CYSTEINE METABOLISM

CYSTEINE METABOLISM

1. Metabolism of Cysteine Gandham . Rajeev Email:[email protected]

2. It is non-essential & glucogenic amino acid. Cysteine is present in large quantity in keratin of hair & nails. Formation of cysteine is by using the carbon skeleton contributed by serine & sulfur originating from methionine.

3. Synthesis of cysteine Homocysteine formed from methionine is a precursor for the synthesis of cysteine. Homocysteine condenses with serine to form cystathionine .

4. This reaction is catalysed by a PLP-dependent cystathionine synthase. The enzyme cystathioninase (PLP-dependent) cleaves & deaminates cystathionine to cysteine & α - ketobutyrate .

5. Synthesis of cysteine from methionine Methionine Homocysteine Cystathionine Cysteine α - ketobutyrate Serine H2O Cystathionine β -synthase Succinyl CoA γ - Cystathioninase Homocysteinemia type-1

6. Cysteine formation

7. Homocysteine & heart attacks Homocysteine is an intermediate in the synthesis of cysteine from methionine. Elevation in plasma homocysteine ( normal <15 pmol /l) has been implicated in coronary artery disease. Homocysteine reacts with collagen to produce reactive free radicals , besides interfering with collagen cross links . Homocysteine is also involved in the aggregation of LDL particle & leads to atherosclerosis.

8. Degradation of cysteine Cystine & cysteine are interconvertible by an NAD + dependent cystine reductase . Cysteine on decarboxylation produces mercaptoethanolamine which is involved in the biosynthesis of coenzyme A from the vitamin pantothenic acid .

9. Decarboxylation Cysteine Decarboxylase, PLP

10. The enzyme cysteine dioxygenase oxidizes cysteine to cysteine sulfinate , on further oxidation, is converted to cysteic acid . Cysteic acid undergoes decarboxylation to produce taurine which conjugates with bile acids. Cysteic acid can also be degraded to pyruvate, which is glycogenic.

11. Formation of taurine from cysteine 1. Cysteine dioxygenase , 2. Decarboxylase

12. 3'-phosphoadenosine 5'-phosphosulfafe (PAPS ) Cysteine sulfinate cleaves off alanine to produce sulfite which is converted to sulfate & excreted in urine. Some amount of sulfate condenses with ATP to form active sulfate or 3 '-phosphoadenosine 5'- phosphosulfafe (PAPS ).

13. Active sulfate (PAPS) is utilized for the synthesis of mucopolysaccharides . Used in detoxification . Sulfate is also a structural component of proteins & lipids. Cysteine can be degraded by desulfhydrase to liberate sulfur (as H2S), ammonia & pyruvate . Cysteine is a component of glutathione.

14. PAPS

15. Metabolic Functions of Cysteine Cysteine is required for formation of Glutathione. Glutathionine is required for transport of amino acids. Glutathione is present in the RBCs. This is used for inactivation of free radicals formed inside RBC.

16. Glutathione helps to detoxify several compounds. Glutathione keeps the enzymes in reduced, active state . Cysteine residues in polypeptide chains form disulfide bridges to make active proteins, e.g. insulin & immunoglobulins .

17. Inborn errors of sulfur amino acid metabolism Cystinuria ( cystine-lysinuria ): The most common inherited disease. It is characterized by increased excretion of cystine ( 25-40 times normal). Elevation in the urinary output of lysine , arginine & ornithine is also observed.

18. A specific carrier system exists in kidney tubules for the reabsorption of amino acids, namely cysteine , ornithine, arginine & lysine (COAL to recall). In cystinuria , this carrier system becomes defective leading to the excretion of all these four amino acids in urine.

19. Cystine is relatively insoluble & increased concentrations leads to precipitation & formation of cystine stones in kidney & urinary tract . Cystinuria is usually identified in the laboratory by cyanide nitroprusside test . The treatment includes restricted ingestion of dietary cystine & high intake of fluids.

20. Cystinosis ( cystine storage disease ) Cystine crystals are deposited in many tissues & organs of reticuloendothelial system throughout the body . These include spleen, lymph nodes, liver , kidney , bone marrow etc. A defect in the Iysosomal function. Cystine accumulates in the lysosomes of various tissues.

21. In cystinosis , renal function is impaired. It is characterized by generalized amino aciduria . The affected patients die within 10 years, mostly due to renal failure. It is also due to defect in the enzyme cystine reductase (interconverting enzyme).

22. Homocystinurias Homocystinurias are a group of metabolic disorders characterized by the accumulation & increased urinary excretion of homocysteine & S- adenosylmethionine (SAM). Plasma concentration of methionine is increased .

23. Homocystinuria type I Enzyme defect: Cystathionine synthase. Accumulation of homocystetne . It results in various complications - thrombosis , osteoporosis & mental retardation. The deficiency of cystathionine is associated with damage to endothelial cells which might lead to atherosclerosis.

24. Two forms of type I homocystinurias One of them can be corrected with vitamin B6 supplementation (B6 responsive) while the other does not respond to B6 . The treatment includes consumption of diet low in methionine & high in cystine . The patients of homocystinuria have high levels of homocysteine & usually die of myocardial infarction, stroke.

25. Homocystinuria ll : N 5 - N 10 - Methylene THF reductase . Homocystinuria lll : N 5 - N 10 - Methyl THF homocysteine methyltransferase . This is mostly due to impairment in the synthesis of methylcobalamin . Homocystinurla lV : N 5 - Methyl THF homocysteine methyl transferase . This is primarily due to a defect in the intestinal absorption of vitamin B 12 .

26. References Textbook of Biochemistry - U Satyanarayana Textbook of Biochemistry - DM Vasudevan

27. Thank You