Is Prpp a Feed Forward Mechanism
Phosphoribosyl Pyrophosphate
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.
From: Gout & Other Crystal Arthropathies , 2012
Disorders of Purine and Pyrimidine Metabolism
Robert M. Kliegman MD , in Nelson Textbook of Pediatrics , 2020
Phosphoribosylpyrophosphate Synthetase Superactivity and Deficiency
Phosphoribosylpyrophosphate (PRPP) is a substrate involved in the synthesis of essentially all nucleotides and important in the regulation of the de novo pathways of purine and pyrimidine nucleotide synthesis. The synthetase enzyme (PRPS) produces PRPP from ribose-5-phosphate and ATP (seeFigs. 108.1 and108.2). PRPP is the first intermediary compound in the de novo synthesis of purine nucleotides that lead to the formation of inosine monophosphate, then to ATP and GTP.
Genetic disorders of this enzyme affect only the PRPS-1 isoform; PRPS-2 mutations have not been described. PRPS-1 disorders are all X-linked and are divided into "superactivity," which occurs as 2 phenotypes (infantile or early childhood onset, and a milder form with late-juvenile or early-adult onset), and "deficiency," which is a spectrum disorder that is distinguished clinically according to severity as 3 disorders: Arts syndrome, Charcot-Marie-Tooth disease X-linked-5, and X-linked deafness-2.
Superactivity of the enzyme results in an increased generation of PRPP in dividing cells. Because PRPP aminotransferase, the first enzyme of the purine de novo pathway, is not physiologically saturated by PRPP, the synthesis of purine nucleotides increases, and consequently the production of uric acid is increased. PRPP synthetase superactivity is one of the few hereditary disorders in which the activity of an enzyme is enhanced. The infantile or early childhood form of PRPS-1 superactivity has severe neurologic consequences accompanied by uric acid overproduction, whereas individuals with the late-juvenile or early-adult presentation are neurologically normal but still have uric acid overproduction.
Deficiency of PRPS-1 produces depleted purine nucleotide synthesis in tissues dependent on PRPS-1, which includes brain as well as other neural tissues and lung.
Genetics
Three distinct complementary DNAs for PRPS have been cloned and sequenced. Two forms, PRPS-1 and PRPS-2, are X-linked to Xq22-q24 and Xp22.2-p.22.3 (escapes X inactivation), respectively, and are widely expressed. The 3rd locus maps to human chromosome 7 and appears to be transcribed only in the testes. PRPS-1 defects are thus inherited as X-linked traits and present with varying degrees of severity. Thelate-onset form of superactivity arises from increased transcription of normal messenger RNA; the cause of this has not been discovered. Theearly-onset form of superactivity arises from mutations affecting allosteric regulation of the protein that controls feedback inhibition by inorganic phosphate and dinucleotides. At the same time, these mutations destabilize the protein, so that in slow or nonreplicating cells, such as neurons and red blood cells (RBCs), the enzyme becomes inactive. In contrast, the deficiency phenotypes of PRPS-1 are produced by mutations directly affecting enzyme function, usually in the substrate binding site. Even though the defect is X-linked, it should be considered in a child or young adult of either sex with hyperuricemia and/or hyperuricosuria and normal HPRT activity in lysed RBCs.
Nucleotide Metabolism
N.V. Bhagavan , Chung-Eun Ha , in Essentials of Medical Biochemistry (Second Edition), 2015
Formation of 5-Phosphoribosyl-1-Pyrophosphate
5-Phosphoribosyl-1-pyrophosphate (PRPP) is a key intermediate 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.:
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. 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. 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).
Read full chapter
URL:
https://www.sciencedirect.com/science/article/pii/B9780124166875000257
Hyperuricemia
Fred F. Ferri MD, FACP , in Ferri's Clinical Advisor 2022 , 2022
Etiology
Factors associated with urate variation are summarized inTable E1. Overproduction of uric acid accounts for a minority of cases of hyperuricemia. Most cases are a result of decreased renal clearance of uric acid and high dietary purine consumption.Fig. E1 describes factors affecting urate balance.Table E2 describes classification of hyperuricemia and gout.
FIG. E1. Factors affecting urate balance.
The systemic urate pool and the likelihood of gout are determined by the dynamic balance among dietary purines, endogenous synthesis and recycling, and disposal by the kidney and gut.ATP, Adenosine triphosphate.
