Alifah Syarafina A5-DMS | Case 5

URIC ACID METABOLISM

Purines :Adenine and Guanine Pyrimidines : Cytosine. Timin, Uracil

Uric acid is the final end product of purine metabolism. The formation of uric acid depends upon two factors :

the quantity of purines ingested in the diet the formation of purines in the body

Actually, there are 2 pathway in synthesis of purine : De novo pathway Involved the synthesis of purine, and form uric acid. First substrate needed is ribose 5-phosphate, which will changed through a series of intermediate substance into purine nucleotide (inosinate acid, guanylate acid, adenylate acid) Major determinant of this pathway is 5-phosphoribosyl-1-pyrophosphate (PRPP), and its synthesis is controlled by PRPP synthetase There are feedback inhibition mechanism by purine nucleotide, which function is to prevent excessive formation Salvage Pathway Formation of purine nucleotide through its free purine bases, nucleic acid breakdown, or from food intake Require far less energy than de novo synthesis These reactions are catalized by 2 enzyme Hypoxantine and guanine phosphoribosyl transferase (HGPRT) and Adenine phosphoribosyl transferase (APRT)

Alifah Syarafina A5-DMS | Case 5

Although purine nucleotides are synthesized and degraded in all tissues, urate is produced only in tissues that contain xanthine oxidase, primarily the liver and small intestine. Urate production varies with the purine content of the diet and the rates of purine biosynthesis, degradation, and salvage. Normally, two-thirds to three-fourths of urate is excreted by the kidneys, and most of the remainder is eliminated through the intestines The total-body urate pool is the net result between urate production and excretion. Urate production is influenced by dietary intake of purines and the rates of de novo biosynthesis of purines from nonpurine precursors, nucleic acid turnover, and salvage by phosphoribosyltransferase activities. The formed urate is normally excreted by urinary and intestinal routes. Hyperuricemia can result from increased production, decreased excretion, or a combination of both mechanisms. When hyperuricemia exists, urate can precipitate and deposit in tissues as tophi

Formation of Uric Acid Adenine is converted into adenine monophosphate under the effect of the enzyme adenine phosphoribosyl-pyrophosphate synthetase. Adenine monophosphate is then converted to Adenosine under the effect of the enzyme nucleotidase. Adenosine is then converted to Inosine under the effect of the enzyme adenosine deaminase. Inosine is then converted to Hypoxanthine under the effect of the enzyme nucleoside phosphorylase. Hypoxanthine is then converted to Xanthine by the enzyme xanthine oxidase. Xanthine is converted into uric acid under the effect of enzyme xanthine oxidase. Guanosine is converted to Guanine by nucleoside phosphorylase. Guanine is then converted to Xanthine by guanase Xanthine is then converted to uric acid too, by Xanthine Oxidase

Alifah Syarafina A5-DMS | Case 5

Uric Acid Excretion in Kidney The kidneys clear urate from the plasma and maintain physiologic balance by utilizing specific organic anion transporters (OATs) including urate transporter 1 (URAT1) and human uric acid transporter (hUAT). URAT1 and other OATs carry urate into the tubular cells from the apical side of the lumen. Once inside the cell, urate must pass to the basolateral side of the lumen in a process controlled by the voltage-dependent carrier hUAT. Until recently, a four-component model has been used to describe the renal handling of urate/uric acid: (1) glomerular filtration, (2) tubular reabsorption, (3) secretion, and (4) postsecretory reabsorption. Although these processes have been considered sequential, it is now apparent that they are carried out in parallel by these transporters. URAT1 is a novel transporter expressed at the apical brush border of the proximal nephron. Uricosuric compounds directly inhibit URAT1 on the apical side of the tubular cell (so-called cis-inhibition). In contrast, antiuricosuric compounds (those that promote hyperuricemia), such as nicotinate, pyrazinoate, lactate, and other aromatic organic acids, serve as the exchange anion inside the cell, thereby stimulating anion exchange and urate reabsorption (trans-stimulation). The activities of URAT1, other OATs, and sodium anion transporter result in 812% of the filtered urate being executed as uric acid.

A increase in formation or a decrease in the excretion of uric acid will result in the accumulation of uric acid in the blood. When the blood levels of uric acid cross the normal values then that condition is called Hyperuricemia. This is the precursor stage of gout. Accumulation of uric acid in the joints most widely available in the form of monosodium urate crystals. The accumulation of uric acid will cause formation of chalkwhite precipitate called TOFI / tofus (tophus) in cartilage and joint capsule. In place of the accumulation will trigger a granulomatous inflammatoryreaction, characterized by masses of amorphous urate (crystals) surrounded by macrophages, lymphocytes, fibroblast and foreign body of giant cell. Crystal precipitation causes irritation of the synovial membrane of the joint and results in inflammation, pain and swelling. If accumulation occurs in the kidney, it willl form uric acid kidney stone, which usually called kidney stones. Factors that cause a increase in formation of uric acid in the body :

Dietary consumption that contains high purine (jeroan, ikan sarden, dll), Deficiency of enzymes hypoxanthinephosphoribosyl-transfrase, Increased activity of enzyme phospho-ribosyl-pyrophosphate synthetase, Psoriasis, Pagets disease. Alcoholism, Obesity Factors that cause a decrease in excretion of uric acid by the kidneys

Failure of the kidneys, Lead toxicity, High blood pressure, Hypothyroidis, Drug (aspirin, levodopa,cyclosporine,ethambutol)