introduction to uric acid metabolism

7/29/2019 Introduction to Uric Acid Metabolism

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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, it’s eliminated via

urine or feaces.

Defect in this elimination results hyperuricemia and

gout, and contribute to renal calculi

PURINE BIOCHEMISTRY

Purine base = pyrimidine ring (5C) + an Imidazole ring

(6C)

- We’ve 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 α, β, and γ

FUNCTIONS OF PURINE BASES

i. Building blocks for RNA and DNA

ii. Precursor of cyclic nucleotides like cAMP,

cGMP, … that r involved in signal transduction

iii. Source of chemical energy e.g. ATP, GTP

iv. Precursor of purine cofactors and co-enzymes

such as NAD (nicotinamide adenine

dinucleotide)

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 5-

phosphoribosyl 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 Amido-

phosphoribosyl 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 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 xanthineoxidase and the rxn it catalyzed is irreversible i.e. once

hyoxanthine is formed, uric acid is sure to be formed



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PHYSIOCHEMICAL PROPERTIES OF URIC ACID AND

URATE

- It is a weak acid

- 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 thepH 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.

Elimination via kidney takes place in 4 stages;

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 There’s 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

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



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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

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 featurei. 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

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

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. early onset of gout

ii. high incidence of uric acid stones in urinary

tract

iii. Less neurologic lesions

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

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 crystalsshow strong negative birefrigence when

examined under the polarizing microscope.

introduction to uric acid metabolism

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