From Hochberg MC et al:Rheumatology, ed 5, St Louis, 2011, Mosby. TABLE E1. Factors Associated with Urate Variation
| Genetic Factors | Dietary Influences | Clinical Associations |
|---|---|---|
| Male sex Common variants associated with hyperuricemia (replicated)
| Associated with increased urate
| Older age Postmenopause in women Medical comorbidities
|
FJHN, Familial juvenile hyperuricemic nephropathy;HPRT, hypoxanthine-guanine phosphoribosyltransferase;MCKD, medullary cystic kidney disease;PRPP, 5-phosphoribosyl 1-pyrophosphate.
From Hochberg MC:Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
Pediatric Neurology Part III
H.A. Jinnah , ... Georges Van Den Berghe , in Handbook of Clinical Neurology, 2013
Phosphoribosylpyrophosphate synthase defects
Phosphoribosylpyrophosphate (PRPP) synthase provides an example of how different mutations in the same gene may lead to different clinical phenotypes. Mutations in the PRPS1 gene that increase the activity of PRPP synthase lead to sensorineural hearing loss. Approximately half of these patients also have psychomotor retardation to varying degrees.
Mutations in the PRPS1 gene that reduce but do not eliminate PRPP synthase activity have been linked with some cases of the Charcot–Marie–Tooth syndrome, type CMTX5. Affected individuals have sensorineural hearing loss, optic neuropathy, and peripheral sensorimotor neuropathy. Mutations leading to a null PRPP synthase have been linked with Arts syndrome, which is characterized by hearing and visual loss, psychomotor retardation, and recurrent infections.
The mechanisms by which abnormalities in PRPP synthase cause neurological dysfunction are not known. 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). The clinical syndromes associated with PRPP synthase defects do not resemble the syndromes associated with APRT or HPRT defects. Thus neurological manifestations linked with PRPP synthase may result from alterations in nonpurine pathways.
Read full chapter
URL:
https://www.sciencedirect.com/science/article/pii/B9780444595652000526
Crystal Arthropathies
Edward J. Wing MD, FACP, FIDSA , in Cecil Essentials of Medicine , 2022
Pathophysiology of Hyperuricemia
Uric acid is the end product of purine metabolism in humans. Unlike many other species, humans lack the enzyme uricase, which catalyzes the conversion of uric acid into allantoin, a very soluble metabolite. Most individuals maintain uric acid levels between 4 and 6.8 mg/dL and a total body uric acid pool of approximately 1000 mg. However, uric acid levels may increase, leading to supersaturation of urate in blood. MSU crystals form in some patients with serum uric acid levels greater than 6.8 mg/dL. Only about 20% of hyperuricemic patients develop gout during their lifetime. Factors controlling crystal formation are poorly understood, but urate solubility may be affected by temperature, pH, salt concentration, and cartilage matrix components. Urate crystallization is a critical step in the progression from asymptomatic hyperuricemia to clinical gout. Unlike soluble urate molecules, MSU crystals are a potent promoter of acute inflammation.
The total body uric acid pool depends on the balance between dietary intake, synthesis, and excretion. About two thirds of the daily excretion of uric acid occurs in the kidneys; the rest is eliminated by the gut. Renal underexcretion is the cause for approximately 90% of hyperuricemia cases (Table 84.1). In the remaining 10%, hyperuricemia is caused by uric acid overproduction (>1000 mg in a 24-hour urine collection while on a standard Western diet) or by a combination of overproduction with renal underexcretion.
Fig. 84.1 summarizes the de novo biosynthesis and salvage pathways of purine metabolism. Abnormalities in the activities of key enzymes can lead to increased serum uric acid levels and development of gout. The de novo synthesis of purine is driven by the enzyme 5′-phosphoribosyl 1-pyrophosphate (PRPP) synthetase. In PRPP synthetase overactivity, overproduction of PRPP increases purine production. In salvage pathways, tissue-derived intermediate purine products (hypoxanthine, guanine, and adenine) are reutilized rather than undergoing further degradation to xanthine and uric acid. Deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity result in impaired purine salvage and increased substrate for uric acid generation (Lysch-Nyhan syndrome and Kelley-Seegmiller syndrome). Overall, inborn errors of metabolism account for a small fraction of uric acid overproduction.
