uric acid

see also:

• hyperuricaemia
• gout
• uricosuric agents

• uric acid has the formula C₅H₄N₄O₃.
• uric acid (UA) is the end product of purine metabolism in humans due to the loss of uricase activity by various mutations of its gene during the Miocene epoch, which led to humans and great apes having higher UA levels than other mammals.
  • in other mammals, UA is further oxidized to allantoin by uricase
  • in birds and reptiles, uric acid is the main form of nitrogen excretion however it is excreted in faeces rather than urine which conserves water.
• the loss of uricase activity and reduced renal excretion result in the elevated UA levels which presumably had evolutionary benefits to hominids and such hypotheses include:
  • UA is a powerful antioxidant
    • in humans, over half the antioxidant capacity of blood plasma comes from hydrogen urate ion
    • the loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid, leading to the suggestion that urate may partially substitute for ascorbate in such species
  • increase in UA could be a mechanism to maintain blood pressure in times of very low salt ingestion
  • increased UA levels is associated with the rise in intelligence of hominids
  • UA has protective effects against several neurodegenerative diseases, suggesting it could have interesting actions on neuronal development and function
    • reduced risk of developing Parkinson's disease thought to be due to an extracellular antioxidant effect ¹⁾
  • beneficial effects is food scarcity scenarios
    • metabolism and immune systems developed hand-in-hand from an evolutionary and survival perspective as resisting starvation and mounting an immune response to pathogens was paramount, nutrients use the pathogen-sensing systems to trigger inflammatory responses. Most humans do not have to face food scarcity, thus, once beneficial, uric acid metabolism triggers the accumulation of fats and inflammation even without infection, a biological process driving renal impairment. A metabolomic analysis in 2023 found a characteristic metabolite profile for gout, in which 10 of 46 metabolites showed marked differences, and nearly all were related to metabolic inflammation: ²⁾

• UA is the end product of purine metabolism (see below) and uric acid, in turn, inhibits AMP-activated protein kinases, which promotes more AMP metabolism through AMP deaminase, resulting in more uric acid production ³⁾
• uric acid and most urates have low water solubility and this is affected by temperature, pH and sodium concentration
  • the solubility threshold of urate at pH of 7.4 and temperature of 37°C in humans is 6.8 mg/dl (416 mmol/l) (and this is the regarded upper limit of normal serum range in men) ⁴⁾
  • this can result in crystals forming such as in:
    • renal stone formation
    • gout - monosodium urate (MSU) crystals
• 90% of UA filtered by the kidneys is reabsorbed, instead of being excreted
  • net reabsorption is via an inhibitable specific transporter which allows luminal uric acid to be exchanged with cellular anions (including PAH);
  • the uric acid then exits the cell via a different transporter on basolateral membrane not involving PAH;
• ~25% of UA is excreted into the gut and further metabolized by gut bacteria
  • GIT microbiota may not only metabolise uric acid via uricase but some may also produce uric acid from purine metabolism via secretion of xanthine dehydrogenase (eg. E.coli, Proteus), while some secrete uric acid transporters
  • hence git flora may have important roles in uric acid balance
• hyperuricaemia
  • ~20% of adults in USA now have elevated levels however less than 4% have gout - ~36% of patients with hyperuricemia will eventually develop into patients with gout.
  • 90% of hyperuricaemia is due to inadequate renal excretion ⁵⁾
  • in humans elevated levels are mainly due to genetic mutations in the urate transport proteins responsible for the excretion of uric acid by the kidneys:
    • SLC2A9; ABCG2; SLC17A1; SLC22A11; SLC22A12; SLC16A9; GCKR; LRRC16A; and PDZK1.
      • GLUT9, encoded by the SLC2A9 gene, is known to transport both uric acid and fructose.
  • the following may also result in high levels:
    • high purine intake
    • high fructose intake eg. high fructose corn syrup (HFCS), orange juice, etc - this may be the leading cause for the increasing hyperuricaemia epidemic
      • fructose is the only commonly ingested carbohydrate that produces uric acid during metabolism ⁶⁾
      • in small oral intakes, ingested fructose is metabolised in the small intestine and only when this becomes saturated does the liver receive a fructose load where the rapid conversion to fructose-1-phosphate results in rapid depletion of ATP, phosphate and the production of uric acid via increasing ATP degradation to AMP then to inosine monophosphate (IMP), then to inosine, then hypoxanthine, a uric acid precursor, and thus, within minutes after fructose infusion, serum uric acid levels rise. In addition, de novo purine synthesis is accelerated. ⁷⁾
      • hepatic metabolites of fructose enter the triose phosphate pool distal to PFK 1, bypassing the PFK 1 regulatory step. Thus, fructose loads can cause significant, rapid augmentations in the triose and hexose phosphate pools, potentially providing more substrate for all central carbon metabolic pathways, such as glycolysis, gluconeogenesis, glycogenesis, oxidative phosphorylation, and lipogenesis.
    • decreased uric acid excretion eg. thiazide diuretics, renal impairment
    • obesity, hypertension, cardiac failure
    • fasting or rapid weight loss
    • tumour lysis syndrome, a complication of certain cancers or chemotherapy, due to nucleobase and potassium release into the plasma

• purines are the most widely occurring nitrogen-containing heterocycles in nature and are found in high concentration in meat and meat products.
  • the purine bases are guanine (G) and adenine (A) and are the building blocks for guanosine, adenosine, DNA, RNA, cyclic AMP, ATP, GTP, NADH, and coenzyme A
  • high purine sources:
    • meats include internal organs such as brain, sweetbread, liver and kidney, anchovies, sardines, herrings, scallops, game meat, meat extracts and gravy
    • high-purine plants and algae include some legumes (lentils and black eye peas) and spirulina.
    • other high-purine sources include yeast as in yeast extract and beer
  • moderate purine sources:
    • a moderate amount is found in other meats and seafood, asparagus, caulifower, spinach, mushrooms, green peas, lentils, beans, oatmeal, wheat bran, and wheat germ
  • when purines are formed, they inhibit the enzymes required for more purine formation and activate enzymes needed for pyrimidine formation as both are needed in cells in an equal proportion
  • nearly all organisms (including bacteria) are able to carry out de novo biosynthesis of purines, although some archaeal species unable to synthesize purines are able to acquire exogenous purines for growth
  • purines are biologically synthesized as nucleosides (bases attached to ribose)

• guanine nucleotides are degraded sequentially by a series of enzymes to xanthine and then by xanthine oxidase to uric acid
• adenine nucletotides are degraded sequentially by a series of enzymes to inosine then to hypoxanthine and then by xanthine oxidase to xanthine and then to uric acid (each reaction also forming hydrogen peroxide, and xanthine oxidase can also form superoxides)
  • NB. hypoxanthine is also a spontaneous deamination product of adenine

• excess purines can also be salvaged into new nucleotides via either:
  • adenine phosphoribosyltransferase (APRT) (acts on adenine)
  • hypoxanthine-guanine phosphoribosyltransferase (HGPRT) salvages guanine and hypoxanthine (genetic deficiency of HGPRT causes Lesch–Nyhan syndrome)