Disorders of Purine
Metabolism
Overview
•
•
•
•
•
•
•
•
•
•
Introduction
Purine (types)
Purine functions
Sources of purines
Metabolic disorders
Nucleotide degradation
Uric acid and hyperuricemia
In-born errors of Uric acid metabolism
Disorders due to purine catabolism
Disorders due to salvage pathway
What are purines?
• Purines are heterocyclic compound consisting of a
pyrimidine ring fused to an imidazole Ring
Purines
• Other minor purine base include
• 1. Xanthine 2. Hypoxanthine 3. Uric acid
• The above occur in free state in the cells
N6 –Methyladenine
N6 N6 Dimethyladenine
N7-Methylguanine
• Occur in mamalian RNA
Purines
• 1,3-Dimethylxanthine(theophylline) found in TEA
• 3,7-Dimethylxanthine(theobromine)found in
COCOA
• 1,3,7-Trimethylxanthine(caffeine) found in coffee
• These are pharmacologically important.
Functions
• Key functions include;
Provision of Energy e.g. ATP, GTP
Building blocks for DNA and RNA (along side
pyrimidines)
Basic co-enzymes i.e. NAD and NADH
Play role in signal transduction e.g. GTP, cAMP,
cGMP
Sources of purine
• ENDOGENOUS
• They may be synthesized DE NOVO from small
molecules
• EXOGENOUS
• They may be derived from the breakdown of
ingested nucleic acid, mostly from cell-rich meat
• Plant diets generally poor in purines
Metabolic disorders of purines
• They cover a broad spectrum of illnesses with various
presentations.
• Examples of presentations include;
• Hyperuricemia
• Acute renal failure
• Gout
• Unexplained neurologic defects (seizures, muscle weakness
etc)
• Developmental disorders
• Compulsive self injury and aggression
• Immune deficiency
• Deafness
Major Categories of Disorders
• Two major types of disorders occur;
1) Those that arise from a Blockage in purine
nucleotide degradation pathway
2) Arising from increased activity of nucleotide
degradation pathway
Nucleotide degradation
• Nucleic acids can survive the acid of the stomach
• They are degraded into nucleotides by pancreatic nucleases and intestinal
phosphodiesterase in the duodenum.
• Components cannot pass through cell membranes, so they are further
hydrolyzed to nucleosides.
• Nucleosides may be directly absorbed by the intestine or undergo further
degradation to free bases and ribose or ribose-1-phosphate by nucleosidases
and nucleoside phosphorylase.
Nucleoside + H2O
Nucleoside + Pi
Nucleosidease
base + ribose
Nucleosidephosphorylase
base + ribose-1-P
Catabolism of purines
ADA
Catabolism of purines
• Purine nucleotide degradation refers to a regulated series of
reactions by which purine ribonucleotides and
deoxyribonucleotides are degraded to uric acid in humans.
• As indicated earlier, two major types of disorders occur in
this pathway;
1. A block of degradation occurs with syndromes involving;• immune deficiency.
• myopathy or
• renal calculi.
2. Increased degradation of nucleotides occurs with
syndromes characterized by;• hyperuricemia and gout,
• renal calculi,
• anemia or acute hypoxia.
Uric Acid (2,6,8-trioxypurine)
• This is the end product of purine metabolism in
humans.
• Accumulation of uric acid in blood is referred to as
hyperuricemia.
• Uric acid is highly insoluble therefore a very slight
alteration in the production or solubility will
increase levels in blood.
• Due to poor solubility, levels in blood are usually
near the maximal tolerable limits.
Excretion of uric acid
• Uric acid is filtered through the glomeruli and most
is reabsorbed in the proximal tubules.
• More than 80% of uric acid formed in the urine is
derived from distal tubular secretion.
• Renal secretion may be enhanced by uricosonic
drugs (e.g. probenecid or sulfinpyrazone),which
block tubular urate reabsorption.
