Pathways

ASI MAMALON

Purines Catabolism. Focusing on definciency of ADA, causing SCID.

Pseudouridine is phosphorylated by interacting with atp and a psuK resulting in the release of an ADP, a hydrogen ion and a pseudouridine 5'-phosphate. The latter compound then reacts with water through a pseudouridine 5'-phosphate glycosidase resulting in the release of a uracil and D-ribofuranose 5-phosphate

The purine deoxyribonucleosides degradation starts with deoxyadenosine reacting with a water molecule and a hydrogen in through a deoxyadenosune deaminase resulting in the release of ammonium and a deoxyinosine. Deoxyinosine reacts in a reversible manner with phosphate through a deoxyinosine phosphorylase resulting in the release of a hypoxanthine and a 2-deoxy-alpha-D-ribose-1-phosphate. Deoxyadenosine reacts with a phosphate through a deoxyadenosine phosphorylase resulting in the release of adenine and a 2-deoxy-alpha-D-ribose-1-phosphate. This compound in turn reacts with guanine through a deoxyguanosine phosphorylase resulting in the release of a phosphate and a deoxyguanosine. Deoxy-alpha-D-ribose 1-phosphate reacts with a deoxyribose 1,5-phosphomutase resulting in the release of a 2-deoxy-D-ribose 5 phosphate. This compound in turn reacts with deoxyribose-phosphate aldolase resulting in the release of an acetaldehyde and a a D-glyceraldehyde 3-phosphate.

