Purines metabolism

Inosinic acid (IMP) is the first purine formed, overall 6 high energy phosphate bonds are consumed to produce IMP. 

The PRPP amidotransferase enzyme exists as an active monomer and an inactive polymer (see Introduction to Metabolism Lecture). IMP, GMP and AMP all inactivate the enzyme causing a shift towards the polymerized inactive form. PRPP causes a shift towards the active monomeric form. 

AMP is a competitive inhibitor (see Enzymes Catalysis and Kinetics Lecture) of Adenylosuccinate Synthetase, GMP competitively inhibits IMP Dehydrogenase. Note GTP is required for AMP syndesis and ATP is required for GMP synthesis, hence there is coordinated regulation of these nucleotides. 

Note PNP = Purine Nucleotide Phosphorylase HGPRT = Hypoxanthine-Guanine Phosphoribosyl Transferase 

Note H2O2, a product of this reaction must be scavenged by Glutathione Reduced (see PPP/Gluconeogenesis Lecture). 

The assay for 17 a-hydroxylase was carried out under the same conditions except pregnenolone (human) or progesterone (rat) was used as the substrate. For either assay, the quenched reactions are shaken for 5 minutes and then centrifuged to separate the layers. The upper phase was discarded and the interface was washed with CHCU/MeOH/HzO (3 48 47). Following removal of the wash, the lower phase was evaporated to dryness at 40°C under nitrogen. The extracted metabolites were dissolved in the mobile phase. 

The enzyme preparations used were microsomes prepared from human or rat testes. 

126 Medical Biochemistry at a Glance, Third Edition. J. G. Salway. 2012 John Wiley Sons, Ltd. Published 2012 by John Wiley Sons, Ltd. 

The purine nucleotides GTP and ATP are very important in intermediary metabolism and the regulation of metabolism. Adenine is also a component of cyclic AMP, FAD, NAD, NADP and coenzyme A. Moreover, GTP, ATP and their deoxy derivatives dGTP and dATP are important precursors for the synthesis of RNA and DNA respectively, which are essential for cell growth and division. Purine biosynthesis (Fig. 59.1) needs the amino acids giutamine, giycine and aspartate. Also, tryptophan is needed to supply formate which reacts with tet-rahydrofolate (THF) to produce A -formyl THF, which donates the formyl group to the purine structure. A molecule of CO2 is also needed. 

Purine cataboiism produces urate, which has the disadvantage of 

Adenosine deaminase deficiency and severe combined immunodeficiency (SCID) 

Adenosine deaminase (ADA) deficiency is a very rare autosomal recessive disease and is responsible for 20-30% of recessively inherited cases of SCID. It causes ATP and dATP to accumulate, which feed-back to inhibit ribonucleotide reductase in thymocytes and peripheral blood B-ceUs. This in turn restricts the formation of DNA and hence the production of T- and B-ceUs (SCID). Infants are extremely vulnerable to infection as exempUfled by the case in the 1970s of David Vetter who spent his entire life of 12 years protected inside a plastic bubble and is immortalised in the film The Boy in the Plastic Bubble. Clinical trials of gene therapy for ADA-SCID are encouraging. 

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C. Allantoin is the end product of purine metabolism, and is excreted in the urine of most mammals, exceptions being man and the anthropoid apes. 

Uric acid is the endproduct of purine metabolism in man. Uric acid has a lower solubility than its progenitor metabolites, hypoxanthine and xanthine. Impaired uric acid elimination and/or increased uric acid production result in hyperuricemia and increase the risk of gouty arthritis. At physiological pH, 99% of the uric acid molecules are actually in the form of the urate salt. A decrease in pH increases the fraction of uric acid molecules relative to urate molecules. Uric acid possesses lower solubility than urate. 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Curto R> Voit EO, Cascante M Analysis of abnormalities in purine metabolism leading to gout and to neurological dysfunctions in man. Biochem J 1998 3 29 477. 

DeMoll E, T Auffenberg (1993) Purine metabolism in Methanococcus vannielii J Bacterial 175 5754-5761. 

The mechanism for the production of O2" in ischaemic tissue appears to involve changes in purine metabolism within ischaemic cells. Sublethal hypoxia decelerates mitochondrial oxidative phosphorylation, rendering the production of ATP dependent upon the... 

Gout A group of disorders of purine metabolism, manifested by various combinations of hyperuricemia recurrent acute inflammatory arthritis induced by crystals of monosodium urate monohydrate tophaceous deposits of monosodium urate monohydrate crystals in and around the joints of the extremities, which may lead to crippling destruction of joints and uric acid urolithiasis. 

Uric acid A by-product of purine metabolism in mammals, including humans. A high serum uric acid concentration is a major risk factor for gout. 

Adenine phosphoribosyltransferase (APRT) deficiency is an inherited disorder of purine metabolism and is inherited in an autosomal recessive manner (K18, V7). This enzyme deficiency results in an inability to salvage the purine base adenine, which is oxidized via the 8-hydroxy intermediate by xanthine oxidase to 2,8-di-hydroxyadenine (2,8-DHA). This produces crystalluria and the possible formation of kidney stones due to the excretion of excessive amounts of this insoluble purine. Type I, with virtually undetectable enzyme activity, found predominantly in Caucasians, is found in homozygotes or compound heterozygotes for null alleles. Type II, with significant APRT activity, found only in Japan, is related to a missense mu-... 

Uric acid is one of the principal products of purine metabolism in man 12 13). However, in many other organisms further oxidative degradation of the purine molecule occurs. One of the most important enzymes involved in uric acid oxidation is uricase, which has been studied to some extent in vitro. 

Uric acid is the end-product of purine metabolism in humans, other primates, birds and reptiles. It is produced in the liver by the oxidation of xanthine and hypoxanthine (Figure 12.16),... 

Purine metabolism in some mammals is characterized by a further oxidation of uric acid to al-lantoin by the enzyme urate oxidase. Allantoin is significantly more water soluble than uric acid and is also freely excreted via the renal route. 

Mutations in the gene for adenylosuccinate lyase (ASL), inherited as an autosomal recessive disorder in purine metabolism, are associated with severe mental retardation and autistic behavior, but apparently not self-mutilation [10, 11]. This enzyme catalyzes two distinct reactions in the de novo biosynthesis of purines the cleavages of adenylosuccinate (S-Ado) and succinylaminoimidazole carboxamide ribotide (SAICAR), both of which accumulate in plasma, urine and cerebrospinal fluid of affected individuals [12]. Measurements of these metabolites in urine... 

Nyhan, W. L. The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. /. Inherit. Metab. Dis. 20 171-178,1997. 

Dietary purines play an unimportant role in the generation of hyperuricemia in the absence of some derangement in purine metabolism or elimination. 

Sterol biosynthesis Bile acid biosynthesis C2rSteroid hormone metabolism Androgen and estrogen metabolism Nucleotide Metabolism Purine metabolism Pyrimidine metabolism Nucleotide sugar metabolism Amino sugar metabolism Amino Acid Metabolism Glutamate metabolism Alanine and aspartate metabolism Glycine, serine, and threonine metabolism... 

Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric add is the metabolic end product of purine metabolism. [NIH]... 

Enzymes in general vary widely in their substrate specificity, and this wide variation is found in the purine-metabolizing enzymes, as will be seen from the... 

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