Excretion of uric acid
• 75% urate leaving the body is in urine.(2/3)
• The remaining 25% passes into the intestinal lumen,
where it is broken down by intestinal
bacteria(URICOLYCIS).(1/3)
Hyperuricaemia
• This is increase in blood levels of uric acid that is
greater than 0.42 mmol/l in men and more than
0.36mmol/l in women
• It can occur by two mechanisms:
1) Increased production(Over Production)
2) Decreased Excretion (under excretory)
Conditions that lead to Increased Uric
acid Production
•
•
•
•
•
•
•
•
– Malignancies
– Reyes Syndrome
– Downs Syndrome
– Sickle cell anemia
– Glycogen storage diseases types I,III, IV and V
– Hereditary fructose intolerance
– Gout
– Acyl CoA dehydrogenase deficiency
Factors contributing to Hyperuricemia
• Increased synthesis of purines (primary Gout)
• Secondary GOUT (Other disorder in which there is
rapid tissue break down or rapid cellular turnover)
• Increase intake of purines
• Increase turnover of Nucleic Acids
• Increased rate of urate formation
• Reduced rate of Excretion
Factors contributing to Hyperuricemia
• Sex(plasma uric acid is higher in male than
females).
• Obesity (Obese people tends to high plasma level of
urate).
• Diet (subject with high protein diet ,which is also
rich in Nucleic acids and who do have high alcohol
consumption have high levels of plasma urate.
• Genetic factor (These are very important factor in
high plasma urate levels).
Other causes may include
• Eclampsia
• Lead toxicity
• Chronic alcohol ingestion
• NOTE Hypouricemia is not an important chemical
disorder in itself.
Management of disorders
Management of disorders of purine nucleotide
degradation is dependent upon modifying the
specific molecular pathology underlying each
disease state.
• Common treatment for gout: allopurinol
• Allopurinol is an analogue of hypoxanthine that
strongly inhibits xanthine oxidase. Xanthine and
hypoxanthine, which are soluble, are accumulated
and excreted.
In born errors of Uric Acid Metabolism
1. Phosphorybosylpyrophosphate synthase (PRS)
superactivity
There are two form;
I. The severe form which appears in infancy
II. The mild form which presents in adolescence
• In both forms, kidney or bladder stone is often the
first symptom.
• Gout and impairment of kidney function may develop
if the condition is not adequately controlled with
medication and dietary restrictions.
2. Adenylosuccinase deficiency
• Due to lack of the enzyme adenylosuccinate lyase
• In general, affected individuals may have a mix of
neurological symptoms, which usually includes
abnormalities with cognition and movement, autistic
features, epilepsy, muscle wasting, and feeding
problems.
Disorders due to purine catabolism
Myoadenylate Deaminase Deficiency
• Also called muscle adenosine monophosphate
deaminase deficiency
• This is a genetic disease that interferes with the muscle
cells processing of ATP, the key energy molecule of a
cell.
• The lack of an enzyme that converts ATP to inosine and
ammonia may present no symptoms or it may cause
exercise-induced cramping.
• The disorder is diagnosed through the accumulation of
ammonia or inosine monophosphate in muscle tissue
• Treatment typically consists of exercise modulation.
Xanthine Oxidase Deficiency
(XANTHINURIA)
• This is a rare hereditary disorder in which there is a
deficiency of liver xanthine oxidase
• The catabolism of purine stops with xanthinehypoxanthine stones.
• The blood uric acid is very low and there is a high
level of urinary excretion of xanthine
• There is reduced excretion of urinary uric acid
• Xanthine oxidase deficiency, is an inherited metabolic
disorder in which there is deficiency of an enzyme
needed to process xanthine, a substance found in
caffeine and related substances.
• If left untreated, xanthinuria can lead to kidney stone
formation and subsequent urinary tract diseases.
• Additionally, this condition can lead to muscle
disorders, due to deposits of xanthine in muscle tissue.
• Treatment of the condition involves avoiding foods and
drinks that contain xanthine derivatives, such as coffee,
tea and colas and maintaining a high fluid
Adenosine Deaminase Deficiency
• This is a genetic disorder that impairs the immune system
and is the basis of severe combined immunodeficiency, or
SCID.
