INTRODUCTION TO URIC ACID METABOLISM Uric acid is a purine base, amongst others (adenine, guanine, xanthine and hypoxanthine),

that is derived from (i) de novo synthesis of purines or (ii) dietary purines. It is the end-product of purine metabolism Its metabolism (anabolism + catabolism) involves ONLY its anabolism becos once formed, it cannot be degraded by the human body; so, its eliminated via urine or feaces. Defect in this elimination results hyperuricemia and gout, and contribute to renal calculi

PURINE METABOLISM Purine anabolism/synthesis Involves 2 ways o De novo synthesis o Salvage pathway, an alternate pathways Sources of purine for anabolism o ENDOGENOUS: They may be synthesized de novo from small molecules o EXOGENOUS (or dietary): derived from the breakdown of ingested nucleic acid, mostly from cell-rich meat. Plant diets are generally poor in purines.

De novo Synthesis: First a preparatory phase takes place whereby a backbone of ribose 5-phosphate denoted by 5phosphoribosyl phosphate (= ribose 5-phosphate + ATP) is formed, catalysed by Phosphoribosyl phosphate synthase (PRPP synthase) Next, is the synthesis of purine by sequential adding of small molecule precursors (of uric acid) to this PRPP. The 1st rxn is the committed step, catalyzed by Amidophosphoribosyl transferase, and is the major site of regulation of the pathway because this enz can be inhibited by the products of the rxn or by the PRPP, the substrate. The Salvage pathway: It involves 2 enzymes: Adenine Phosphoribosyl transferase (APRT) and Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT)

PURINE BIOCHEMISTRY Purine base = pyrimidine ring (5C) + an Imidazole ring (6C) Weve mentioned the important purines bases: o Adenine, Guanine, Hypoxanthine, xanthine, Uric acid

They ALL show lactam-lactim isomerism Purine nucleoside = purine base + a pentose (ribose) sugar joined by N-glycosyl bond btw carbon atom 1 (of the pentose) and Nitrogen atom 9 of the purine There r 2 categories of purine Nucleoside; o Ribonucleoside contain D-ribose o Deoxynucleoside contains Deoxyribose The names of the nucleoside will be Adenosine, Guanosine, xanthosine,

Purine nucleotide = purine nucleoside (i.e. Ribonucleoside or Deoxyribonucleosid) + phosphate in ester linkage with C-5 of the pentose The phosphate are designated , , and

Purine catabolism: involves degradation of purine nucleotides (from DNA or from free Purines) to hypoxanthine, xanthine and then to uric acid. The most impt enz involved in this pathway is xanthine oxidase and the rxn it catalyzed is irreversible i.e. once hyoxanthine is formed, uric acid is sure to be formed

FUNCTIONS OF PURINE BASES i. ii. iii. iv. Building blocks for RNA and DNA Precursor of cyclic nucleotides like cAMP, cGMP, that r involved in signal transduction Source of chemical energy e.g. ATP, GTP Precursor of purine cofactors and co-enzymes such as NAD (nicotinamide adenine dinucleotide)

PHYSIOCHEMICAL PROPERTIES OF URIC ACID AND URATE It is a weak acid

1. Glomerular filtration: o Almost all urate in plasma r filtered. The rest are bound at low affinity and reversibly to albumin; this is of no physiological significance in man. 2. Reabsorption at the PCT o Theres almost complete reabsorption (99% reabsorption) 3. Tubular secretion (of 50% of absorbed urate) o Neither the site nor the mechanism for this urate secretion has been precisely identified in Man. 4. Post-secretory reabsorption @ the ascending limb of loop of Henle (80% of re-secreted urate). In the end abt 10% of filtered urate (approx. 600mgms/day) is excreted in urine.

