Arts Syndrome and Loss-of-Function Mutations - Research Paper Example

Arts Syndrome and Loss-of-Function Mutations 1. Introduction: Phosphoribosyl pyrophosphate synthetase is a metabolic enzyme that plays a vital role in the energy breakdown processes along with the ATP. The focus of this assignment is to enhance the in-depth knowledge about PRPP synthetase gene and its role in causing genetic disorders. It plays a vital role in the biosynthetic process which results in the synthesis of purine, pyrimidine nucleotides and the pyridine nucleotides. This assignment examines the metabolic reactions occurring during the PRPP pathways and the synthesize of purine, pyrimidines and pyridine nucleotides. It further tries to trace out the hidden causes of inherited diseases. The PRPP synthetase has a regulatory role in the PRPP Synthesis and the purine and Purine nucleotide formation. The study also focuses on the role of Humane PRPP synthetase gene, such as the role in physiological process and the intermediation of biosynthesis of the amino acids, histidine and tryphan. In studying the PRPP Synthetase, the study also deals with its significance in yeast and bacteria. The researchers have found that the PRPP plays a vital role in maintaining health and purine pathways. Before concluding the study, list out the role of PRPP in causing the inherited disorders such as Arts Syndrome Phosphoribosyl Pyrophosphate (PRPP) Synthetase Defects, Xanthinuria, Myoadenylate Deaminase Deficiency, Adenine Phosphoribosyltransferase (APRT) Deficiencies., etc., 2. PRPP utilization and regulatory role: PRPP Utilization: The purine nucleotide synthesize in mammalian cells has received extensive research enquiries and studies. This process is carried out with the utilization of PRPP. The potential utilization of PRPP in the cells is carried out through a number of multiple reactions. There are a number of factors affecting the PRPP utilization. They are the PRTase; the intracellular concentration of PRPP and its co-substrates and the effectors such as allosteric regulators etc; certain cells contain increased concentration of PRPP and PRTase. The utilization of PRPP is carried out with PRTase such as hypoxanthine – guanine and amido enzymes. It acts as the catalyst in the utilization process of PRPP in purine salvage and de novo pathways. The PRTase has an important role in the utilization of the PRPP. The purine PRTase is a group of enzymes which helps in the utilization of PRPP. The PRTase uses PRPP along with a nitrogenous base to form purine, pyrimidine and pyrimidine nucleotides. All these are common to the metabolic reaction in mammalians. As an exception, the human cell has the normal rate of purine synthesis and PRPP utilization. Normally, the PRPP utilization rate is lower with adenine when compared to hypoxanthine salvage. In mammalian cells, it limits the availability of adenine by a compound called phosphorolysis of methylthioadenosine. “Phosphoribosyl pyrophosphate utilization proceeds in large part through specific PRTase catalyzed reaction in each of which the ribosylphosphate moiety of PRPP is transferred to one or more nitrogenous base acceptors, with formation of an N- glycoside bond at the C’1 position” (Moldave 2001, p.121). By using S - adenosylmethionine as a substrate ATP can be formulated by an alternative pathway with PRPP. It is essential for synthetase to the de novo purine formation. PRPP Regulation: The PRPP acts both as a coordinator and a regulator in the process of intracellular metabolism for the production of purine and pyrimidine nucleotide synthesize. The PRPP has an effective role to play along with ATP in both the de novo synthesis of purine and the purine based salvage. “Purine nucleotides are synthesized by alternative pathways, each requiring the key regulatory intermediate 5-phosphoribosyl 1-pyrophosphate (PRPP), which is synthesized from ATP and ribose-5-P in a reaction catalyzed by PRPP synthetase.” (Terkeltaub et al 2006). The regulation of nucleotide is carried out along with two processes. De nova synthesize and the Salvage pathway. De nova is a Latin word which is used to denote simple to complex. In the de novo synthesis of PRPP, synthetase acts as a catalyst to form PRPP from ATP and Rib-5 P. The purine nucleotides are formed in two ways. They are salvage path way and the de novo synthesis. In both the processes, the PRPP synthetase has essential role. “A wealth of evidence supports the concept that the sequential PRPP synthetase and amido PRTase reactions comprise the dominant regulatory domain for purine nucleotide synthesis.” (Moldave 2001, p.122). The de nova synthesis of purine formation occurs through a series of ten reactions. The second step of the process is called the AmidoPRT step. The regulation of the synthesis of nucleotides is carried out mainly in this step by both the activation of the PRPP and the AmidoPRT enzyme. The PRPP synthetase reaction will also affect the purine nucleotide products. 