Disorders of purine metabolism

The metabolism and associated disorders of purine metabolism

1. Disorders of Purine Metabolism
Dr. G. K. Maiyoh
Department of Medical
Biochemistry, School of Medicine,
MU
March 21, 2013 1GKM/MUSOM/NSP 210:PATH.2012.2013
Lecturer:

2. 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
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3. WHAT ARE PURINES?
•Purines are heterocyclic
compound consisting of
a pyrimidine ring fused
to an imidazole Ring
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4. Purines
•Other minor purine base include:
1.Xanthine
2.Hypoxanthine
3.Uric acid
•The above occur in free state in the cells
4N
6
–Methyladenine
5N
6
N
6
Dimethyladenine
6N
7
-Methylguanine
•Occur in mamalian RNA
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5. PURINES
71,3-Dimethylxanthine(theophylline) found in
TEA
83,7-Dimethylxanthine(theobromine)found in
COCOA
91,3,7-Trimethylxanthine(caffiene ) found in
coffee
This are pharmacologically important
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6. Functions
Key functions include;
Provision of Energy e.g. ATP, GTP
Building blocks for DNA and RNA (along side
pyrimidines)
Basic conenzymes i.e. NAD and NADH
Play role in signal transduction e.g GTP, cAMP,
cGMP
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7. 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
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8. 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 e.tc)
•Developmental disorders
•Compulsive self injury and aggression
•Immune deficiency
•Deafness
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9. Two major types of disorders occur;
i.Those that arise from a Blockage in purine
nucleotide degradation pathway
ii.Arising from increased activity of nucleotide
degradation pathway
Major Categories of Disorders
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10. Nucleotide degradation
•Nucleic acids can survive the acid of the stomach
•They are degraded into nucleotides by pancreatic
nucleases and intestinal phosphodiesterases 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 nucloside
phosphorylase.
Nucleoside + H
2
O base + ribose
Nucleoside + P
i
base + ribose-1-P
Nucleoside
phosphorylase
nucleosidase

11. Major pathways of purine
catabolism in animals.
ADA
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Catabolism of purines

12. •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;
• A block of degradation occurs with syndromes involving;-
• immune deficiency.
•myopathy or
•renal calculi.
•Increased degradation of nucleotides occurs with syndromes
characterized by;-
• hyperuricemia and gout,
•renal calculi,
•anemia or acute hypoxia.
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Catabolism of purines

13. Uric Acid (2,6,8-trioxypurine)
•This is the end product of purine metabolism in
humans
•Accumulation of uric acid in blood is reffered 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
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14. 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
•Urinary excretion is slightly lower in males than
females,which may contribute to the higher incidence
of hyperuricaemia in men
•Renal secretion may be enhanced by uricosonic
drugs(e.g probenecid or sulfinpyrazone),which block
tubular urate reabsorption

15. Excretion of uric acid
•75% urate leaving the body is in urine
•The remaining 25% passes into the intestinal
lumen,where it is broken down by intestinal
bacteria(URICOLYCIS)

16. 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 excretors)

17. 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
–AcylCoA dehydroginase defficiency
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18. Factors contributing to Hyperuraecimia
•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

19. Factors contributing to Hyperuraecimia
•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 NUCLIEC 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)

20. Other causes may include:
•Eclampsia
•Lead toxicity
•Chronic alcohol ingestion
•NOTE Hypouricaemia is not an important
chemical disorder in itself

21. Management of disorders of purine nucleotide
degradation is dependent upon modifying the specific
molecular pathology underlying each disease state.
Management of disorders
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22. 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.
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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.

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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.

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Disorders due to purine catabolism

26. Myoadenylate Deaminase Deficiency
•Also called muscle adenosine monophosphate
deaminase deficiency
•This is a genetic disease that interferes with the
muscle cell's 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.
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27. 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 xanthine-
hypoxanthine 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

28. •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
intake to minimize the likelihood of forming stones.
Xanthine Oxidase Deficiency
(Xanthinuria)
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29. 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 delay, motor function disorders and
hearing loss often occur.
•Left untreated, children with SCID usually survive
only a year or two.
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30. Disorders due to salvage pathway
There are two critical enzyme defficiencies;
I.Hypoxanthine guanige phosphorybosyltransferase (HPRT)
defficiency
– May be total (Lesch-Nyhan syndrome ) or partal
defficiency
Partial HPRT-deficient patients present with symptoms similar to
total but with a reduced intensity, and in the least severe forms
symptoms may be unapparent.
I.Adenine phosphorybosyltransferase (APRT) defficiency
–The disorder results in accumulation of the insoluble Purine 2,8-
dihydroxyadenine.
–It can result in nephrolithiasis (kidney stones), acute renal failure
and permanent kidney damage.
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A salvage pathway is a pathway in which nucleotides (Purine and
pyrimidine) are synthesized from intermediates in the degradative pathway
for nucleotides.

31. Lesch-Nyhan Syndrome
•Lesch-Nyhan syndrome is a metabolic disorder
caused by a deficiency of an enzyme (HPRT)
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
facial grimacing, involuntary writhing and repetitive
movements.
•The mental deficits and behavior do not react well to
therapy. There is no known cure, but many patients
can survive to adulthood.
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32. Gout
•Characterised by the accumulation of
monosodium urate crystal deposits which
result in inflamation in joints and surrounding
tissues.
•Presentation
–Hyperuricemia
–Uric acid nephrolithiasis
–Acute inflamatory arthritis
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33. Gout
•Commonly monoarticular (Affecting the
metatarsophalangeal joint of the big toe.
•However deposits of sodium urates may aslo
occur in;
–The elbows
–Knees
–Feet
–Helix of the ear
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34. Figure 28-29The Gout, a cartoon by James Gilroy (1799).
P
a
g
e

1
0
9
7
Gout is a disease characterized by elevated levels of uric acid in body fluids.
Caused by deposition of nearly insoluble crystals of sodium urate or uric acid.
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35. 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
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36. Types of Gout
•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
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37. 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
•Dehydration
•Lactic acidosis
•Ketoacidosis
•Stavation
•Diuretic therapy
•Renal failure
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Also;
•Excessive purine intake
•Alcohol intake
•Carbohydrate ingestion

38. Hereditary disorders associated
with gout
•These include 3 key enzymes resulting in
hyperuricemia
•These are;
1.Severe HPRT defficiency (Lesch-Nyhan
syndrome)
•Also Partial HPRT defficiency
1.Superactivity of PP-ribose-p synthetase
2.Glucose -6-phosphatase defficiency (glycogen
storage disease type 1)
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39. Hereditary disorders associated
with gout - cnt
•1
st
two are caused by hyperuricemia due to
purine nucleotide and uric acid
overproduction
•The 3
rd
due to excess uric acid production and
impaired uric acid secretion
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40. Familial Juvenile Gout (Familial Juvenile
Hyperuricemic Nephropathy (FJHN)
•Due to severe renal hypoexcretion of uric acid
•Presentation usually occurs at puberty to the
3
rd
decade
–Has also been reported in infancy
Characteristics
–Hyperuricemia
–Gout
–Familial renal disease
–Low urate clearance relative to GFR
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