Disorders of purine metabolism

Disorders of Purine Metabolism

Dr. G. K. MaiyohDepartment of Medical

Biochemistry, School of Medicine, MU

March 21, 2013 1GKM/MUSOM/NSP 210:PATH.2012.2013

Lecturer:

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

March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 2

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. Hypoxanthine3. Uric acid• The above occur in free state in the cells4 N6 –Methyladenine5 N6 N6 Dimethyladenine6 N7-Methylguanine• Occur in mamalian RNA


PURINES

7 1,3-Dimethylxanthine(theophylline) found in TEA

8 3,7-Dimethylxanthine(theobromine)found in COCOA

9 1,3,7-Trimethylxanthine(caffiene ) found in coffee

This are pharmacologically important


Functions

Key functions include;Provision of Energy e.g. ATP, GTPBuilding blocks for DNA and RNA (along side

pyrimidines)Basic conenzymes i.e. NAD and NADHPlay role in signal transduction e.g GTP, cAMP,

cGMP


Sources of purineENDOGENOUS• 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 e.tc)• Developmental disorders• Compulsive self injury and aggression• Immune deficiency• Deafness


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


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 + H2O base + ribose

Nucleoside + Pi base + ribose-1-P

Nucleoside phosphorylase

nucleosidase

Major pathways of purine catabolism in animals.

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;

• 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.


Catabolism of purines

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


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

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)

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)

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


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

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)

Other causes may include:

• Eclampsia• Lead toxicity• Chronic alcohol ingestion

• NOTE Hypouricaemia is not an important chemical disorder in itself

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

Management of disorders


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 Metabolism1. Phosphorybosylpyrophosphate synthase (PRS)

superactivityThere are two form;

i. The severe form which appears in infancyii. 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 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.


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

•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)


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.


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.March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 30

A salvage pathway is a pathway in which nucleotides (Purine and pyrimidine) are synthesized from intermediates in the degradative pathway for nucleotides.

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.


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


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


Figure 28-29 The Gout, a cartoon by James Gilroy (1799).

Pag

e 10

97

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.


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


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


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


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 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)


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 Hyperuricemic Nephropathy (FJHN)

• Due to severe renal hypoexcretion 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


Disorders of purine metabolism

Documents

Transcript of Disorders of purine metabolism