Most cases of uric acid overproduction result from increased reutilization of purine bases through salvage pathways (seeFig. 84.1). The purine precursors come from exogenous (dietary) sources or endogenous metabolism (synthesis and cell turnover) Purine-rich foods such as red meat, organ meats (e.g., sweetbreads, liver), seafood, high-fructose corn syrup–sweetened beverages, and alcohol comprise a significant portion of the daily purine load and can worsen hyperuricemia. On the other hand, consumption of low-fat dairy products is associated with reduced serum urate levels and may decrease the risk of gout.
Purine Metabolism in the Pathogenesis of Hyperuricemia and Inborn Errors of Purine Metabolism Associated With Disease
Rosa Torres Jiménez , Juan García Puig , in Gout & Other Crystal Arthropathies, 2012
Pathophysiology
PRS catalyzes the PRPP synthesis from Mg-ATP and ribose-5-phosphate in a reaction that requires Mg2+ and inorganic phosphate (Pi) as activators. 18 Pi enzymatic activation involves two mechanisms: Pi stabilizes the enzyme loop involved in the binding of ATP, facilitating the substrate binding of Mg-ATP complex, and Pi is also an allosteric competitor of the enzyme inhibitor ADP. PRS reaction is subject to inhibition in a feedback mechanism by purine nucleotides as ADP and GDP. 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. In addition to de novo synthesis of purine, PRPP is used in the pyrimidine and pyridine nucleotide synthesis. PRPP is cofactor for uridine monophosphate synthetase (UMPS), which converts orotic acid into UMP, the precursor of all other pyrimidine nucleotides. Finally, PRPP is utilized for pyridine nucleotide synthesis by nicotinate phosphoribosyl transferase (NAPRT) and nicotinamide phosphoribosyl transferase (NAMPT) for the nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) synthesis.
PRS overactivity causes an increase in intracellular PRPP, which in turn is the cause of increased purine synthesis and uric acid overproduction. However, the pathophysiology of the neurologic dysfunction remains unclear.
Although PRS activity is coded by three different genes—PRPS1, PRPS2, and PRPS3 or PRPS1L1, to date, PRS overactivity is caused exclusively by an alteration in PRPS1 (MIM 311850), which codes for PRS-I or ribose-phosphate pyrophosphokinase 1. PRPS1 is located in chromosome X, and mutations in this gene have been also associated with three syndromes in which PRS-I activity is decreased: Arts syndrome (MIM 301835), 19 Charçot-Marie-Tooth disease-5 (MIM 311070), 20 and X-linked nonsyndromic sensorineural deafness or DFN2 21 (MIM 304500). Clinical manifestations of these syndromes include sensorineural deafness, mental retardation, hypotonia, peripheral neuropathy with demyelination, ataxia, and optic atrophy.
Severe PRS superactivity phenotype is caused by point mutations in the PRPS1 gene. 11,13,22 These mutations result in an alteration in the enzyme regulation with decreased inhibition by purine nucleotides and a higher Pi affinity and activation (Fig. 3-3). Mutations causing PRS-I superactivity are located by disturbing the allosteric sites, directly or by altering the homodimer interface (see Fig. 3-3). This fact explains the loss of feedback inhibition but may also result in a decrease protein stability. 23 Thus, in these patients, PRS activity determined in hemolysate is usually decreased due to the instability of the mutant protein in erythrocytes. Nucleotide levels are also low in erythrocytes. These facts suggest that PRS activity could be also decreased in neuronal cells, causing neurologic symptoms that develop only in the severe phenotype. However, a mild phenotype is caused by an increased PRPS1 expression of unknown mechanism. 24 In these patients, a higher Vmax is present due to a higher protein concentration and PRS activity is high in all cells tested. 24,25
Read full chapter
URL:
https://www.sciencedirect.com/science/article/pii/B978143772864410003X
Scientific Fundamentals of Biotechnology
J. Martinussen , ... M. Kilstrup , in Comprehensive Biotechnology (Second Edition), 2011
1.08.2 Synthesis of Phosphoribosyl Diphosphate (PRPP)
A common precursor in the biosynthesis of purines and pyrimidines is 5-phospho-d-ribosyl-1,α-diphosphate (PRPP). The phosphoribosyl moiety of nucleotides is derived from PRPP through the action of phosphoribosyltransferases that, therefore, play an important role in both salvage and de novo pathways as described below. 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:
PRPP synthases are divided into three classes depending on differences in which effectors influence the activity of the enzyme. Class I is activated by phosphate ions and inhibited by adenosine 5′-diphosphate (ADP), and sometimes guanosine 5′-diphosphate (GDP). Class II enzymes, so far only found in plants, are independent of phosphate ions and the purine nucleoside diphosphates, are simple competitive inhibitors. A third class of PRPP synthase was discovered in the archaean Methanocaldococcus jannaschii and was found to only be activated by phosphate ions, but not allosterically inhibited by nucleotides.