3. Human PRPP synthetase gene: Researchers and the professionals of health science have often documented the fact that phosphoribosyl pyrophosphates or ribose – phosphate diphosphokinase is one of the enzymes. Researchers have noticed that the Phosphoribosyl Pyrophosphates Synthetase helps to convert ribose 5 – phosphate in to phosphoribosyl pyrophosphate. A Phosphoribosyl Pyrophosphates Synthetase (PRS) catalyzes the synthesis of phosphoribosyl pyrophosphate or ribose – phosphate diphosphokinase and it also plays the role of an intermediate in the process of nucleotide metabolism. Another significant fact is that it also works as an intermediate in the biosynthesis of the amino acids histidine and tryptophan. Previous studies and researches have discovered that the Phosphoribosyl Pyrophosphates Synthetase is caused by the undetected inherited diseases in human body. The online article entitled, increased activity of PRPP synthetase helps the reader to think about the role of phosphoribosyl pyrophosphates in human body. The article explains that: “Human PRPP synthetase exists as heterogeneous aggregates composed of the 34kDa catalytic subunits (PRSI and PRSII) and other 39kDa and 41kDa components designated PRPP synthetase-associated protein (PAP39 and PAP41).” (Rinsho 2008, pp.698-8). By analyzing the functions of human body, one can find the fact that in physiological functions Phosphoribosyl Ppyrophosphate Synthetase’s (PRS) tremendous movement is differentiated by hyperuricemia and hyperuricosuria and it is separated in to inexorable phenotype with undeveloped, immature or early-childhood commencement. A reader can find that it also estranged with milder phenotype with late-juvenile or early adult commencement. The mild type of diseases is uric acid crystalluria or a urinary stone. Other types of erratic amalgamations are sensor neural hearing loss, hypotonic and ataxia, and it is not habitually presented in the mild type. We consider that purine plays an important role in our metabolism. So purine metabolism has affected different diseases. Defective genes are the main cause of these metabolic disorders. As a result, the enzyme amount is too little. Phosphoribosyl pyrophosphate synthetases defects are the result of two different faults linked with the enzyme. Mental diseases, anemia, and other disorders are enzyme deficiency diseases. The web article, The Purine Research Society annotates that “Enzyme deficiency results in convulsions, autistic behavior, anemia, and severe mental retardation. Excessive enzyme activity causes gout, along with various neurological symptoms, such as deafness. Aside from the treatment of gout, no treatment for the symptoms of these diseases is available at this time.” (What We Learn About Metabolic Disease Will Benefit Each and Every One of Us, 2009). Phosphoribosyl Pyrophosphate Synthetase (PRPP) action and the intracellular attentiveness of ribose – phosphate diphosphokinase were examined in erythrocytes as of patients with most important hyperuricemia and primary metabolic gout. Adenosine (ADP), Guano sine diphospate (GDP) and 2, 3 diphospho glycerate are the embarrassment reactions of the enzyme’s sensitivity. In PRPP synthetase movement in erythrocytes from gouty patients was very comparable to that of normal feed-back reserve by adenosine (ADP), Guano sine diphosphate (GDP) and 2, 3 diphospho glycerate be integral. The web article entitled Arts Syndrome Is Caused by Loss-of-Function Mutations in PRPS1 remarks that; “The PRPP synthetase activity in the patient fibroblasts was compared with that in fibroblasts from eight unrelated healthy control individuals.” (Brouwer et al 2007, pp.508-518). Researchers have emphasized that the attentiveness of Phosphoribosyl Pyrophosphate in erythrocytes was of lower rate in normal males than in lower female and the rate of its function is varied in both male and female. At the same time, it is very lower in hyperuricemic patients captivating allopurinol than in hyperuricemic patients. One of the striking remarks is that gouty patients and hyperuricemic patients have differentiated in their intracellular level of Phosphoribosyl Pyrophosphate and the level of Phosphoribosyl Pyrophosphate in hyperuricemic patients and gout patients not important in human body. Recent studies and researches have proved that Phosphoribosyl Pyrophosphate Synthesize (PRS) is one of the important chromosomes – linked disorders of Purine metabolism in human body and it influences