In 1948 “John Buchanor” obtains the first clues as to how this process occurs. Denovo by feeding a variety of isotopically labeled compounds to pigeons and chemically determining the position of the labeled atoms in their excreted Uric acid. The results of the studies are Purine synthesis.
- Nucleic Acids are the Molecular Language of life
- Basic Components of Nucleic Acids – Purines and Pyrimidines
- Nucleic Acids Structures
The biosynthetic organs of Purine ring atoms note that C4, C5, and N7 come from a single Glycine molecule but each of the other atoms is derived from an independent precursor.
- N1→ came from Asparagine
- C2 and C8 → came from formate (THF)
- N3 and N9 → came from Glutamine
- C4, C5, and N7 → came from HCO3–
Purine Synthesis Pathways
Purine synthesis can be explained in two different pathways
- De-Novo Pathway
- Salvage Pathway (also called Dust-bin Pathway)
De Novo Purine Synthesis :
In this De novo synthesis of purines, each atom in the purine nucleotide came from different sources as mentioned above structure and data. There are 3 major steps are involved in this Purine synthesis pathway.
- Ribose-5-Phosphate to IMP synthesis
- Synthesis of AMP from IMP
- Synthesis of GMP from IMP
Ribose-5-Phosphate to IMP synthesis
The starting material for purine biosynthesis is Ribose-5-P, a product of the Hexose MonoPhosphate Shunt or Pentose Phosphate pathway (HMP Shunt). The ribose-5-P is converted into phosphoribosyl pyrophosphate by Pyrophospho Kinase in this reaction ATP is consumed.
PRPP is converted into Phosphoribosyl amine in the presence of the enzyme Amidophosphoribosyl transferase. Here amide group donor is Glutamine.
The phosphoribosyl amine is condensed with glycine it forms Glycinamide ribotide (GAR). This reaction is catalyzed by GAR Synthase.
Glycinamide ribotide is converted into Formyl glycine amide ribotide (FGAR). This reaction is catalyzed by transformylase. Here Formyl donor is N10-Formyl-THF.
Formyl Glycine ribotide is converted into Formylglycinaidine ribotide (FGAM) in the presence of the enzyme FGAM synthetase. Here amide donor is Glutamine and it is ATP consumed reaction.
FGAM is converted into 5-amino imidazole ribotide (AIR). This reaction is catalyzed by AIR Synthetase. Here ATP is consuming.
Amino imidazole ribotide is converted into CarboxyAmino Imidazole Ribotide (CAIR). This reaction catalyzed by AIR carboxylase. In this reaction, Carbonic acid is substituted on a 4th carbon atom as in the form of Carboxyl group (CAIR).
Carboxy Amino Imidazole has converted into 5-AminoImidazole (N-Succinylocarboxamide) ribotide (SACAIR). This reaction is catalyzed by SACAIR synthatase. In this reaction, one Aspartic acid linked with Carboxyl group ATP is consumed.
SACAIR is converted into 5-AminoImidazole-4-CarboxyAmide Ribotide (AICAR). This reaction is catalyzed by Adenosuccinate Lyase. The linked Aspartic acid hydrolyzed as Fumarate, which directly enters into TCA cycle.
AICAR is converted into 5-FormaminoImidazole-4-Carboxamide Ribotide (FAICAR). This reaction is catalyzed by Transformylase. Here formyl group donor is N10-Formyl THF.
FAICAR is converted into Inosine Mono Phosphate (IMP) by the catalyzation process. This reaction is catalyzed by IMP Cyclohydrolase.
Synthesis of AMP from IMP
IMP is the central intermediate of both AMP and UMP.
The IMP is converted into adenyloSuccinate by taking Aspartate and GTP, Which gives the power by the UTP to GTP and inorganic phosphate. This reaction is catalyzed by Adenylo Succinate synthatase.
Adenylo Succinate is converted into AMP by releasing Aspartate as in the form of Fumarate. This reaction is catalyzed by Adenylo Succinate Lyase.
Synthesis of GMP from IMP
IMP is converted into Xanthosine Monophosphate in the presence if the enzyme IMP-dehydrogenase. This is the dehydrogenation.
XMP is converted into GMP by the enzyme GMP synthase. Here Amino group donor is Glutamate.
Regulation of Purine Biosynthesis
- The activator molecule for Purine synthesis is PRPP, which activates the enzyme AmidoPhospho Ribosyl transferase
- The initiator molecule for the synthesis is Ribose-5-Phosphate. The optimum concentration of Ribos-5-Phosphate is maintained by the enzyme Glucose-6-Phosphate dehydrogenase, which is the regulatory enzyme of Hexose Mono Phosphate Shunt.
- The rate-limiting enzyme “Ribose-5-Phosphate Pyrophospho kinase” the enzyme inhibited Nucleotides AMP, ADP, ATP, GMP, GDP, GTP by Feedback inhibition mechanism.
- The Enzyme Amino phosphoribosyl transferase is inhibited by AMP, ADP, ATP, GMP, GDP, GTP adenylosuccinate and XMP.
- The Amp inhibits Adenylo succinate synthatase GMp inhibits IMP dehydrogenase.
Salvage Pathway (or) Dust-bin Pathway
This is another type of Purine Nucleotide Synthesis from scratch. So this is also called “Dust-bin pathway”. Most cells have an active turnover of many of their nucleic acids, results in the Adenine, Guanine, and Hypoxanthine.
Purines that result from the normal turnover of cellular nucleic acids or that is obtained from the diet and not degraded. It can be reconverted into Nucleoside tri phosphate and used by the body. This is referred to as the “Salvage pathway” for Purines.
Two enzymes are involved in this pathway.
- APRT means Adenosyl Phosphoribosyl Transferase
- This enzyme catalyzes in the reaction of Adenine to AMP conversion. In this reaction the secondary substrate is PRPP and byproduct is PPi.
Adenine + PRPP ↔ AMP + PPi
- HGPRT means Hypoxanthine-Guanine Phospho Ribosyl Transferase.
- This enzyme catalyzes the reaction of GMP formation from Hypoxanthine and PRPP.
Hypoxanthine + PRPP ↔ IMP + PPi
Guanine + PRPP ↔ GMP + PPi