Apart from small molecule effectors, PRPP synthases from yeast and mammals are regulated through the formation of high-molecular-weight oligomeric structures composed of different subunits. In mammals, inactive subunits that resemble PRPP synthase at the sequence level are termed PAPs (PRPP synthase-associated proteins). The exact role that these supposedly regulatory subunits play in controlling the activity of PRPP synthase in these organisms is not clear at the moment, but for yeast it appears that among five different subunits only certain combinations are active.
Read full chapter
URL:
https://www.sciencedirect.com/science/article/pii/B9780080885049000106
Primary Metabolic and Renal Hyperuricemia
Kimiyoshi Ichida , ... Hitoshi Endou , in Genetic Diseases of the Kidney, 2009
Single Gene Disorder for Overproduction Type Hyperuricemia
Lesch-Nyhan Syndrome
HPRT catalyzes the salvage reactions of hypoxanthine and guanine with PRPP to form IMP and GMP (Figure 38.2). Though HPRT expresses ubiquitously among mammalian tissues, HPRT activity levels markedly change at different developmental stages. HPRT activity is usually higher in rapidly dividing cells. The HPRT gene was cloned and spans approximately 45 kb on Xq26-q27.2 (Shows & Brown 1975, Pai et al 1980, Jolly et al 1982). HPRT gene consists of nine exons (Figure 38.3). A large number of HPRT mutations in HPRT deficiency have been reported since 1983 (Wilson & Kelley 1983, Wilson et al 1983). Though some hot spots for HPRT mutations have been discussed, mutations causing disease appear throughout the HPRT gene (Figure 38.3).
Figure 38.3. The nine exons of the gene are shown as individual boxes, with the coding regions in gray and the non-coding regions pale. Those associated with the Lesch-Nyhan disease phenotype are shown above the gene, those associated with HPRT-related hyperuricemia with or without neurogenic dysfunction, below. (A) Single hprt base substitutions leading to amino acid substitutions. Individual point mutations are shown as circles. (B) Single hprt base alterlations leading to premature stop. Individual point mutations are shown as crosses. (C) Deletion mutations in the hprt gene. Short base deletions are shown as squares, and long deletions are shown as a horizontal line spanning the deleted segment. (D) Insertion mutation in the hprt gene. Short base insertions are shown as triangles
HPRT deficiency, designated Lesch-Nyhan syndrome, is an X-1inked recessive disorder. The clinical features of HPRT deficiency are classified into excessive purine production, and neurological and behavioral manifestations. The approximate clinical phenotype demonstrates a good correlation with the amount of residual enzyme activity. Patients with less 1.5% of residual enzyme activity, designated Lesch-Nyhan disease, have all the above three clinical features. Patients with l.5–8% of residual enzyme activity, designated Lesch-Nyhan disease variant or neurologic variant, demonstrate uric acid overproduction and neurological abnormalities without the behavioral abnormalities such as self-injurious behaviors. Patients with more than 8% of residual enzyme activity, designated Kelley-Seegmiller syndrome (MIM: 300323) or HPRT-related hyperuricemia, demonstrate only clinical manifestations of uric acid overproduction. Though the spectra of HPRT deficiency and the manifestation are a continuum and the terms are sometimes confusing, this classification is intelligible and supportive for understanding.
