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Purine metabolism

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Salvage pathway of purine Adenine + PRPP Mg 2+ APRTase Adenylate + PPi (AMP) Catalyzed by adenine phosphoribosyl transferase (APRTase) .

Hypoxanthine + PRPP Mg 2+ HGPRTase Inosinate + PPi ( IMP) Guanine + PRPP Mg 2+ HGPRTase Guanylate + PPi (GMP) HGPRTase = Hypoxanthine-guanine phosphoribosyl transferase .

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Purine and pyrimidine degradation .

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Formation of uric acid from hypoxanthine and xanthine catalysed by xanthine dehydrogenase (XDH). .

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Adenine phosphoribosyltransferase deficiency .

The alternative pathway is catalysed by xanthine oxidase.8-dihydroxyadenine. .The normal function of adenine phosphoribosyltransferase (APRT) is the removal of adenine derived as metabolic waste from the polyamine pathway and the alternative route of adenine metabolism to the extremely insoluble 2. which is operative when APRT is inactive.

. respectively. hypoxanthine and guanine. catalysed by HGPRT (1) in the presence of PP-riboseP. to IMP and GMP. The defect in HPRT is shown.The salvage pathway of the purine bases.

The importance of HPRT in the normal interplay between synthesis and salvage is demonstrated by the biochemical and clinical consequences associated with HPRT deficiency. accompanied by rapid catabolism of these bases to uric acid. . Gross uric acid overproduction results from the inability to recycle either hypoxanthine or guanine. which interrupts the inosinate cycle producing a lack of feedback control of synthesis. PP-ribose-P not utilized in the salvage reaction of the inosinate cycle is considered to provide an additional stimulus to de novo synthesis and uric acid overproduction.

• The disease is transmitted as an X-linked recessive trait.• HGPRT is determined by a gene on the long arm of the x-chromosome at Xq26. . • Lesch-Nyhan syndrome • Allopurinol has been effective reducing concentrations of uric acid.

7. . only the 16 and 32 subunits having significant activity. and is subject to complex regulation by different nucleotide end-products of the pathways for which PP-riboseP is a substrate.Phosphoribosyl pyrophosphate synthetase superactivity Phosphoribosyl pyrophosphate synthetase (PRPS.6.1) catalyses the transfer of the pyrophosphate group of ATP to ribose-5- phosphate to form PP-ribose-P. EC 2. It requires Mg2+. is activated by inorganic phosphate. particularly ADP and GDP. The enzyme exists as a complex aggregate of up to 32 subunits.

in which the interaction of glutamine and PP-ribose-P is catalysed by amidophosphoribosyl transferase. resulting in accelerated uric acid formation and overexcretion.PP-ribose-P acts as an allosteric regulator of the first specific reaction of de novo purine biosynthesis. insensitive to normal regulatory functions. Purine nucleotides cause a rapid reversal of this process. . producing the inactive form. or with a raised specific activity. This results in continuous PP-ribose-P synthesis which stimulates de novo purine production. inactive dimer to an active monomer. producing a slow activation of the amidotransferase by changing it from a large. Variant forms of PRPS have been described.

and the feedback control normally exerted by these nucleotides on de novo purine synthesis. .The role of PP-ribose-P in the de novo synthesis of IMP and adenosine (AXP) and guanosine (GXP) nucleotides.

Adenine deaminase deficiency (SCID) •SCID because of dATP accumulation from dA phosphorylation – leading to RR inhibition (DNA synthesis choked off. and the resultant accumulation of dATP when ADA is defective.cell proliferation blocked) •Lymphoid tissue very active in dA phosphorylation •The importance of adenosine deaminase (ADA) for the catabolism of dA. but not A. A is normally salvaged by adenosine kinase and deficiency of ADA is not significant in this situation .

2. • Less severe form of SCID as compared to ADA deficiency • Useful in the treatment of autoimmune diseases such as rheumatoid arthritis.1) • PNP catalyses the degradation of the nucleosides inosine.Purine nucleoside phosphorylase deficiency Purine nucleoside phosphorylase (PNP. guanosine or their deoxyanalogues to the corresponding base. EC 2. IDDM. T cell lymphomas and leukemias . • The mechanism appears to be the accumulation of purine nucleotides which are toxic to T cells.4.

in PNP deficiency is also apparent. The lack of functional HGPRT activity.Purine nucleoside phosphorylase (PNP) is required for normal catabolism and salvage of both nucleosides and deoxynucleosides. . through absence of substrate.

Myoadenylate deaminase (AMPDA) deficiency Purine nucleotide cycle AMPDA in the deamination of AMP to IMP. and the reconversion of the latter to AMP via Adenylosuccinate synthetase and lyase through adenylosuccinate Fumarate is added on for enhanced Kreb’s cycle (anaplerotic reaction) Patients suffer from fatigue and muscular cramps .

Eventually. leading to acute gout attacks. the uric acid may form needle-like crystals in joints. elevated levels of uric acid in the blood may lead to deposits around joints. Uric acid may also collect under the skin or in the urinary tract as kidney stones. .Intracellular uric acid crystal under polarised light (left) and under non-polarised light (right) With time.

Small Toe And Ankle Gout-Early Stage: No Joint Damage Gout-Late Stage: Arthritic Joint .Additional Gout Foot Sites: Inflamation In Joints Of Big Toe.

Disorders of pyrimidine metabolism .

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Symptoms: Secretion of orotic acid in urine. which catalyse the last two steps of the de novo pyrimidine synthesis. retarded growth and severe anemia Treatment: administration of uridine and / or cytidine. resulting in the formation of UMP.Hereditary orotic aciduria The UMP synthase (UMPS) complex. UMP inhibits CPSII . a bifunctional protein comprising the enzymes orotic acid phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (ODC).

A deficiency of DHPD leads to accumulation of uracil and thymine. .Dihydropyrimidine dehydrogenase (DHPD) is responsible for the catabolism of the end-products of pyrimidine metabolism (uracil and thymine) to dihydrouracil and dihydrothymine. Dihydropyrimidine amidohydrolase (DHPA) catalyses the next step in the further catabolism of dihydrouracil and dihydrothymine to amino acids. A deficiency of DHPA results in the accumulation of small amounts of uracil and thymine together with larger amounts of the dihydroderivatives.

CDP-choline phosphotransferase deficiency CDP-choline phosphotransferase catalyses the last step in the synthesis of phosphatidyl choline. A deficiency of this enzyme is proposed as the metabolic basis for the selective accumulation of CDP-choline in the erythrocytes of rare patients with an unusual form of haemolytic anaemia. .