1. Metabolism of Sulfur containing amino acids
Dr. Ketki K Assistant Professor Dept of Biochemistry
HIMS Varanasi

2. Sulfur containing amino acids
The sulfur – containing amino acids:
Methionine, cysteine & cystine
Methionine is glucogenic & essential amino acid
Serves as a precursor for the synthesis of cysteine & cystine which are non-essential
Cysteine & cystine are interconvertible
Cystine is found exclusively in protein

3. Methionine: required for the initiation of protein biosynthesis
The sulfur - containing amino acids: almost an exclusive dietary source of sulfur to the body

4. Metabolism of Methionine
It may be divided into three parts
Activation of methionine & transmethylation reaction
Conversion of methionine to cysteine & cystine
Degradation of cysteine & its conversion to specialized products

5. Synthesis of SAM

6. Methionine metabolism
Methionine adenosyltransferase
Methionine
SAM
2Pi + Pi
THF
ATP
Acceptor
Methyl transferase
CH3
Methylated product
N5-Methyl THF
Adenosylhomocysteinase
Homocysteine
S-adenosylhomocysteine
Adenosine
H2O

7. Activation of methionine
Methionine has to be activated to S-adenosylmethionine (SAM) or active methionine [to donate the methyl group]
The synthesis of SAM occurs by the transfer of adenosyl group from ATP to sulfur atom of methionine

8. This reaction is catalysed by methionine S-adenosyltransferase (MAT)
3 isoenzymes for MAT
Three high energy phosphates (3ATP) are consumed in the formation of SAM
SAM is the main source of methyl groups in body

9. Methyl transfer:
SAM transfers the methyl group to an acceptor & gets itself converted to S-adenosyl-homocysteine (SAH) → enzyme: methyltransferase
Homocysteine:
S-Adenosylhomocysteine (SAH) is hydrolysed (adenosyl group is removed) to homocysteine & adenosine → enzyme: adenosine homocysteinase

10. Methionine synthesis (from homocysteine):
Homocysteine can be remethylated to methionine by N5-methyl tetrahydrofolate
This methyl group is donated from one-carbon pool, with the help of vitamin B12
In this manner, methionine can be regenerated for reuse

11. Homocysteine degradation:
Homocysteine condenses with serine to form cystathionine
This is catalysed by PLP dependent cystathionine-β-synthase
Absence of this enzyme leads to homocystinuria

12. Cysteine synthesis:
Hydrolysis of cystathionine to form homoserine & cysteine → enzyme: cystathionase
Net result: SH group is transferred from methionine to serine to form cysteine
It is c/a trans-sulfuration reaction

13. Final oxidation
Homoserine is deaminated & then decarboxylated to form propionyl CoA
Which enters into TCA cycle as succinyl CoA
Which is converted to glucose

15. Transmethylation
The transfer of methyl group (-CH3) from active methionine/SAM to an acceptor is known as transmethylation
SAM acts as donor of methyl group to the acceptor ,so that acceptor is converted to methyl acceptor
The enzymes involved in the transfer of methyl group : collectively k/a methyl-transferases

16. Origin of methyl group: derived from one carbon pool
Methyl THFA can transfer methyl group to homocysteine
Vit B12 acts as co-enzyme
Explain folate trap

18. Transmethylation reactions
Methyl group acceptor
Methylated product
Guanidinoacetate
Creatine
Norepinephrine
Epinephrine
Metanephrine
Ethanolamine
Choline
Nicotinamide
N-Methylnicotinamide
Acetyl serotonin
Melatonin
Phosphatidylethanolamine
Phosphatidylcholine
Serine
Carnosine
Anserine
t-RNA bases
Methylated t-RNA bases
Lysine
Methyl lysine

19. "As soon as the fear approaches near, attack and destroy it
"As soon as the fear approaches near, attack and destroy it." Chanakya quotes (Indian politician, strategist and writer, 350 BC-275 BC)  

20. Cysteine Metabolism

21. Content Introduction Synthesis of cysteine Degradation of cysteine
Metabolic function of cysteine
Disorders a/w cysteine metabolism

22. Cysteine (Cys)(C) Non-essential Glucogenic amino acid
Cysteine : 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

23. Synthesis of Cysteine

24. Degradation of Cysteine
Trans-amination
May be removed as H2S
Decarboxylation

25. Pyruvate formation from cysteine

26. Decarboxylation of cysteine

27. Metabolic Functions of Cysteine
Formation of Glutathione
Amino acid transport
Co-enzyme role
RBC membrane integrity
Prevents met-hemoglobinemia
Conjugation for detoxification
Activation of enzymes
Formation of Taurine
Keeping correct structure of proteins

28. Glutathione

29. Role of glutathione in Amino acid transport

30. Role of glutathione as Co-enzyme
2GSH ( Reduced)→ GS-SG (Oxidized) + H2
Hydrogen released is used for reducing other
substrates
Maleylacetoacetate → Fumarylacetoacetate
Cysteic acid → Taurine
(Iodine) I2 + 2GSH → 2HI + GS-SG

