involved in glycerophospholipid synthesis.
Nucleotides and their pathways
a. Thus, it is critical that the cell be able to readily make the nucleotides it needs from basic chemical sources or to recycle nucleotides, and also to degrade excess nucleotides and excrete the resulting metabolic products.
b. Since nucleotides are critical for cell division, pharmacological inhibition of these pathways is a strategy that has been used in medications that have anti-cancer, anti-bacterial and anti-viral activities.
c. As we saw with complex lipids, if a person has an inborn error of metabolism where nucleotide synthesis or degradation pathways are disrupted, toxic metabolites can accumulate and cause diseases such as gout and Severe Combined Immunodeficiency Syndrome (SCID).
Purine and Pyrimidine
a. There are 2 main parts to purines and pyrimidines:
i. the base which is a single or double ringed structure that contains N, C, O and H
ii. a sugar that may or may not be phosphorylated.
b. A nucleoside is a base combined with a pentose sugar.
i. If the sugar is phosphorylated, then the molecule is called a nucleotide.
Nucleotide and Nucleoside
a. A nucleoside is a base combined with a pentose sugar.
b. If the sugar is phosphorylated, then the molecule is called a nucleotide.
Where Purines and Pyrimidines come from
a. Most of the purines and pyrimidines that are present in the body come either through de novo synthesis from other component molecules or through ‘recycling’ of pre-existing bases which are combined with sugar moieties.
b. Dietary purines and pyrimidines typically contribute minimally to total body pools of these molecules.
c. Once a nucleotide is made, it is important to be able to alter/interconvert the state of phosphorylation (GTP + ADP –> GDP + ATP).
d. Additionally, ribonucleotides need to be converted to deoxy-ribonucleotides for use in DNA synthesis
These Purine and Pyrimidine compounds need to be degraded and excreted or recycled.
We will therefore now discuss:
- de novo Purine nucleotide synthesis
- de novo Pyrimidine nucleotide synthesis
- Changes in phosphorylation states and conversion of rNDPs to dNDPs
- Nucleotide degradation
- Salvage pathways
- Important diseases of nucleotide metabolism
- Drugs that target these pathways
Nucleotides
a. Nucleotides contain purine and pyrimidine bases.
b. There are five common ones:
i. guanine and adenine (purines)
ii. uracil, thymine, and cytosine (pyrimidines).
c. A, G, C, and T are found in DNA, while A, G, C, and U are found in RNA.
d. Unusual bases are found in places like tRNA and rRNA, but these are primarily post-transcriptional modifications of the 5 common bases.
e. Bases, when covalently linked to ribose sugars and phosphates, become nucleotides.
Nucleoside vs Nucleotide
a. A nucleoside consists of a nitrogenous base covalently attached to a sugar (ribose or deoxyribose) but without the phosphate group.
b. A nucleotide consists of a nitrogenous base, a sugar (ribose or deoxyribose) and one to three phosphate groups.
Nucleoside = Sugar + Base Nucleotide = Sugar + Base + Phosphate
How Purines and Pyrimidines are made
a. Purines and pyrimidine bases can be made in de novo synthetic pathways (from other molecule precursors), or recycled in salvage pathways.
b. In general, the body uses the salvage pathways for most of its needs.
The de novo pathways introduction
a. When the de novo synthesis pathways of the purine and pyrimidine bases are examined, we find they differ in several ways.
b. This includes:
1. whether the base is made on the ribose sugar or made separately (and then added to the sugar)
2. where the atoms come from
3. the intermediates that are produced,
and
4. how these intermediates are converted to yield the full set of bases.
c. The synthesis of the activated sugar moiety is a key regulated step that you will see in several parts of these pathways.
i. The enzyme that catalyzes this key regulated step is PRPP synthetase.