Purines are heterocyclic aromatic organic compounds that each consist of a pyrimidine ring fused to an imidazole ring. Common in nature, these water-soluble nitrogenous bases can form deoxyribonucleotides (as deoxyadenosine or deoxyguanosine) or ribonucleotides (as adenosine (AMP) or guanosine (GMP)), which are respectively the building blocks of DNA and RNA, both of which are formed by approximately equal amounts of purines and pyrimidines in most eukaryotes. Notable purines include adenine, guanine, caffeine, xanthine, and uric acid. In Arabidopsis thaliana (thale cress), purine metabolism consists of eighteen main key reactions that lead to nucleoside/nucleotide formation, all with well-characterized enzymatic catalysts, although this pathway includes more reactions in order to link purine metabolism to other cellular pathways, such as the pentose phosphate pathway; alanine, aspartate, and glutamate metabolism; thiamine metabolism; histidine metabolism; arginine biosynthesis; folate biosynthesis; riboflavin metabolism; glycine, serine, and threonine metabolism; urate degradation to glyoxylate, and its metabolism. In the chloroplast, adenosine diphosphate ribose is converted to D-ribose 5-phosphate in a reaction catalysed by a chloroplastic hydrolase, after which chloroplastic ribose-phosphate pyrophosphokinase 2 (also known as phosphoribosyl pyrophosphate synthase 2, or PRS II) catalyses the formation of phosphoribosyl pyrophosphate in the chloroplast stroma, which then reacts to form 5-phosphoribosylamine. GAR synthetase, a ligase, then catalyses the formation of 5’-phosphoribosylglycinamide (GAR). 5,10-Methenyltetrahydrofolate and GAR feed into IMP biosynthesis via de novo pathway, beginning with a reaction catalysed by a formyltransferase. In mitochondria or chloroplasts, a probable synthase catalyses the next reaction. Essential to the male gametophyte development, phosphoribosylformylglycinamidine synthase catalyses the ATP-dependent conversion of formylglycinamide ribonucleotide (FGAR) and glutamine to yield formylglycine amidine ribonucleotide (FGAM) and glutamate in the purine biosynthetic pathway. Subsequently, FGAM is converted into aminoimidazole ribotide (AIR) in a reaction catalysed by an ATP- and copper ion-dependent cyclo-ligase. AIR, catalysed by a carboxylase, then forms 1-(5-phospho-D-ribosyl)-5-amino-4-imidazole carboxylate (CAIR), which can form 1-(5’-phosphoribosyl)-5-amino-4-(N-succinocarboxamide)-imidazole (SAICAR) in a reaction catalysed by a chlorolastic synthase. SAICAR can feed into de novo AMP biosynthesis. The next reaction can take place in the cytosol (isoform 2) or in the chloroplast (isoform 1), depending on which protein is expressed. This pathway shows adenine phosphoribosyltransferase isoform 1 (chloroplastic), which catalyzes a salvage reaction resulting in the formation of AMP that is energetically less costly than de novo synthesis. It contributes primarily to the recycling of adenine into adenylate nucleotides, but is also involved in the inactivation of cytokinins by phosphoribosylation and also catalyzes the conversion of cytokinins from free bases (active form) to the corresponding nucleotides (inactive form). The subsequent few reactions take place in the cytosol, leading to the formation of various nucleotides, such as GMP. and indirect cGMP cycling. The nucleoside-diphosphate kinase (which exists in peroxisomes, nuclei, and the cytosol) plays a major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. This enzyme has a role in response to reactive oxygen species (ROS) stress. This reaction is bidirectional, but certain pyrophosphatases may act in one direction to catalyse similar reactions (not shown). Another pyrophosphatase hydrolyzes non-canonical purine nucleotides such as inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) or xanthosine 5’-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms, probably excluding non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions. A cytosolic GDP reductase provides the precursors necessary for DNA synthesis and catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. R1 contains the binding sites for both substrates and allosteric effectors and carries out the actual reduction of the ribonucleotide. Ribonucleotide reductase (RNR) complex function is essential for efficient organellar DNA degradation in pollen. It is involved in chloroplast division. Xanthine is formed via a phosphoribosyltransferase-catalysed reaction. Upon NADH oxidase activity via xanthine dehydrogenase, xanthine can react to form uric acid. This enzyme is key to purine catabolism; it catalyses the oxidation of hypoxanthine to xanthine and the oxidation of xanthine to urate in order to regulate the level of ureides and as such, it plays an important role during plant growth and development, senescence and response to stresses. Due to its cofactors, it may contribute to the generation of superoxide anions in planta. Urate oxidase, in the peroxisome, catalyses the oxidation of uric acid to 5-hydroxyisourate, which is further processed to form (S)-allantoin, while (R)-allantoin can form spontaneously. Allantoin, also known as glyoxyldiureide or 5-ureidohydantoin, belongs to the class of organic compounds known as imidazoles. Imidazoles are compounds containing an imidazole ring, which is an aromatic five-member ring with two nitrogen atoms at positions 1 and 3, and three carbon atoms. Allantoin exists as a solid, slightly soluble (in water), and a very weakly acidic compound (based on its pKa). Within the cell, allantoin is primarily located in the cytoplasm, and it has been detected in most biofluids. Allantoin exists in all living organisms, ranging from bacteria to humans. Allantoin is a potentially toxic compound to humans. This reaction is part of the urate degradation pathway, which is itself part of purine metabolism. Allantoinase, a zinc-dependent enzyme in the endoplasmic reticulum (that may also be found in the cell cytosol) catalyses the conversion of allantoin (5-ureidohydantoin) to allantoate by hydrolytic cleavage of the five-member hydantoin ring. The hydrolase can bind 2 manganese ions per subunit and can also use nickel and cobalt with lower activity. It catalyses the first step of the ureide allantoin degradation followed by the sequential enzymatic activity to allow complete purine breakdown without the intermediate generation of urea. In the cytosol, urea can form and is converted into ammonia in a reaction catalysed by the nickel-dependent urea hydrolase, which is involved in nitrogen recycling from ureide, purine, and arginine catabolism. The ATP-activated AMP deaminase and ectonucleotide pyrophosphatase enzymes catalyze reactions in the plant vacuole, feeding into arginine biosynthesis and the formation of ammonia, IMP, and ATP.