• Children diagnosed with SCID are typically deficient in
almost all immune protection from pathogens and are
vulnerable to chronic infections caused by "opportunistic"
organisms that ordinarily do not cause disease in healthy
people with a normal immune response.
• Symptoms of SCID include pneumonia and chronic diarrhea,
with impeded growth compared to healthy children.
• Additionally, neurological problems such as developmental
Disorders due to salvage pathway
• A salvage pathway is a pathway in which nucleotides (Purine
and pyrimidine) are synthesized from intermediates in the
degradative pathway for nucleotides.
• There are two critical enzyme deficiencies;
I. Hypoxanthine guanine phosphoribosyltransferase (HGPRT)
deficiency
– May be total (Lesch-Nyhan syndrome ) or partial deficiency Partial
HGPRT
-deficient patients present with symptoms similar to total but with a
reduced intensity, and in the least severe forms symptoms may be
unapparent.
II. Adenine phosphoribosyltransferase (APRT) deficiency
– The disorder results in accumulation of the insoluble Purine 2,8dihydroxyadenine.
– It can result in nephrolithiasis (kidney stones), acute renal failure and
permanent kidney damage
Lesch-Nyhan Syndrome
• Lesch-Nyhan syndrome is a metabolic disorder caused
by a deficiency of an enzyme (HGPRT) produced by
mutations in a gene located on the X chromosome.
• The disease is marked by a buildup of uric acid in all
body fluids that results in conditions known as
hyperuricemia and hyperuricosuria.
• Symptoms often include severe gout, impaired muscular
control, moderate mental retardation and kidney
problems.
• These complications frequently emerge in the first year
of life. Neurological symptoms can include grimacing,
facial involuntary writhing and repetitive.
Gout
• Characterised by the accumulation of monosodium
urate crystal deposits which result in inflammation
in joints and surrounding tissues.
• Presentation
– Hyperuricemia
– Uric acid nephrolithiasis
– Acute inflammatory arthritis
• Commonly monoarticular (Affecting the
metatarsophalangeal joint of the big toe.
• However deposits of sodium urates may also occur
in;
– The elbows
– Knees
– Feet
– Helix of the ear
• Types of Gout
• Primary Gout
• – Occurrence: Middle aged men (mostly)
• – Cause: Overproduction of Uric Acid Decreased
renal excretion or both
• Biochemical Etiology: Not clearly known and is
considered a polygenic disease
• Secondary Gout
• – Occurrence: Children
• – Cause: other condition in which there is rapid
tissue breakdown or cellular turnover
• – Such condition leads to either;
• Increased production of Uric acid
• Decreased clearance of Uric acid
• Other conditions that could lead to gout
• Any other condition that may lead to either;
– Decreased uric acid clearance or
– Increase in production
•
•
•
•
•
•
•
•
These may include;
Malignancy therapy
Starvation
Dehydration
Lactic acidosis
Ketoacidosis
Diuretic therapy
Renal failure
Also;
•Excessive purine intake
• Alcohol intake
•Carbohydrate ingestion
Hereditary disorders associated with gout
• These include 3 key enzymes resulting in
hyperuricemia
• These are;
1. Severe HGPRT deficiency (Lesch-Nyhan
syndrome)
2. Super activity of PP-ribose-p synthetase
3. Glucose -6-phosphatase deficiency (glycogen
storage disease type 1)
Hereditary disorders associated with gout - cnt
• 1st two are caused by hyperuricemia due to purine
nucleotide and uric acid overproduction
• The 3rd due to excess uric acid production and
impaired uric acid secretion
Familial Juvenile Gout (Familial Juvenile
Hyperuricemia Nephropathy (FJHN)
• Due to severe renal hypo excretion of uric acid
• Presentation usually occurs at puberty to the 3rd
decade
– Has also been reported in infancy
Characteristics
– Hyperuricemia
– Gout
– Familial renal disease
– Low urate clearance relative to GFR