31. Role of glutathione in maintaining RBC membrane integrity
Free radical scavenging

32. Role of glutathione in preventing met-hemoglobinemia
2 Met-Hb-(Fe 3+) + 2 GSH → 2Hb –(Fe 2+) + 2 H + + GS-SG Glutathione is required to convert met-Hb(ferric state) to normal Hb (ferrous state)

33. Role of glutathione in conjugation for detoxification
Helps to detoxify several compounds by transferring the cysteinyl group,
Eg:
1) Organophosphorus compounds
2) Halogenated compounds
3) Heavy metals
4) Drug metabolism

34. GST
Peptidase
Acetylase

35. Role of glutathione in keeping the enzymes in reduced ,active state

36. Formation of taurine Cysteine to cystic acid and then taurine
Taurine is used for conjugation of bile acids
Taurine + Cholyl CoA → Tauro cholate + CoA SH
Taurine: Inhibitory Neurotransmitter in CNS

37. Formation of taurine from cysteine

38. Role of glutathione in Keeping correct structure of proteins
Cysteine residues in polypeptide chains form disulfide bridges to make active proteins, e.g. insulin & immunoglobulins

39. Inborn errors of sulfur containing amino acid metabolism
Cystinuria
Cystinosis
Homocystinuria
Cystathioninuria
Acquired Hyperhomocysteinemia

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

41. A specific carrier system exists in kidney tubules for the reabsorption of amino acids, namely cystine, 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 (cause)

42. Cystine is relatively insoluble & increased concentrations leads to precipitation & formation of cystine stones in kidney & urinary tract (c/f)
Cystinuria is usually identified in the laboratory by cyanide nitroprusside test
The treatment includes restricted ingestion of dietary cysteine & high intake of fluids
Garrod’s tetrad: alkaptonuria,albinism,cystinuria,pentosuria

43. Cystinosis (cystine storage disease)
Cystine crystals are deposited in many tissues & organs of reticulo-endothelial 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

44. 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

45. Homocystinurias Homocystinurias :
A group of metabolic disorders characterized by the accumulation & increased urinary excretion of homocysteine & S-adenosyl methionine, decreased cysteine in urine
Plasma concentration of methionine is increased

46. Homocystinuria type I Enzyme defect: Cystathionine beta synthase
Accumulation of homocysteine & methionine,excreted in urine
Plasma cysteine reduced
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.

48. Homocystinuria ll:
N5 - N10 - Methylene THF reductase deficiency
Homocystinuria lll:
N5 Methyl THF homocysteine methyltransferase deficiency
This is mostly due to impairment in the synthesis of methylcobalamin
Homocystinurla lV:
N5 - Methyl THF homocysteine methyl transferase deficiency
This is primarily due to a defect in the intestinal absorption of vitamin B12

50. Charley chaplin gait/ Skeletal deformity
C/F:
Mental retardation
Charley chaplin gait/ Skeletal deformity
Ectopia lentis,myopia,glaucoma
Thrombosis
ACTIVATION OF HAGEMAN’S FACTOR, INCREASED PLATLET ADHESIVENESS,THROMBOSIS

51. Investigation:
Aminoaciduria: Homocysteine in urine
Increased methionine & homocysteine(normal level: 5-15 µmol/L) in blood
Cyanide-nitroprusside test: positive in urine ,it indicates urine homocysteine > 300 mg/24h

52. Treatment:
The treatment includes consumption of diet low in methionine & high in cysteine
PLP given in large doses (500 mg) : corrects the defect

53. The patients of homocystinuria have high levels of homocysteine & usually die of myocardial infarction, stroke.
Homocysteine & heart attack:

54. Homocysteine & heart attack
Homocysteine interacts with lysyl residue of collagen ↓ Interfere with collagen cross linking & also defective protein fibrillin forms homocysteine thiolactone which binds with LDL particles Particles aggregate & endocytosed by macrophages increased tendency for atherogenesis

55. Providing adequate PLP,Folic acid, Vitamin B12 keep homocysteine in blood at normal level
Maternal hyperhomocysteinemia:
Increase chance of neural tube defect in fetus,so high doses of folic acid advised during pregnancy

56. Cystathioninuria
Autosomal recessive condition Enzyme defect: cystathionase deficiency C/F: Mentalretardation,anemia,thrombocytopenia Investigation: Cystathionine in blood & urine, Negative cyanide nitroprusside test Treatment: cysteine rich diet, diet low in methionine, PLP in large doses( mg)

57. Acquired Hyperhomocysteinemia
Causes
Nutritional: B12,folic acid,PLP deficiency
Metabolic: hypothyroidism,chronic renal disease
Drug induced: Folate antagonist,B12 antagonist, Pyridoxine antagonist
Oasthouse syndrome is due to malabsorption of methionine. Such children excrete methionine, aromatic & branched chain amino acids in urine

58. Thank You