Purine metabolism

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

Purine and pyrimidine degradation

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

Adenine phosphoribosyltransferase deficiency

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 2,8-dihydroxyadenine, which is operative when

APRT is inactive. The alternative pathway is catalysed by xanthine

oxidase.

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

The importance of HPRT in the normal interplay between synthesis and salvage is demonstrated by the biochemical and clinical
consequences associated with HPRT deficiency. 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, accompanied by rapid catabolism of these bases to uric acid. 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.

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

Phosphoribosyl pyrophosphate synthetase superactivity

Phosphoribosyl pyrophosphate synthetase (PRPS, EC 2.7.6.1) catalyses the transfer of the pyrophosphate group of ATP to ribose-5-

phosphate to form PP-ribose-P.

The enzyme exists as a complex aggregate of up to 32 subunits, only the 16 and 32 subunits having significant activity. It requires Mg2+, is activated by inorganic phosphate, and is subject to complex regulation by different nucleotide end-products of the pathways for which PP-riboseP is a substrate, particularly ADP and GDP.

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

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

Adenine deaminase deficiency (SCID)

SCID because of dATP accumulation from dA phosphorylation leading to RR inhibition (DNA synthesis choked off- cell proliferation blocked)

Lymphoid tissue very active in dA phosphorylation

The importance of adenosine deaminase (ADA) for the catabolism of dA, but not A, and the resultant accumulation of dATP when ADA is defective. A is normally salvaged by adenosine kinase and deficiency of ADA is not significant in this situation

Purine nucleoside phosphorylase deficiency

Purine nucleoside phosphorylase (PNP, EC 2.4.2.1)
PNP catalyses the degradation of the nucleosides inosine, guanosine or their deoxyanalogues to the corresponding base. The mechanism appears to be the accumulation of purine nucleotides which are toxic to T cells. Less severe form of SCID as compared to ADA deficiency Useful in the treatment of autoimmune diseases such as rheumatoid arthritis, IDDM, T cell lymphomas and leukemias

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

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 Krebs cycle (anaplerotic reaction) Patients suffer from fatigue and muscular cramps

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

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

Disorders of pyrimidine metabolism

Hereditary orotic aciduria

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

Dihydropyrimidine dehydrogenase (DHPD) is responsible for the catabolism of the end-products of pyrimidine metabolism (uracil and thymine) to dihydrouracil and dihydrothymine. A deficiency of DHPD leads to accumulation of uracil and thymine. 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.