the various genetic transactions in human body. The standard persons and nucleotide succession of pyrophosphate synthetase 2 cDNAs in patients are extremely indistinguishable. At the same time, the pyrophosphate synthetase 1 cDNAc from the patients has able to be seen with some dissimilarity from the normal PRS1 cDNA. One can find evidences in the online article Human X-linked Phosphoribosylpyrophosphate Synthetase Superactivity Is Associated with Distinct Point Mutations in the PRPSl Gene. It clearly remarks that; “The abnormal kinetic properties of N. B. and S. M. PRSs constitute only indirect evidence for a primary structural alteration in PRS, and no precise demonstration of aberrant PRS protein structure or PRS cDNA sequence has, to date, been achieved.” (Roessler et al 1993, p.1). Phosphoribosyl Pyrophosphate plays a vital role in various physiological activities and it is one of the substances that affect all kinds of nucleotides synthesis. Different enzymes pathway associations or links help to create this Phosphoribosyl Pyrophosphates Synthesis. So this synthesis makes relation to purine de novo and salvage pathways, and the pentose phosphate pathway to the pyrimidine. Studies have also proved that it is also related to other different enzyme pathways in various bodily activities. PRPP Synthesis has its own disadvantages also. In a human body, excessive level of PRPP synthesis makes problems in human purine metabolism. Researchers and scientists have often recorded that it makes different disorders in human body especially the disease associated with purine nucleotide and uric acid overproduction etc. Researchers and doctors have often warned that the over production of enzymes causes inflexible deficiency as well as catalytic abnormalities in human body. 4. Function of bacterial PRPP synthetase: Phosphoribosyl Pyrophosphate (PRPP) Synthetase contributes to the bacteria of purine nucleotides, pyrimidine nucleotides, tryptophan, histidine, and the pyridine nucleotide coenzymes. So it is a part of different bacterial nucleotides and other coenzymes. Some time Phosphoribosyl Pyrophosphate Synthesis is controlled in some bacteria in human body and it makes a rigid admiration among feedback inhibition by purine nucleotides. The online article Biosynthesis of D-arabinose in mycobacteria – a novel bacterial pathway with implications for antimycobacterial therapy explained that “Decaprenyl-phospho-arabinose has been a lead compound for the chemical synthesis of substrates for mycobacterial arabinosyltransferases and of new inhibitors and potential antituberculosis drugs. The peculiar (ω, mono-E,octa-Z) configuration of decaprenol has yielded insights into lipid biosynthesis, and has led to the identification of the novel Z-polyprenyl diphosphate synthases of mycobacteria.” (Wolucka 2008). Different enzymes help in the formation of anthranilate, especially Glutamine, endowed with an indispensable amino group. So PRPP is producing several carbons and it provides the Trp, as a result of PRPP, one of the important and imperative high –energy metabolite. The article Regulation and Mechanism of Phosphoribosylpyrophosphate Synthetase: Repression by End Products permitted that “Addition of end products to the growth medium, singly or in combination, resulted in small decreases in the specific activity of PRPP synthetase, but levels of the enzyme were never decreased to less than half of those found when the bacteria were grown on minimal medium. Growth of the bacteria on several different carbon sources or starvation for phosphate had little effect on the specific activity of PRPP synthetase.” (White et al 1971, pp.122-131). The excessive making of histidine in a histidine dictatorial mutant would be anticipated in to the reduction of intracellular PRPP pools. Auxotrophic strains of S. typhimurium will check up the levels of The Phosphoribosyl pyrophosphate (PRPP) synthetase. And it had been famished for the end product of PRPP. 5. Function of yeast PRPP synthetase: Phosphoribosyl Pyrophosphate is an important intermediate in various biosynthetic pathways. PRPP acts as the link between carbon and nitrogen metabolism. The yeast, Saccharomyces cerevisiae has four PRS genes. These four genes were cloned, sequenced and showed more similar characters with the amino acid sequences of rat, man and E. coli. The PRS genes play important roles in the energy generation and they are the main cause for the synthesis of PRPP, which is an indispensable factor for the nucleotide production. Mutations in these five genes will lead to several defects. This S. cerevisiae and PRPP will be interrelated to find many of the distinct cellular functions. In S. cerevisiae, Phosphoribosyl Synthetase (Prs) enzyme