Lesch-Nyhan disease is the most common cause of hyperuricemia in infancy and childhood and the frequency approximates one in 380000 births (Crawhall et al 1972). The clinical manifestations of Lesch-Nyhan disease include urolithiasis or gout due to uric acid overproduction and overexcretion, mental and growth retardation, choreoathetosis, dystonia, compulsive self-injurious behavior, and sometimes megaloblastic anemia. Infants with Lesch-Nyhan disease appear normal at birth and usually develop normally for the first 3–8 months. The first manifestation is usually the occurrence of large quantities of 'orange sand' in the diaper caused by uric acid crystals and hematuria. The majority of patients with Lesch-Nyhan disease are recognized when they are between 3 and 12 months of age with motor disability or hypotonia. Extrapyramidal signs such as choreoathetosis and dystonia and pyramidal signs such as hyperreflexia and extensor plantar reflex typically begin to develop between 1 and 2 years of age. The patients can eventually neither stand nor sit unassisted because of the motor impairments. Self-injurious behavior is the hallmark of the Lesch-Nyhan disease and occurs in most of the patients with the disease. The average age of the behavior onset was 3 years, with a range of 1 to 8 years (Anderson & Ernst 1994). The characteristic behavior is self-destructive biting of 1ips, fingers, arms, and tongue. Other self-injurious behaviors include banging or snapping the head, injuring hands or feet with objects. Patients with Lesch-Nyhan disease do not wish to injure themselves.
The absence of HPRT leads to the tendency to accumulate its substrates, hypoxanthine and guanine. Serum concentration and urinary amount of the end product, uric acid, increase in HPRT deficiency. The intermediate product, xanthine, also tends to increase in the blood and urine of the patients with HPRT deficiency. As all patients with Lesch-Nyhan disease overproduce large quantities of uric acid, hyperuricemia – serum uric acid over 10 mg/dl – is present in most patients. Serum uric acid levels, however, occasionally remain in normal range because of efficient renal clearance.
Amount of urinary uric acid excretion and urinary uric acid to creatinine ratio of the patients increase over 50 mg/kg/day and 2, respectively, and are useful for the diagnosis. The measurement of HPRT enzyme activity is the conclusive confirmatory test for HPRT deficiency. The assays can be commonly conducted with cell lysates from any tissues, such as peripheral blood cells, though the lysates rarely provide misleading results. The measurement of HPRT enzyme activity of fibroblasts or lymphocytes in the culture accurately reflects the more actual activity.
Although Lesch-Nyhan disease leads to hyperuricemia resulting in gout, gout is relatively uncommon in children with Lesch-Nyhan disease. However, gout develops in most patients with Lesch-Nyhan disease without antihyperuricemic treatment. Hyperuricosuria frequently leads to stone formation in the renal medullae or the urological system in untreated patients and even after control of uric acid production with xanthine dehydrogenase inhibitor such as allopurinol.
PRPP Synthetase Overactivity (Superactivity)
PRPS catalyzes the transfer of the pyrophosphate group of ATP to ribose 5-phosphate to form PRPP. PRPP, an important regulator of de novo purine synthesis pathways, is a substrate in the initial step of the de novo pathway and for purine salvage reactions (Figure 38.2). The molecular weight of PRPS, widely expressed, is about 1000000 (Becker et al 1977, Taira et al 1989). PRPS is an aggregate complex of two catalytic subunits, PRPSl and PRPS2, and two associated subunits, PRPP synthetase-associated protein (PRPSAP) 1 and 2 (Becker et al 1990, Ishizuka et al 1996a, Katashima et al 1998). PRPSl gene and PRPS2 gene are located on the X chromosome at Xq22-24 and Xp22.3-22.2, PRPSAP1 gene and PRPSAP2 gene on the 17q24-q25 and 17p12-p11.2, respectively (Becker et al 1990, Ishizuka et al 1996, Katashima et al 1998). PRPS3 cDNA was also identified and maps to human chromosome 7, but is transcribed only in the testes (Taira et al 1989, 1990).
PRPS overactivity was described at first as a familial disorder characterized by excessive purine production, gout, and accelerated erythrocyte PRPS in the early 1970s (Sperling et al 1972, Becker et al 1973). PRPS overactivity is an X-1inked recessive disorder and about 30 families have been reported. Only a small number of point mutations in PRPSl has been identified in patients with PRPS overactivity (Figure 38.4). Values for PRPS activity in PRPS overactivity have varied widely and the variant enzymes are insensitive to normal regulation or with catalytic activity 2–4 times greater activity than normal.
