CREATININE METABOLISM, uric acid biosynthesis and melanin synthesis

1. CREATININE METABOLISM

2. Creatinine
• Biosynthesis
– Occurs in kidney and liver
– Require 3 amino acids
– Takes up by muscle and brain from blood
– Store energy as creatinephosphate

3. GLYCINE
ARGININE
GUANIDOACETATE
ORNITHINE
ARGININE-GLYCINE TRANSAMINASE
IN KIDNEY

4. GUANIDOACETATE
CREATINE
S-ADENOSYL METHIONINE (SAM)
S- ADENOSYL HOMOCYSTEINE
(SAH)
GUANIDOACETATE
METHYLTRANSFERASE
IN LIVER

5. CREATINE
CREATINE PHOSPHATE
ATP
ADP
CREATININE
H2O
Pi
CREATINE KINASE
NON-ENZYMATIC

6. Normal level
• Serum
– Creatine – 0.2-0.6 mg/dl
– Creatinine – 0.7-1.4 mg/dl
• Urine
– Creatine - <50mg/day
– Creatinine – 1-2 g/day

7. Uric Acid Biosynthesis and Its Disorder

9. Factors affecting formation of uric acid
• Depends on
– De novo synthesis of purines
– The metabolism of endogenous DNA, RNA, and
other purine containing molecule such as ATP
– The breakdown of dietary nucleic acid

10. Significance of uric acid
• Potent antioxidant
– Very effective scavenger of free radicals.

11. Excretion
• Via the kidney : major
• Via the gut : smaller amount

12. Clinical significance
• Normal range 4 to 7 mg/dl
• At physiological pH, it is mostly ionized and
present in plasma as sodium urate.
• Elevated serum urate concentration is known
as hyperuricaemia
• Uric acid and urate are relatively insoluble and
readily precipitate out of the aquous solutions
such as urine or synovial fluid
• Condition called gout

13. Cause of hyperuricaemia
• Due to increased uric acid formation
– Primary (genetic)
• Due to enzyme defects in:
– PRPP synthase
– PRPP aminotransferase
– HGPRTase
– Secondary
• Due to increased:
– Dietary intake
– Nucleic acid turnover
– ATP breakdown
– Deficiency of glucoase -6-phosphatase

14. • Due to decreased uric acid excretion
– Primary idiopathic
– Secondary due to:
• Renal insufficiency
• Metabolic acidosis
• Lactic acidosis
• Ketoacidosis
• Starvation
• Diabetes mellitus
• Increased tubular reabsorption

15. Gout
• Elevated uric acid level associated with either
increased formation of uric acid or decreased
renal excretion
• Classification
– Primary gout
– Secondary gout
• Symptoms
– Patients with primary gout often show deposition of
urate as tophi in soft tissues that affects the joints and
leads to painful arthritis
– Kidneys are also affected lead to renal failure

16. Primary Gout
• Inherited due to an inborn error of
metabolism caused by defective enzymes of
purine biosynthesis
– Partial deficiency of HGPRTase
– Loss of feed back regulation
• PRPP synathase
• PRPP amidotransferase

17. Secondary Gout
• Elevated destruction of cells or defective elimination of uric
acid
– Over production of urate due to increased destruction or
turnover of cells
• Myeloproliferative disorders ( e.g. leukaemia, polycythaemia)
• Cytotoxic drug ( antimetabolites) therapy
• Psoriasis
– Defective elimination of uric acid due to
• Reduced glomerular filtration rate
• In diuretic therapy due to reduced distal tubular secretion of uric acid
– Hyper-catabolic states and starvation
• Lactic acidosis and ketoacidosis
– Inherited metabolic disorders
• Eg. Von gierke’s disease

18. Treatment
• Foods rich in nucleotides and nucleic acids
such as liver or coffee and tea, which contain
the purines caffeine and theobromin are
withheld from the diet
• Use of drug allopurinol

19. LESCH-NYHAN SYNDROME
• Inherited X-linked disorder
• Complete deficiency of HGPRTase
• Symptoms
– Hyperuricaemia
– Gout
– Urinary tract stones
– Mental retardation
– Spasticity
– Self-mutilation
• Treatment
– allopurinol

20. Hypouricaemia
• Decreased serum uric acid less than 2mg/dl
• Causes
– Xanthinuria
– Adenosine deaminase (ADA) deficiency
– Purine nucleoside phosphorylase deficiency

21. Melanin synthesis

23. Albinism
• greek: albino – white
• Inborn error, due to alck of synthesis of the
pigment melanin
• Autosomal recessive disorder with frequency
of 1 in 20000

24. • Causes
– Deficiency or lack of the enzyme tyrosinase
– Decrease in melanosomes of melanocytes
– Impairment in melanin polymerization
– Lack of protein matrix in melanosomes
– Limitation of substrate (tyrosine) availability
– Presence of inhibitors of tyrosinase

25. • Clinical manifestation
– Skin cancer
– Photophobia
– White hair