Upload
chinedu-h-duru
View
233
Download
0
Embed Size (px)
Citation preview
7/29/2019 Introduction to Uric Acid Metabolism
http://slidepdf.com/reader/full/introduction-to-uric-acid-metabolism 1/3
1
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
7/29/2019 Introduction to Uric Acid Metabolism
http://slidepdf.com/reader/full/introduction-to-uric-acid-metabolism 2/3
2
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
7/29/2019 Introduction to Uric Acid Metabolism
http://slidepdf.com/reader/full/introduction-to-uric-acid-metabolism 3/3
3
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.