Figure 38.4. The seven exons of the gene are shown as individual boxes, with the coding regions in gray and the noncoding regions pale. Single prps1 base substitutions leading to amino acid substitutions associated with PRPS overactivity. Individual point mutations are shown as circles
The clinical manifestations of PRPS overactivity include urolithiasis or gout due to hyperuricemia and hyperuricosuria similar to HPRT deficiency, and neurological deficits frequently including sensorineural deafness. There is a wide spectrum of the neurological deficits in severity. Patients with the greater severity show symptoms such as sensorineural deafness, cerebellar ataxia, muscular hypotonia, mental and motor retardation since early childhood and signs of uric acid overproduction (Simmonds et al 1982, Christen et al 1992). Two-thirds of the patients with PRPS overactivity, however, have presented with severe gout or kidney stones without neurological deficits in adolescence or early adulthood. The heterozygous females are sometimes hyperuricemic, hyperuricosuric and deaf in the premenopausal period. It should be suspected in any child or young adult of either sex with marked hyperuricemia and hyperuricosuria, but with normal HPRT activity in lysed red cells.
Glycogen Storage Disease
Hyperuricemia and gout frequently occur in glycogen storage disease types I and VII, and less so in types III and V (Mineo et al 1987, Maire et al 1991, Talente et al 1994, Rake et al 2002).
Glycogen Storage Disease Type I
Glycogen storage disease type I (GSD I; Von Gierke disease) is an autosomal recessive inborn error of carbohydrate metabolism caused by defects of the glucose-6-phosphatase (G6Pase) complex. G6Pase catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate in the terminal steps of gluconeogenesis and glycogenolysis. The genes responsible for GSD I including G6Pase and G6P transporter genes have been identified and various mutations in the genes of GSD I patients have been reported (Lei et al 1993, Lin et al 1998). G6Pase deficiency results in excessive accumulation of glycogen in the liver and kidney, leading to progressive hepatomegaly and renal enlargement. Clinical manifestations of GSD I including coma, seizures, irritability and increased respiratory rate caused by hypoglycemia, lactic acidosis and ketonemia, and hepatomegaly, present in early infancy. The recurrent hypoglycemia leads to the elevation of plasma glucagon levels, activating glycogen phosphorylase. The activation promotes the further elevation of G6P levels, resulting in a decrease of intrahepatic phosphate that inhibits AMP deaminase. This decrease stimulates AMP deaminase, resulting in the degradation of adenine nucleotides and consequent overproduction of uric acid (Greene et al 1978, Cohen et al 1985). Lactic acidosis and ketonemia also decreases renal uric acid excretion by stimulation of uric acid reabsorption via URAT1. Conclusively, both overproduction and underexcretion of uric acid cause hyperuricemia in GSD I.
Glycogen Storage Disease Types III, V, and VII
Glycogen storage disease types VII (Tarui desease; phosphofructokinase deficiency), V (McArdle disease; glycogen phosphorylase deficiency), and III (glycogen debranching enzyme deficiency) are autosomal recessive disorders. Muscle-related manifestations, muscle cramps with exertion and myoglobinuria with extreme exertion, are typical clinical features of glycogen storage disease types VII and V, while hepatomegaly and hypoglycemia, sometimes muscle weakness and wasting type III, occur. Phosphofructokinase, a rate-limiting enzyme in the glycolysis pathway, and muscle glycogen phosphorylase, catalyze the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate and the breakdown of glycogen to glucose-1-phosphate, respectively. Glycogen debranching enzyme has the two catalytic activities, amylo-1,6-glucosidase and oligo-1,4-1,4-glucanotransferase, that function independently at separate catalytic sites.
The mechanism of myogenic hyperuricemia in glycogen storage disease types VII, V, and III is related to excessive ATP breakdown in muscle during exercise as a result of impaired ATP synthesis (Mineo et al 1987). Excessive ATP breakdown and an accumulation of ADP or AMP result in the increase of the degradation to purine metabolites leading to overproduction of uric acid, the end metabolite of purines.
Read full chapter
URL:
https://www.sciencedirect.com/science/article/pii/B9780124498518000383
Purine, Pyrimidine, and Single-Carbon Metabolism
John W. Pelley PhD , in Elsevier's Integrated Biochemistry, 2007
Phosphoribosylamine Synthesis
The first component of the purine ring, an amine, is added to PRPP by an amidotransferase enzyme to form 5-phosphoribosylamine (Fig. 14-2). This is also the committed and rate-limiting step in purine synthesis. Feedback regulation of this reaction by the end products of the pathway—adenosine monophosphate (AMP), guanosine monophosphate (GMP), and inosine monophosphate (IMP)—prevents their overproduction. Feed-forward regulation by high concentrations of PRPP will override AMP, GMP, and IMP inhibition.