CLINICAL CORRELATES HYPERURECEMIA - The solubility limit is abt 7.0 mg/dl (0.42mmol/L) in men or abt 6.0 mg/dl (0.36mmol/L) in women. - Above this concentration, plasma (and other ECFs) becomes saturated with urate - The solubility of uric acid in urine rises (i.e. more urate is formed) exponentially as the pH increases above 4. - However, in the plasma, synovial fluid and other tissues, there is little change in solubility within the pH range that may exit in these tissues. - As Temperature falls, both urate and uric acid solubility falls URATE SYNTHESIS Urate sources: are purine nucleotides URATE ELIMINATION Is via kidney (approx. 2/3 of produced urate) and via alimentary canal (remaing 1/3 of urate). Elimation via alimentary canal varies with plasma urate conc. Under Normal condition, negligible amt of urate is found in feces because it is degraded by colonic bacteria (uricolysis) On the other hand, in sterilized bowel, urate does not undergo uricolysis and may be found in feces. Definition: it is a clinical condition in which there is elevation of serum urate above 0.42mmol/L in men and above 0.36mmol/L in women. Etiology: Hyperuricemia is caused by either overproduction or under-secretion of urate or a combination of both. 1. Overproduction of urate is caused by o High dietary intake. o Increased purine synthesis (no more than 10% of patient with hyper urecemia) Idiopathic Inherited (several genetic mechanisms have been described) o Increased nucleic acid turnover Myeloproliferative disorders (e.g., leukemias) Psoriasis. Secondary polycythemia Chronic hemolytic anemias Carcinoma Cytotoxic drugs o Accelerated ATP degradation in: Glycogen storage dxs (type I, II, III, IV) Fructose ingestion Hereditary fructose intolerance Hypoxemia and underperfusion Sever muscle exertion Alcohol abuse

Elimination via kidney takes place in 4 stages;

2. Under-secretion of urate occurs with Chronic renal disease o Drugs Diuretics like Thiazide Salicylate (a.k.a aspirin) o Poisons e.g. lead o Increased organic acid concentration in

The genes that code for these enzymes are located in the X-chromosome (X-linked gene). Thus heterozygous men are affected if this gene is mutated. In partial deficiency of HGPRT and milder forms of superactivity of PRPP synthase, there will be: i. ii. iii. early onset of gout high incidence of uric acid stones in urinary tract Less neurologic lesions

blood Lactic acid Acetoacetic acid Beta-hydroxybutyrate o hyperparathyroidism

Classification of Hyperuricemia 1. Uric acid overproduction a. Primary Hypeuricemia: condition due to disordered uric acid metabolism that is not associated with another acquired disorder & in which gout is a prominent clinical feature i. Idiopathic ii. HGPRT deficiency (partial and complete) iii. PRPP synthase superacitivity b. Secondary Hyperuricemia: due to genetic or acquired disorders in which gout is a minor clinical feature i. Excessive dietary purine intake ii. Increase nucleotide turnover iii. Accelerated ATP degradation

In sever HGPRT deficiency, there will be more neurologic lesions i. spasticity, chorioathetosis, mental retardation and compulsive self-mutilation (Lesch-Nyhan syndrome)

GOUT Definition It is a disorder of purine metabolism characterized by hyperuricemia and deposition of salts of urate in connective tissues and cartilage. The term was first used in the 13th century A.D., derived frm the Latin word gutta Clinical features hyperurecemia acute gouty arthritis: around joints and other areas of soft tissues (like Achilles tendon, olecranon bursa, helix of ear) urolithiasis: uric acid stone in kidney and urinary collecting system chronic interstitial nephropathy; dx related to the deposition of monosodium urate monohydrate crystals in the substance of the kidney itself

2. Uric acid undersecretion a. Primary hyperuricemia i. Idiopathic b. Secondary hyperuricemia i. Diminished renal fxn ii. Inhibition of tubular urate secretion iii. Enhanced tubular urate reabsorption iv. Mechanism incompletely defined Hypertension Hyperparathyroidism Certain drugs - low dose aspirin, - many diuretics, - lead NB: urate overproduction is centred on the accumulation of PRPP which is caused by PRPP synthase superactivity or HGPRT deficiency

Epidemiology predominant in adult males than females Male prevalence = 10-20/1000 Female prevalence = 1-6/1000

Diagnosis 1. Characteristic clinical presentation. 2. Elevated serum urate level. 3. Microscopy of joint fluid: long needle crystals show strong negative birefrigence when examined under the polarizing microscope.