Rxn:
Ribose-5 phosphate—> 5-Phosphoribosyl-1 Pyrophosphate
PRPP Synthetase uses an MG
Purine nucleotide synthesis
(purine de novo synthesis)
Lare Overview
a. The purine metabolic/catabolic pathways contain feedback loops and feed into the salvage pathways.
b. The atoms that make up the purine base come from a variety of sources including several amino acids as well as small molecule sources.
c. The purine base is made by starting with a ribose sugar and then building the base on the sugar, one step at a time. Many enzymes are involved.
d. The key regulated step of purine de novo synthesis is at the start, when PRPP (contains the ribose sugar) and glutamine are used by glutamine phosphoribosyl pyrophosphate amidotransferase to add the first nitrogen to the PRPP.
e. The secondary regulated step is conversion of a ribose 5’-phosphate to PRPP.
f. The pathway involves the addition of several amino acids and CO2 to the growing base as well as tetrahydrofolate and ATP as important elements in the pathway.
g. The first base that is produced by this pathway is inosine mono-phosphate (IMP). IMP is then used to make the GMP and AMP bases by the action of enzymes that act on the IMP. Failure of one of the enzymes involved in AMP synthesis can lead to a form of autism.
h. Feedback loops are a critical mechanism of regulation in purine synthesis. Specifically, IMP, GMP, and AMP inhibit enzymes that act early in the pathway.
Purine De Novo Synthesis
- The purine base is made by starting with a ribose sugar and then building the base on the sugar, one step at a time.
i. Many enzymes are involved. - The key regulated step of purine de novo synthesis is at the start, when PRPP (contains the ribose sugar) and glutamine are used by glutamine phosphoribosyl pyrophosphate amidotransferase to add the first nitrogen to the PRPP.
- The secondary regulated step is conversion of a ribose 5’-phosphate to PRPP.
- The pathway involves the addition of several amino acids and CO2 to the growing base as well as tetrahydrofolate and ATP as important elements in the pathway.
5 The first base that is produced by this pathway is inosine mono-phosphate (IMP).
i. IMP is then used to make the GMP and AMP bases by the action of enzymes that act on the IMP.
ii. Failure of one of the enzymes involved in AMP synthesis can lead to a form of autism.
- Feedback loops are a critical mechanism of regulation in purine synthesis.
i. Specifically, IMP, GMP, and AMP inhibit enzymes that act early in the pathway.
The key regulated step of purine de novo synthesis is..
a. The key regulated step of purine de novo synthesis is at the start, when PRPP (contains the ribose sugar) and glutamine are used by glutamine phosphoribosyl pyrophosphate amidotransferase to add the first nitrogen to the PRPP.
b. Feedback loops are a critical mechanism of regulation in purine synthesis.
i. Specifically, IMP, GMP, and AMP inhibit enzymes that act early in the pathway.
What is the end bases of Purine Nucleotide Synthesis
a. The first base that is produced by this pathway is inosine mono-phosphate (IMP).
b. IMP is then used to make the GMP and AMP bases by the action of enzymes that act on the IMP.
c. Both adenine and guanine are derived from the nucleotide inosine monophosphate (IMP), which is the first compound in the pathway to have a completely formed purine ring system.
d. Failure of one of the enzymes involved in AMP synthesis can lead to a form of autism.
Purine Biosynthesis
According to Wiki
(Strong and good summary)
a. Purines are biologically synthesized as nucleotides and in particular as ribotides, i.e. bases attached to ribose 5-phosphate
i. The purine base is made by starting with a ribose sugar and then building the base on the sugar, one step at a time.
ii. Many enzymes are involved
b. The first committed step is the reaction of PRPP, glutamine and water to 5’-phosphoribosylamine (PRA), glutamate, and pyrophosphate
i. catalyzed by glutamine phosphoribosyl pyrophosphate amidotransferase , which is activated by PRPP and inhibited by AMP, GMP and IMP.
ii. Need to know this for test!
Many Enzyme Reactions..
c. The last step is catalyzed by Inosine monophosphate synthase.
i. The first base that is produced by this pathway is inosine mono-phosphate (IMP). IMP is then used to make the GMP and AMP bases by the action of enzymes that act on the IMP.
FAICAR → IMP + H2O
d. Both adenine and guanine are derived from the nucleotide inosine monophosphate (IMP), which is the first compound in the pathway to have a completely formed purine ring system.
Glutamine phosphoribosyl pyrophosphate amidotransferase
a. The key regulated step of purine de novo synthesis is at the start, when PRPP (contains the ribose sugar) and glutamine are used by glutamine phosphoribosyl pyrophosphate amidotransferase to add the first nitrogen to the PRPP.
b. Wiki–>The first committed step is the reaction of PRPP, glutamine and water to 5’-phosphoribosylamine (PRA), glutamate, and pyrophosphate catalyzed by glutamine phosphoribosyl pyrophosphate amidotransferase
glutamine phosphoribosyl pyrophosphate amidotransferase –>which is activated by PRPP and inhibited by AMP, GMP and IMP.