Methionine, cysteine, homocysteine, and taurine are the 4 common sulfur-containing amino acids, but only the first 2 are incorporated into proteins. Sulfur belongs to the same group in the periodic table as oxygen but is much less electronegative

1. METABOLISM OF SULPHUR
CONTAINING AMINO ACIDS
Dr. Garima Baradia
Associate Professor
Dept. of Biochemistry
1

2. METHIONINE
2

3. • Methionine-is an essential amino acid
• Sulphur containing amino acid
• Glucogenic amino acid in nature
• Methionine degrades to cysteine synthesis
 Metabolism of S containing amino acids:
1. Activation of methionine to SAM:
• In the major pathway, methionine is activated to
‘active methionine’ or SAM
• Adenosyl group is transferred to S atom
3

4. 4

5. + HOMOSERINE
5

6. • Methyl transfer: Methionine has a very stable -
THIO-ETHER LINKAGE (C-S-C)
2. In SAM (S-Adenosyl Methionine) there is a high
energy bond, methyl group can be transferred
to other acceptors. SAM gets converted to S-
adenosyl homocysteine (SAH)
3. Homocysteine Formation:
SAH
Adenosine homocysteinase Adenosyl group
Homocysteine (HCys)
6

7. 4a Formation of Methionine:
METHYL THF THF
METHIONINE SYNTHASE
• Homocysteine -------------------------- Methionine
VITAMIN B12
7

8. 4b Homocysteine degradation:
Homocysteine + Serine
(PLP)
CYSTATHIONINE 𝛽 SYNTHASE
------- HOMOCYSTINURIA
Cystathionine
.
8

9. 5. Cysteine synthesis: Cystathionine is hydrolysed
by cystathionase to form cysteine and
homoserine.
• Net result is- SH group from methionine is
transferred to serine to form cysteine. This is
called trans-sulfuration reaction.
6. Final oxidation: Homoserine is deaminated &
then decarboxylated to propionyl CoA.
• Enters TCA cycle as succinyl CoA or
• Forms Glucose by Gluconeogenesis
9

10. Role of Met in Transmethylation Reactions
Some important products formed are…
-- Creatine *Reactions of Methyl
groups transfer;
derived
-- Epinephrine from 1 C pool
-- Choline *SAM
10

11. SYNTHESIS OF CREATINE
11

12. 12

13. • Methyl THF can transfer the methyl group only to
homocysteine (HCys) in the presence of Vitamin B12
as co-enzyme
• Vitamin B12 deficiency accounts to the deficiency of
folate too, called the
• “FOLATE TRAP”.
• SAM is the methyl donor for all the
trans methylation reactions.
13

14. 14

15. CYSTEINE
15

16. • Cysteine is non-essential amino acid
• Glucogenic in nature
• Cysteine is present in keratin of hair & nails
• Formation of cysteine is by using the carbon skeleton
contributed by serine and sulphur from methionine.
Met SAM SAH HCY+ Ser Cysteine
16

17. Degradation of Cysteine
• Transamination: Cysteine transaminates to form
beta mercapto pyruvic acid and finally pyruvate.
The sulphur may be removed either as H2S/
elemental sulphur
• Cysteine on decarboxylation gives beta mercapto
ethanolamine. This is used for synthesis of co-
enzyme A after combining with pantothenic acid
and phosphate.
17

18. 18

19. GLUTATHIONE (GSH)
19

20. Metabolic Functions of Cysteine
A. Formation of Glutathione
• Glutathione is gamma-glutamyl cysteinyl glycine.
It is generally abbreviated as GSH, to indicate SH
group.
Glutamate + Cysteine Gamma-glutamyl cysteine
Gamma glutamyl cysteine Glutathione
• Both steps need hydrolysis of each ATP.
1. Role of GSH in amino acid transport :
Glutathione is involved in the absorption of amino
acid.
20