The purine pathway involves nine reactions that incorporate the various components of the purine ring, leading to the production of IMP (Fig. 14-3). The purine ring includes contributions from the entire glycine skeleton, the amino nitrogen of aspartate, the amide nitrogen of glutamine, carbon and O2 from CO2, and two single-carbon additions from tetrahydrofolate. The end product of this pathway, IMP, serves as an intermediate for synthesis of both AMP and GMP.
PATHOLOGY
Gout in Von Gierke's Disease
Von Gierke's patients have a buildup of PRPP due to an increase in the nonoxidative branch of the pentose phosphate pathway. The buildup of glucose 6-phosphate (G6P) results in excess concentrations of all glycolytic intermediates including glyceraldehyde 3-phosphate (G3P) and fructose 6-phosphate (F6P), both of which can lead to an elevation of ribose 5-phosphate. This in turn increases the concentration of PRPP, which forces overproduction of purines, leading to elevation of uric acid and gout.
Read full chapter
URL:
https://www.sciencedirect.com/science/article/pii/B9780323034104500201
Neurologic Aspects of Systemic Disease Part II
Roger E. Kelley , Hans C. Andersson , in Handbook of Clinical Neurology, 2014
Phosphoribosylpyrophosphate synthetase
In the salvage pathway, purine nucleotides are assembled from preformed nucleobases and 5-phosphoribosyl-1-pyrophosphate (PRPP). The synthesis of PRPP from Mg-ATP and ribose-5-phosphate is catalyzed by a family of the isoforms of the enzyme phosphoribosylpyrophosphate synthetase (PRPS) (Fox and Kelley, 1972). There is an X-linked disorder of purine metabolism related to increased activity of PRPS (Becker et al., 1988a) resulting in uric acid overproduction with gout. Neurologic manifestations can include sensorineural hearing loss as well as mental retardation and hypotonia (Becker et al., 1988b). Three isoforms of PRPS have been identified and mutant PRPS1s isoforms have been reported in six hemizygous unrelated males who had PRPS hyperactivity associated with impaired responsiveness to purine nucleotide inhibitor (Becker et al., 1995). Five of the six were reported to have neurodevelopmental delay. The cells of affected individuals were characterized by accelerated PRPP and purine synthesis as biochemical hallmarks (Becker et al., 1987).
Conversely, there have been reports of PRPS deficiency. Wada et al. (1974) reported an infant with mental retardation, hypouricemia and a defect of erythrocytic PRPS. Charcot–Marie–Tooth inherited neuropathy (CMTX5), including peripheral neuropathy, hearing loss, and optic atrophy has been attributed to diminished PRPS1 activity (Kim et al., 2007). This X-linked disorder, attributed to mutations in the PRPS1 gene, was detected by a roughly 50% reduction in enzymatic activity of PRPS in the patient's fibroblasts. There was no associated mental retardation with CMTX5, and the uric acid level was normal.
Arts syndrome is an X-linked disorder characterized by early-onset hypotonia, mental retardation, ataxia, motor development delay, hearing loss, optic atrophy, and susceptibility to recurrent infections. The latter manifestation typically leads to early death. The serum uric acid level is low while urinary purine profiles in this disorder are typified by undetectable hypoxanthine with normal xanthine and uric acid levels. From a genetic standpoint, this is associated with missense mutations in L152P and Q133P causing loss of PRPS1 activity, as has been reported by De Brouwer et al. (2007). These authors found that the greater severity of this disorder, compared to CMTX5, was attributed to quantitatively less PRPS activity, which was found to be absent in erythrocytes and of the order of 0–10% in fibroblasts compared to controls.
In summary, the phenotypic manifestations of PRPS1 gene mutations can reflect either genotypic hyper- or hypoactivity of this enzyme and appear to be a function of the degree of the residual enzymatic activity.
Read full chapter
URL:
https://www.sciencedirect.com/science/article/pii/B9780702040870000553
amendolaanorthems.blogspot.com
Source: https://www.sciencedirect.com/topics/medicine-and-dentistry/phosphoribosyl-pyrophosphate
0 Response to "Is Prpp a Feed Forward Mechanism"
Post a Comment