works as heteromer, because of the five paralogous genes, which contain divalent binding site and a phosphoribosyl pyrophosphate binding site, each of these genes has its own particular function in PRPP synthesis. “S. cerevisiae strains carrying individual deletions of any of the five Prs-encoding genes displayed a variety of phenotypes. In particular, deletions of PRS1 and/or PRS3 resulted in severe reduction in growth rate, enzyme activity and nucleotide content, whereas strains lacking PRS2, PRS4 or PRS5 are less affected in these parameters.” (Vavassori et al 2005, p.1) These enzymes have a major role in phospholipid metabolism and cell wall integrity. The distraction of the PRS1 or PRS3 has an important consequence on the cellular metabolism. The distraction of PRS2 or PRS4 has only small effect when compared to the other. The disorders with these genes will make less enzyme activity. PRS1 has the key role in PRPP synthesis. “Our analysis of the PRS gene family in S. cerevisiae has shown that Prs1p and Prs3p may play a more important role in PRPP biosynthesis than the other members of the family. To be able to understand the level of functional interaction among the PRS gene products, it will be necessary to analyze the phenotypes associated with strains bearing combinations of multiple disruptions of the PRS genes and to determine to what extent PRS activity is influenced by each member of this gene family.” (Hernando et al 1998, p.6407). One experiment showed the discharge of alkaline phosphatase with the loss of PRS1 and PRS3, in presence of caffeine. These show that phosphoribosyl pyrophosphate synthetase will affect the cell integrity. “The purine analogue caffeine affects many cellular processes; caffeine sensitivity has been shown to be associated with defects in components of the MAP (mitogen-activated protein) kinase pathways. prs1 prs3 strains have the most caffeine-sensitive phenotype, failing to grow in the presence of 2 mM caffeine. Caffeine sensitivity can be reversed by incubation in 1 M sorbitol as an osmotic stabilizer. Interestingly, PRS3 was isolated in a colony-sectoring assay to identify genes interacting with WHI2 whose deletion also causes caffeine sensitivity.” (Schneiter et al 2000, p.3276). 6. Purine pathways and health: Importance of purines: Purines are the naturally occurring substances that are found in whole cells of the body. They are widely spread as they contribute to the chemical structure of all genes of plants, animals and humans. Purines are very important for all cells as this is used in the synthesis of ATP, different cofactors, DNA, RNA and other important cell components. All the microorganisms can synthesize their own purines. They are the cyclic nitrogenous bases having several double bonds and they have the aromatic characteristics. Purines, mainly adenine and guanine, consist of two joined rings, while the pyrimidine has only one. The purine and pyrimidine base with a ribose or deoxyribose pentose sugar will make a nucleoside, and a nucleoside consisting of one or more phosphate group attached to the sugar makes a nucleotide. PRPP is used for the de novo synthesis and the salvage pathway of purines. PRPP synthetase is an important enzyme in the metabolism of several compounds. Purine pathways: Purine pathway includes complex 11 steps. The ribose-5-phosphate formed from the pentose phosphate pathway is moved to the nucleotide and amino acid synthesis steps with the transfer of the pyrophosphate from ATP to the OH group of the ribose-5-phosphate, which will form PRPP. These PRPPs are used in the purine, pyrimidine, tryptophan and histidine synthesizes. The pathway begins with the ribose-5-phosphate and the purine structure is built on this sugar. The first step in the pathway is the substitution of pyrophosphate of PRPP by the glutamine amide group. Hence the product formed by this step is 5-phosphoribosylamine (PRA). This is the rate limiting step of the purine pathway. In next step, glycine is added which was produced by ATP hydrolysis. The carboxyl group will make an amine bond to the NH2. The folic acid coenzyme is introduced to the NH2 group of the glycine, which then makes way to the closure of imidazole ring. Then, another NH2 is added to the first carbon of the glycine unit from the glutamine. A carboxylation step of second carbon of glycine is made and to the new carbon, a third NH2 group is added, which was transferred from the aspartate. After that, a second carbon is added to the nitrogen group and the ring will close to produce the purine precursor Inosine MonoPhosphate (IMP). The first product formed is the IMP. There are so many cofactors and enzymes participating in this. The cofactor folic acid is more crucial in this