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Disorders of purine and pyrimidine metabolism 

Disorders of purine and pyrimidine metabolism

Disorders of purine and pyrimidine metabolism

Richard W.E. Watts


November 28, 2013: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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date: 29 April 2017

These disorders are due to abnormalities in the biosynthesis, interconversion and degradation of the purines—adenine and guanine—and of the pyrimidines—cytosine, thymine and uracil. All are heterocyclic bases which exist in tri-, di-, and mono-phosphorylated forms, and as either deoxyribosylated or ribosylated derivatives (deoxyribose and ribose are pentose carbohydrates). The phosphorylated deoxyribosylated and ribosylated derivatives are termed ‘nucleotides’, and the purely ribosylated derivatives, which lack the phosphate group, are ‘nucleosides’.

The purine nucleotides, their cyclic derivatives (cAMP and cGMP), and their more highly phosphorylated derivatives have functions in many aspects of intermediary metabolism. Purine compounds also function as signal transducers, neurotransmitters, vasodilators and mediators of platelet aggregation.

The polynucleotide deoxyribonucleic acid (DNA) contains equimolar amounts of adenylic acid (adenosine monophosphate, AMP), guanylic acid (guanosine monophosphate, GMP), thymidylic acid (thymidine monophosphate, TMP) and cytidylic acid (cytidine monophosphate, CMP). Uridylic acid (uridine monophosphate, UMP) replaces TMP in the polynucleotide ribonucleic acid (RNA).

Disorders of purine metabolism

Most human disease connected with disorders of purine metabolism is due to uric acid and sodium urate monohydrate, crystallization of which in vivo from supersaturated body fluids causes gout (see Chapter 19.10). This results from either overproduction or underexcretion of urate, or from a combination of these defects:

Decreased net tubular urate secretion—the commonest cause of primary (‘idiopathic’) gout and for gout secondary to a wide variety of renal disorders, ranging from simple reduction in glomerular filtration rate (chronic kidney disease) to specific defects, e.g. familial juvenile hyperuricaemic nephropathy caused by mutations in the gene for uromodulin (Tamm–Horsfall protein).

Identifiable enzymatic defects that accelerate de novo urate synthesis, e.g. (1) X-linked hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency—which produces a clinical spectrum extending from hyperuricaemia alone to hyperuricaemia with profound neurological and behavioural dysfunction (Lesch–Nyhan syndrome); (2) X-linked recessive hyperuricaemia and phosphoribosyl pyrophosphate (PRPPS) synthetase superactivity—both of which present with uric acid lithiasis or gouty arthritis in childhood or early adult life. Treatment with newly emerging and established urate-lowering agents as well as anti-inflammatory drugs, is constantly improving;management of these conditions is reviewed here with respect to acute and chronic syndromes of hyperuricaemia and gout.

Hypouricaemia—this may be caused by inherited disorders of uric acid and pyrimidine biosynthesis, e.g. xanthine oxidase deficiency, or to inherited or acquired renal tubule transport defects.

Other diseases of purine metabolism—these cause diverse abnormalities and are generally the result of single gene defects, e.g. adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) catalyse sequential steps in the metabolism of purine ribonucleosides and deoxyribonucleosides and are highly expressed in lymphoid cells; their deficiency causes lymphotoxic substrates to accumulate and leads to lymphopenia and immunodeficiency.

Disorders of pyrimidine metabolism

The de novo synthesis of pyrimidine nucleotides involves a series of six reactions beginning with the formation of carbamyl phosphate and concluding with orotidylic acid, which then undergoes a series of interconversion and salvage reactions. The inherited disorders of pyrimidine metabolism (e.g. orotic aciduria) are much less common, or possibly much less easily recognized, than disorders of purine metabolism.

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