Purine is a water soluble, organic compound. Purines, including purines that have been substituted, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable examples are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The main organ where purine nucleotides are created is the liver. This process starts as 5-phospho-α-ribosyl-1-pyrophosphate, or PRPP, and creates inosine 5’-monophosphate, or IMP. Following a series of reactions, PRPP uses compounds such as tetrahydrofolate derivatives, glycine and ATP, and IMP is produced as a result. Glutamine PRPP amidotransferase catalyzes PRPP into 5-phosphoribosylamine, or PRA. 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted tosuccinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP creates a fork in the road for the creation of purine, as it can either become GMP or AMP. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Purine nucleotides being catabolized creates uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. Nucleotide creation stemming from the purine bases and purine nucleosides happens in steps that are called the “salvage pathways”. The free purine bases phosphoribosylated and reconverted to their respective nucleotides.

Purine is a water soluble, organic compound. Purines, including purines that have been substituted, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable examples are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The main organ where purine nucleotides are created is the liver. This process starts as 5-phospho-α-ribosyl-1-pyrophosphate, or PRPP, and creates inosine 5’-monophosphate, or IMP. Following a series of reactions, PRPP uses compounds such as tetrahydrofolate derivatives, glycine and ATP, and IMP is produced as a result. Glutamine PRPP amidotransferase catalyzes PRPP into 5-phosphoribosylamine, or PRA. 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted tosuccinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP creates a fork in the road for the creation of purine, as it can either become GMP or AMP. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Purine nucleotides being catabolized creates uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. Nucleotide creation stemming from the purine bases and purine nucleosides happens in steps that are called the “salvage pathways”. The free purine bases phosphoribosylated and reconverted to their respective nucleotides.

Purine is a water soluble, organic compound. Purines, including purines that have been substituted, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable examples are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The main organ where purine nucleotides are created is the liver. This process starts as 5-phospho-α-ribosyl-1-pyrophosphate, or PRPP, and creates inosine 5’-monophosphate, or IMP. Following a series of reactions, PRPP uses compounds such as tetrahydrofolate derivatives, glycine and ATP, and IMP is produced as a result. Glutamine PRPP amidotransferase catalyzes PRPP into 5-phosphoribosylamine, or PRA. 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted tosuccinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP creates a fork in the road for the creation of purine, as it can either become GMP or AMP. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Purine nucleotides being catabolized creates uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. Nucleotide creation stemming from the purine bases and purine nucleosides happens in steps that are called the “salvage pathways”. The free purine bases phosphoribosylated and reconverted to their respective nucleotides.

Purines are heterocyclic aromatic organic compounds, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable purines are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. Purines are found in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The major site of purine nucleotide synthesis is in the liver. Synthesis of the purine nucleotides begins with PRPP and leads to the first fully formed nucleotide, inosine 5'-monophosphate (IMP). IMP synthesis begins with 5-phospho-α-ribosyl-1-pyrophosphate, PRPP. Through a series of reactions utilizing ATP, tetrahydrofolate (THF) derivatives, glutamine, glycine and aspartate this pathway yields IMP. The rate limiting reaction is catalyzed by glutamine PRPP amidotransferase which drives the reaction with PRPP and glutamine yielding 5-phosphoribosylamine (PRA). 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted to succinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP represents a branch point for purine biosynthesis, because it can be converted into either AMP or GMP through two distinct reaction pathways. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Catabolism of purine nucleotides ultimately leads to the production of uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. The synthesis of nucleotides from the purine bases and purine nucleosides takes place in a series of steps known as the salvage pathways. The free purine bases, adenine, guanine, and hypoxanthine, can be reconverted to their corresponding nucleotides by phosphoribosylation. Two key transferase enzymes are involved in the salvage of purines: adenosine phosphoribosyltransferase (APRT), which catalyzes the conversion of adenine to AMP and hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which catalyzes the conversion of hypoxanthine to IMP.