De novo PRSP1 mutations have also been reported. Management and treatment Treatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria.
Full Answer
What is PRPP synthetase?
PRPP is an important substrate for the synthesis of purine, pyrimidine, and pyridine dinucleotides. Human PRS exists as complex aggregates composed of the 34 kDa catalytic subunits(PRS1 … Phosphoribosylpyrophosphate(PRPP) synthetase(PRS) catalyzes the formation of PRPP from ATP and ribose-5-phosphate.
What does the PRPS1 gene do?
The PRPS1 gene provides instructions for making an enzyme called phosphoribosyl pyrophosphate synthetase 1, or PRPP synthetase 1. This enzyme helps produce a molecule called phosphoribosyl pyrophosphate (PRPP). PRPP is involved in producing purine and pyrimidine nucleotides.
How is PRPP synthesized from ribose 5 phosphate?
PRPP is synthesized from ribose 5-phosphate by the following reaction: In this reaction, the pyrophosphate group of ATP is transferred to ribose 5-phosphate; the product PRPP is a high-energy compound. PRPP synthetase has an absolute requirement for inorganic phosphate (Pi), which functions as an allosteric activator.
What is the function of the enzyme PRPP?
This enzyme helps produce a molecule called phosphoribosyl pyrophosphate (PRPP). PRPP is involved in producing purine and pyrimidine nucleotides. These nucleotides are building blocks of DNA, its chemical cousin RNA, and molecules such as ATP and GTP that serve as energy sources in the cell.
What causes PRPP synthetase deficiency?
Inheritance. This condition is inherited in an X-linked pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes . In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder.
What is PRPP synthetase inhibited by?
PRPP synthetase has an absolute requirement for inorganic phosphate (Pi), which functions as an allosteric activator. The enzyme is inhibited by many nucleotides, the end products of the pathway for which PRPP is an essential substrate. The gene for PRPP synthetase is located on the X-chromosome.
How is PRPP synthetase regulated?
Non-oxidative pentose phosphate pathway enzymes showed no change in activity, but PRPP synthetase is regulated by phosphate, and we found that phosphate uptake and total intracellular phosphate concentration increased significantly between mid-G1-phase and early S-phase.
What activates PRPP synthetase?
PRS catalyzes the PRPP synthesis from Mg-ATP and ribose-5-phosphate in a reaction that requires Mg2+ and inorganic phosphate (Pi) as activators.
What enzyme deficiency causes gout?
Hypoxanthine:guanine phosphoribosyltransferase deficiency is known to cause hyperuricaemia and gout.
What is the importance of PRPP?
Phosphoribosyl diphosphate (PRPP) is an important intermediate in cellular metabolism. PRPP is synthesized by PRPP synthase, as follows: ribose 5-phosphate + ATP → PRPP + AMP. PRPP is ubiquitously found in living organisms and is used in substitution reactions with the formation of glycosidic bonds.
What are the substrates of PRPP synthetase?
PRPP is substrate of three enzymes of purine metabolic pathway: PRPP amidotransferase, in de novo synthesis pathway, which serves specifically as the rate-limiting reaction for the purine synthesis, and HPRT and APRT in the salvage pathway.
How is purine synthesis regulated?
Purine nucleotide biosynthesis is regulated at several steps IMP synthesis is controlled by the levels of adenine and guanine nucleotides. Additional control is exerted by feedforward activation, which is the stimulation of a subsequent enzyme by the preceding substrate.
Why is PRPP so important in nucleotide metabolism?
(PRPP) plays an important role in cardiac metabolism because it is an essential precursor substrate for the synthesis of purine and pyrimidine nucleotides. The size of the PRPP pool is strictly limited so that the rate of de novo (bio)synthesis of adenine nucleotides is also very small in the rat heart [1,2].
What is PRPP in DNA?
Phosphoribosyl pyrophosphate (PRPP) is a pentose phosphate and a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate. Hence it is a building block for DNA and RNA. The vitamins thiamine and cobalamin, and the amino acid tryptophan also contain fragments derived from PRPP.
What enzyme makes PRPP from ribose-5-phosphate?
Ribose phosphate pyrophosphokinaseRibose phosphate pyrophosphokinase catalyzes the transfer of pyrophosphate from ATP to ribose 5-phosphate to form AMP and phosphoribosyl pyrophosphate (PRPP).