21. 3. Co-enzyme Role
• Metabolic role of GSH is mainly in reduction
reactions.
2GSH GS-SG + H2
• The hydrogen released is used for reducing other
substrates…..
Maleyl acetoacetate Fumaryl acetoacetate
Cysteic acid Taurine
21

22. 4. RBC Membrane Integrity
• Glutathione is present in the RBCs which inactivates
free radicals formed inside RBC by the action of
Glutathione peroxidase, a selenium containing
enzyme.
• Glutathione is regenerated by an NADPH dependent
glutathione reductase. (NADPH is derived from the
HMP shunt pathway)
• The occurence of hemolysis in G6PD deficiency is
attributed to the decreased regeneration of reduced
glutathione.
22

23. 5. Met- hemoglobin
• The met-Hb is unavailable for oxygen transport.
• Glutathione is necessary for the reduction of met-
hemoglobin (ferric state) to normal Hb (ferrous state).
2Met-Hb-(Fe+3) + 2GSH 2Hb-(Fe+2) + 2H+ + GS-SG
6. Conjugation for Detoxification
• Glutathione helps to detoxify several compounds by
transferring the cysteinyl group, e.g. --
Organophosphorus compounds
-- Heavy metals
-- Drug metabolism
23

24. 7. Activation of Enzymes
• Many enzymes having SH groups in the active site
are kept in the active form by the glutathione.
• Such enzymes are active in the reduced form.
Glutathione keeps enzymes in reduced, active
state.e.g.Glyceraldehyde-3-P-dehydrogenase.
24

25. 8. FREE RADICAL SCAVENGING ROLE OF GSH
25

26. B. Formation of Taurine From cysteine
• Cysteine is oxidised to form taurine.
• Alternatively cysteine is oxidised to cysteine
sulfinic acid, decarboxylated by a decarboxylase to
hypotaurine which in turn is oxidised to taurine.
• Taurine is used for conjugation of bile acids.
Taurine+Cholyl CoA Taurocholate+CoA-SH
• Taurine is a modulator of calcium fluxes, calcium
binding and movement.
• In CNS it is an inhibitory neurotransmitter.
26

27. C. Keeping the Correct structure of Proteins
• Cysteine residues in polypeptide chains form
disulfide bridges to make active proteins, e.g.
insulin and immunoglobulins. Protein disulfide
isomerase forms these disulfide bonds.
27

28. METABOLISM OF SULPHUR
• The S present in body may be either organic sulphur
as a component of proteins/as sulfatides and
glycosamino glycans (GAG).
• Inorganic sulfur is derived from the sulfur
containing amino acids by trans-sulfuration or
desulfuration reactions.
• The excretory forms of sulphur in urine are
Inorganic sulfates, Organic or ethereal sulfates and
Neutral sulfur.
28

29. Formation of Active Sulfate
• Active sulfate or phospho adenosine phospho-5’-
sulfate (PAPS) is formed by the reaction between
ATP and SO4 and the sulfate is attached to the
ribose-5’-phosphate.
• PAPS is used for various sulfuration reactions, e.g.
synthesis of sulfatides,GAG
2ATP + SO4 PAPS + ADP + PPi
29

30. Cystinuria
• It is an autosomal recessive condition.
• This is mainly because of deficiency in renal
transport defect in that reabsorption of these
amino acids do not occur.
• Signs and symptoms include:
-- Chief abnormality is the excretion of cysteine and to
a lesser extent lysine, ornithine and arginine.
-- Crystalluria: In acidic pH, cystine crystals are
formed in urine, form calculi (stones).
30

31. Cyanide-nitroprusside Test
• It is a screening test.
• Urine is made alkaline with ammonium hydroxide
and sodium cyanide is added.
• Cystine, if present, is reduced to cysteine. Then
add sodium nitroprusside to get a magenta-red
coloured complex. The intensity of colour is
proportional to free –SH content.
• Specific aminoaciduria may be confirmed by
chromatography.
31