pathway. The folic acid derivatives will give the carbon-2 and carbon-8 to the purine structure. The drug called sulfonamide inhibits the bacterial growth by preventing the synthesis of folic acid. As the inosinic acid is formed, some more steps will be there which produces AMP and GMP, diphosphates and triphosphates by the transfer of phosphate from the ATP. The DNA contains deoxyribose nucleotides which are formed from the reduction of nucleoside di-and tri-phosphates by two different ways. Some of the microorganisms will reduce the triphosphate with the help of vitamin B-12 as the cofactor. Some microorganisms such as E. coli reduces diphosphates. In these steps, the reducing agent is thioredoxine. These steps are referred as de novo synthesis, which occurs actively in liver cytosol. Purine salvage pathway: The salvage pathway is another way of purine synthesis in which the enzyme hypoxanthine guanine phosphoribosyl transfer will play a major role in the subsequent steps which will convert GMP to IMP and then to hypoxanthine which will breakdown to xanthine and then uric acid. The HGPRT enzyme salvages guanine and hypoxanthine. The preformed purines will enhance the intermediates in purine salvage pathway. “The effect on the de novo purine synthesis is manifested in two ways: firstly a depressed activity of PRPP aminotransferase, the enzyme that catalyses the first reaction of the de novo synthesis. Since this enzyme could be inhibited by the feed-back of various purine nucleotides, with ATP and ADP being the most potent inhibitors, and secondly, a reduced supply of a substrate, PRPP, the common substrate for both de novo and salvage pathways. The augmented flow of the purine salvage pathway diverts the PRPP away from the de novo synthesis process. Consequently with a large supply of preformed purines, the de novo synthesis could be reduced to a minimum extent or switched off.” (The overall regulation of purine metabolism, n.d). Purines and health: The purines are found in all foods which will further show that the purines are present in all cells in body. Some food contains concentrated amount of purines. These will be high-protein rich foods which are very essential for the good health. These kinds of food items include kidney of animals, fish, yeast, mushrooms, cauliflowers, etc. Purines are very essential in the diet. As in the purine pathway, the human body can break the purines into uric acid. This uric acid helps in protecting the blood vessels from damage and these frequently occur when the cells die. This uric acid formation from the breakage of purines is a common process in the body and it will keep a healthy condition. The excessive or less formation of uric acid in the body will produce various negative results in the form of disorders like gout. Purines have many important roles in human health and daily life processes. Some of them are used to convert genes into proteins. Purines are used as energy transformers as they transform the energy from the food substance we eat into another energy usage form. Purines act as antioxidants which fight against the oncogenes. They have a significant role as messengers in the cell-cell signal transactions, as in the neuron signaling and they have a particular role in clearing all the surplus nitrogen. Our body could be called as individual chemical factories since enormous metabolic process occurs in our body each moment. The metabolic process is helped by the enzymes in our body to increase the rate of chemical reactions. The enzymes in our body are determined by the genes which are seen in the cells of the body and therefore chemical reactions also occur according to the nature of the enzymes. But occasionally there is a possibility to have defective enzymes which cannot function properly. Even though it does not act properly in accordance with the rest of the enzymes, the accumulated substrate might be toxic for the individual and the ability to survive also might be reduced. The metabolic diseases are handed over genetically and it is present in the individual from birth onwards even though it occurs at any age. Some of the metabolic diseases are sickle cell anemia which develops because of the defect of the protein that carries oxygen, cystic fibrosis which develops because of the defect of the enzyme that carries salt and lactose intolerance which develops because of the defect of the enzyme in the process of the digestion of sugar. Thus purine plays an important role in the health of a human. It is clear that its variations will result in several disorders like gouty arthritis, Lesch-Nyhan syndrome, adenosine deaminase deficiency, adenylosuccinate lyase deficiency, PNP deficiency, etc. The majority of purine diseases