What happens if you have a mutation in PRPS1?
In people with the more severe form of PRS superactivity, PRPS1 gene mutations change single protein building blocks ( amino acids) in the PRPP synthetase 1 enzyme, resulting in a poorly regulated, overactive enzyme. In the milder form of PRS superactivity, the PRPS1 gene is overactive for reasons that are not well understood.
Why is PRPS1 overactive?
PRPS1 gene overactivity increases the production of normal PRPP synthetase 1 enzyme, which increases the availability of PRPP. In both forms of the disorder, excessive amounts of purines are generated.
What is the function of PRPS1?
Certain mutations in the PRPS1 gene cause PRS superactivity . The PRPS1 gene provides instructions for making an enzyme called phosphoribosyl pyrophosphate synthetase 1, or PRPP synthetase 1. This enzyme helps produce a molecule called phosphoribosyl pyrophosphate (PRPP). PRPP is involved in producing purine and pyrimidine nucleotides. These nucleotides are building blocks of DNA, its chemical cousin RNA, and molecules such as ATP and GTP that serve as energy sources in the cell. PRPP synthetase 1 and PRPP also play a key role in recycling purines from the breakdown of DNA and RNA, a faster and more efficient way of making purines available.
When does PRS superactivity start?
There are two forms of PRS superactivity, a severe form that begins in infancy or early childhood, and a milder form that typically appears in late adolescence or early adulthood. In both forms, a kidney or bladder stone is often the first symptom.
How many families have PRS superactivity?
PRS superactivity is believed to be a rare disorder. Approximately 30 families with the condition have been reported. More than two thirds of these families are affected by the milder form of the disease.
What is PRPP synthetase?
PRPP synthetase has an absolute requirement for inorganic phosphate (Pi), which functions as an allosteric activator.
Where is PRPP synthetase located?
The gene for PRPP synthetase is located on the X-chromosome. Mutations in this gene have given rise to PRPP synthetase variants with increased catalytic activity, which leads to overproduction of uric acid (discussed later, under “Gout”). The main source of ribose-5-phosphate is the pentose phosphate pathway (Chapter 14 ).
What is the role of PRPP in purine metabolism?
In addition, PRPP also plays an important role in regulating the expression of genes in purine metabolism as discussed later. The compound PRPP is synthesized by PRPP synthase that transfers the β,γ-diphosphoryl group from ATP to the 1-position of ribose 5-phosphate to give PRPP: ATP + Ribose 5 - phosphate → PRPP + AMP.
What is PRPP in the purine pathway?
PRPP is substrate of three enzymes of purine metabolic pathway: PRPP amidotransferase, in de novo synthesis pathway, which serves specifically as the rate-limiting reaction for the purine synthesis, and HPRT and APRT in the salvage pathway.
What is PRPP in biology?
PRPP serves as a cosubstrate for a diverse family of enzymes, only three of which are involved directly in purine metabolism. These include the first and rate-limiting step of de novo purine synthesis (amidophosphoribosyltransferase (AMPRT)) as well two recycling enzymes (APRT and HPRT).
What is the name of the gene that increases the activity of PRPP synthase?
Mutations in the PRPS1 gene that increase the activity of PRPP synthase lead to sensorineural hearing loss.
What is the role of PRPP in nucleotide biosynthesis?
It is required for de novo synthesis of purine and pyrimidine nucleotides and the salvage pathways, in which purines are converted to their respective nucleotides via transfer of ribose 1-phosphate group from PRPP to the base , i.e.:
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Epidemiology
PRPP synthetase superactivity is a rare disorder with 30 families described in the literature. The severe form accounts for approximately 25% of cases. The disorder predominantly affects males.
Clinical description
The phenotype varies greatly among patients.
Etiology
The disease is due to overactivity of PRPP synthetase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in overproduction of purine nucleotides and uric acid (a waste product of purine breakdown).
Diagnostic methods
Diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by either molecular genetic testing or a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes.
Differential diagnosis
Differential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and psychomotor delay due to S-adenosylhomocysteine hydrolase deficiency.
Antenatal diagnosis
Prenatal genetic testing in male fetuses is possible where a mutation has previously been identified in a family member.