32. Cystinosis (Cystine storage disease)
• Deposition of cystine crystals in lysosomes.
• Cystine accumulates in liver, spleen, bone marrow, WBC,
kidneys, cornea and lymph nodes.
• There is an abnormality in transport of cysteine which is
responsible for the accumulation.
• There may also be an impaired conversion of cystine to
cysteine due to lack of cystine reductase enzyme.
• It is an autosomal recessive condition. Microscopy of blood
shows cystine crystals in WBCs.
32

33. HOMOCYSTINURIAS
• Normal homocysteine in blood is 5-15 micro mol/L
• In diseases, it may be increased to 50-100 times
Moderate increase is seen in aged persons, vitamin B12
or B6 deficiency, tobacco smokers, alcoholics and in
hypothyroidism.
• Large amounts of homocysteine excreted in urine.
• In plasma, homocysteine (with –SH group) and
homocystine (disulphide, S-S group) exist.
• Both of them are absent in normal urine; but if present,
it will be the homocystine (disulphide).
33

34. • If homocysteine level in blood is increased, there is
increased risk for coronary artery diseases.
• It increases the possibility of thrombosis, and also
plaque formation, so damaging the arteries.
• An insufficient concentration of folic acid, vitamin B12
and pyridoxine also increase the homocysteine levelin
blood.
• An increase of 5 micromol/L of homocysteine in serum
elevates the risk of coronary artery disease by as much
as cholesterol increase of 20 mg/dl.
34

35. Causes of congenital homocystinurias:
1. Cystathionine Beta Synthase Deficiency (Classical or
type 1)
• Elevated plasma level of methionine &
homocysteine.Plasma Cys is markedly reduced.
• Excretion of Met & homocystine in urine is more
• General symptoms are mental retardation and
Charley Chaplin gait (long extremities with flat
feet and toes out). Skeletal deformities are seen.
• In eyes, ectopia lentis, myopia and glaucoma may
be observed.
35

36. 36

37. • Homocysteine causes activation of Hageman’s factor.
This may lead to increased platelet adhesiveness and
life-threatening intravascular thrombosis.
• Cyanide-nitroprusside test will be positive in urine.
Urinary excretion of homocystine is more than 300
mg/24h. Plasma homocysteine and methionine levels
are increased.
• Treatment is a diet low in methionine and rich in
cysteine. Sometimes the affinity of apo-enzyme to the
co-enzyme is reduced. In such cases, pyridoxal
phosphate, the co-enzyme given in large quantities
(500 mg) will correct the defect.
37

38. 2.Cobalamin Deficiency
• The enzyme, N5-methyl-THFA-homocysteine-
methyl-transferase is dependent on vitamin B12.
So, B12 deficiency may produce alteration in
methionine metabolism.
• Blood contains increased level of homocysteine,
but methionine level is low.
• Urine contains homocystine.
38

39. 39

40. 3. Deficient N5,N10-Methylene THFA Reductase
• This enzyme catalyses the reaction N5, N10-
methylene-THFA to N5-methyl-THFA.
• Deficiency of this enzyme leads to reduced
methionine synthesis with consequent increase in
homocystine level in urine.
• Behavioral changes and vascular abnormalities
may be observed.
• Folate supplementation is beneficial.
40

41. 4. Cystathioninuria
• It is due to cystathionase deficiency. It is an
autosomal recessive condition.
• Mental retardation, anemia, thrombocytopenia,
and endocrinopathies accompany this condition.
• Acquired Cystathioninuria may be due to
pyridoxine deficiency.
41

42. 5. Acquired hyper-homocysteinemias
• Nutritional deficiency of vitamins, such as
cobalamine, folic acid and pyridoxine.
• Metabolic : Chronic renal diseases,
hypothyrodism.
• Drug induced: Folate antagonists, vitamin B12
antagonists, nitric oxide antagonists.
42

43. 43
Thank You!