occur because of the defects in the phosphoribosyl pyrophosphate synthetase enzymes. The mutation in PRS gene can activate or deactivate this enzyme resulting in various disorders. This will be characterized by mental retardation, ataxia, delayed development, hypotonia, and immunodeficiency. Gout: Gout is a group of diseases associated with the accumulation of uric acid in the blood. High in-take of purine rich foods increases the uric acid levels on the human blood. It will cause the accumulation of urate crystals in the joints and tissues. This will be referred as gouty arthritis also, as it mainly affects the joints, wrists, ankles and knees. This is caused by the overproduction of urate in the body. By using the nucleoside or nucleotide substrates we can control this overproduction of uric acids. A method to control the gout is by using the allopurinol drugs, which are hypoxanthine isomers. It is used as a substrate for the enzyme xanthine oxidase. This allopurinol tightly binds with the enzyme, making it not able to oxidize the substrate, thereby blocking the formation of the uric acid. The controlled use of high purine food and maintaining a healthy balanced diet will also help in reducing the gout. Arts syndrome: Arts syndrome is an X-linked disorder caused by the mutations in phosphoribosyl pyrophosphate synthetase gene. This mutation results in the breakage of amino acid configurations in the PRPP synthetase enzyme. This is seen mostly in males. This syndrome is followed by the loss of almost complete hearing, mental retardation, ataxia, and high rate of infection leading to early death. Arts syndrome is characterized by most of the disorders as in gout. A controlled regulation of PRPP synthetase will produce the prevention of this syndrome. Charcot-Marie-Tooth disease: This is another disease caused by the mutations in the phosphoribosyl pyrophosphate synthetase gene. This will decrease the activity of the enzymes leading to peripheral neuropathy, hearing impairment, blindness. Lesch-Nyhan syndrome: This is one of the known diseases. This is caused by the deficiency of Hypoxanthine Guanine Phosphoribosyl Transferase (HGPRT) enzyme, which is an important enzyme in the purine salvage pathway. This inherited disorder is characterized by loss of muscle control, gout, unintentional twisting, repeat movements of legs and arms, etc. This syndrome is seen in boys by birth. Sometimes this leads to another disease, megaloblastic anemia, caused by the deficiency of vitamin B12 which is formed by the absence of HGPRT. Adenosine deaminase (ADA) deficiency: This is caused by the lack of adenosine deaminase enzyme, which is an important enzyme in the crucial stage of purine salvage pathway. This will cause the immunodeficiency. “The ADA gene consists of a single 32 kb locus containing 12 exons and is located on the long arm of chromosome 20. The enzyme adenosine deaminase is needed to break down metabolic byproducts that become toxic to T-cell lymphocytes, and is essential to the proper functioning of the immune system. Most of the body's cells have other means of removing the metabolic byproducts that ADA helps break down and remain unaffected by ADA deficiency. However, T-cell lymphocytes, white blood cells that help fight infection, are not able to remove the byproducts in the absence of ADA.” (Crow 2010). This enzyme helps in the conversion of adenosine to inosine. These will be treated by bone marrow transplantation or stem cell transplantation; and some gene therapy is also used for its treatment. Purine Nucleoside Phosphorylase (PNP) Deficiency: This deficiency is caused by the lack of purine nucleoside phosphorylase enzyme which is an enzyme with relevant role in purine salvage pathway. This enzyme helps in the degradation of purine and works on the formation of hypoxanthine from inosine and guanosine in the purine pathway. These results in autosomal recessive disorders. There will be accumulation of toxic metabolites and some symptoms like mental retardation, poor muscle control, etc. Xanthinuria: This is a rare disorder caused by the accumulation of xanthine. The enzyme xanthine oxidase helps in the conversion of xanthine to uric acid, which is a final stage in the purine synthesis. The deficiency of the enzyme xanthine oxidase leads to xanthinuria. This may result in high xanthine deposits in blood and urine. No specific treatment has found for this disorder, but the avoidance the high uptake of purine rich foods will reduce this xanthinurea disorder. Adenine Phosphoribosyltransferase (APRT) Deficiency: This is caused by the mutation of the enzyme adenine phosphoribosyl transferase. This metabolic disorder will cause some problems like kidney damage, stone formation, etc. An effective treatment is not there and it is recommended to control purines in the food. Adenylosuccinate Lyase Deficiency: This is caused by the lack of adenylosuccinate lyase enzyme. Adenylosuccinate lyase enzymes will catalyze the conversion of Succinyl Amino Imidazole Carbox Amideribotide (SAICAR) into Aminoimidazolecarboxamideribotide (AICAR), and also the conversion of adenylosuccinate to adenosine monophosphate (AMP). These are characterized by the accumulation of succinylpurines. There are various symptoms like retardation, hypotonia, autistic characters, etc. There is no correct treatment found for this deficiency. Myoadenylate Deaminase Deficiency: Myoadenylate deaminase or AMP deaminase helps in the conversion of adenosine monophosphate (AMP) into inosine monophosphate (IMP). This enzyme deficiency affects the muscle cells. Thus it affects the cell’s potential to reuse ATP, the major energy source of the cell. Phosphoribosyl Pyrophosphate (PRPP) Synthetase Defects: The over activity and the deficiency of the PRPP synthetase will adversely affect the human health. The enzyme deficiency of PRPP synthetase enzymes is characterized by some form of mental retardation and hypouricemia, while the excess PRPP synthetase will cause the hyperuricemia, partial or complete hearing impairment, hypotonia, poor muscle control, etc. Thus these enzymes’ superactivity and deficiency leads to the inherited disorders. 5' Nucleotidase Defect: The excessive activity of the 5' nucleotidase enzyme causes an unusual defect in the purine metabolism, causing unusual behavior, disability to speak or to communicate. There is no specific treatment method. But, this defect can be reduced by controlling the diet. These are some of the disorders affecting the human health associated with the purine metabolism. These disorders are affected by the deficiency or over activity of the different enzymes participating in the purine de novo synthesis and the purine salvage pathway, some of which will be a threat to the human life. 7. Conclusion: The phosphoribosyl pyrophosphate synthetase 1 is a gene which acts as a catalyst in the formation of the PRPP enzyme. Purines and Pyrimidines are formed through the de nova synthesize or from the breakdown of DNA and RNA. The breakdown of DNA and RNA to produce purines and Pyrimidines are known as salvage pathway. The PRPP is essential in the source of energy as Adenosine Triphosphate. Recent studies have revealed that PRPP is equally important in Yeast and bacteria as important in man. The pathway of purine nucleotide synthesis and its regulation is carried out by PRPP. The purines are the major components of the energy mechanisms in the form of ATP, NAD, etc. They have a main role in cellular signaling also. These purines can be synthesized by de novo or by salvage pathway. The end product of this pathway will be uric acid. The enzyme phosphoribosyl pyrophosphate synthetase plays a major role in the purine metabolism. The deficiency or over activity of these enzymes will lead to inherited disorders. In the purine pathway, the important enzyme is phosphoribosyl pyrophosphate synthetase which catalyses the conversion of ribose-5-phosphate to phosphoribosyl pyrophosphate with the help of ATP. The PRPP is the main substrate for purine and pyrimidine nucleotide metabolism. The PRPP synthetase has a crucial role in several other compound metabolism like histidine, tryptophan. From the above studies, it is clear that the enzyme PRPP synthetase will be the major cause for several inherited disorders. The excess PRPP synthetase activity will make several disorders like hyperuricaemia and gout. This will also affect the nerve cells and cause neurological damages. Some of the other after-effects include sensorineural hearing problems, weak muscle activity, coordination and delayed development. The diseases like Arts syndrome, Charcot-Marie-Tooth disease, and various forms of gout are formed because of the overactivities of these PRPP synthetase genes, which results in the deposition of uric acid in the blood and urine in the body. These may result in kidney or renal failure also. This rare recessive disorder is inherited in the X-linked pattern and the males are affected mostly. The up-take of balanced purine foods in the diet will maintain the good health without any of these disorders. Reference List Brouwer, A. P. et al., 2007. Arts syndrome is caused by loss-of-function mutations in PRPS1. [Online] Pub Med Central, 81(3), pp.507-518. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950830/ [Accessed 22 July 2010]. Crow, P., 2010. ADA (Adenosine Deaminase) deficiency: Treatments for ADA deficiency. [Online] Iaea.org. 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