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#4 Sulfur Containing Amino Acids. 1. Uses of MET/CYS 2. Active Methyl Cycle & Trans-Sulfuration Pathway 3. Defects - Vitamin B6 responsive - Homocystinurea - Cystinurea - Cystinosis. Sulfur Containing Amino Acids.

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4 sulfur containing amino acids
#4 Sulfur Containing Amino Acids

1. Uses of MET/CYS

2. Active Methyl Cycle & Trans-Sulfuration Pathway

3. Defects

- Vitamin B6 responsive

- Homocystinurea

- Cystinurea

- Cystinosis

sulfur containing amino acids
Sulfur Containing Amino Acids
  • 2AA: MET & CYS, MET is converted to CYS through trans-sulfuration pathway
  • Cystine: dimer of CYS
  • Homocysteine: not a primary AA

MET - thioether derivative (contains S)

- EAA (3.5% animal protein, 1.5% plant protein)


(i) as a constituent of P, as well as the initiating AA in P synthesis

(ii) source methyl groups for  PL, DNA, RNA, hormones via conversion of MET to S-adenosyl MET

(iii) source S in CYS via trans-sulfuration pathway

(iv) polyamine



(I) protein synthesis

(ii) catalytic site of enzymes where SH is a nucleophile

(iii) synthesis of compounds  CoA, glutathione, taurine

(iv) provides SO4 on complete oxidation


(I) dimer of CYS

(ii) formed through oxidation mediated by O2, Cu2+, Mn2+ or Fe2+

(iii) little free in cells

(iv) important in disulfide bond formation in intact proteins to provide bridges and stabilize conformation of proteins.

synthesis of cys metabolism of met
Synthesis of CYS/Metabolism of MET

Active Methyl Cycle

2 pathways: Active Methyl Cycle and the Trans-Sulfuration Pathway.




H – Cys Cys

first step activation of met sam a high energy compound
First step: Activation of MET→ SAM (a high energy compound)

Most Rxns with SAM are Methyl transferases

Methyl transferred SAM → several compounds where Methyl linked to O or N in acceptor molecule

eg, Methylation RNA, DNA, cathecholamines

adrenaline synthesis


phosphatidyl choline

second step free energy loss sam sah
Second step: Free energy loss:SAM → SAH

SAH: nolonger has a charged sulfonium atom (thioether  MET), rxn irreversible

This represents a branch point in MET metabolism (direction depends on physiological needs of organism).

(I) if MET limited  homoCYS remethylated to MET (closed pathway of active methyl cycle)

(ii) If CYS needed and SAM adequate then homoCYS  trans-sulfuration pathway.

(ii) If both CYS and MET are adequate, then  other pathways

active methyl cycle
Active Methyl Cycle

(i) MET is an EAA

(ii) But mammals can synthesize MET from homoCYS if available (can replace MET in diet) because it is the “homoCYS” that cannot be made

(iii) Can transfer a methyl group back to homo CYS from betaine or (primarily) 5 methyl THF (tetrahydrofolate) Therefore regenerate MET  P synthesis, methylation and CYS synthesis

(iv) Crossroads for 2 important vitamins : folic acid and vitamin B12 (Vitamin B12 deficiency  folate deficient state)

(v) One of the major determinants whether homoCYS  MET is level of 5 methyl THF. SAM blocks 5 methyl THF production therefore decreased MET production when [SAM] increases

trans sulfuration pathway
Trans-Sulfuration Pathway

Trans - Sulfuration pathway is analagous to transamination for AA

(i) Major degradation pathway for MET in mammals

(ii) End Product is CYS

(iii) Two RXNs, both use pyridoxal phosphate as a cofactor (as with transamination)

fate of atoms of met

CH3 methyl transfer



converted to propionyl CoA succinyl CoA CH2   glucose

CH— NH3 NH4+


inborn errors of sulfur containing aa metabolism
Inborn Errors of Sulfur - containing AA Metabolism

(i) Two of these defects - homocystinuria (type I) & cystathioninuria involve enzymes of trans-sulfuration pathway (homo Cys  Cys)

(ii) Homocystinuria (2nd most common genetic AA disease) named due to  homocystine urine (CYS dimer)

 homocystine& MET & homoCYS blood which spills over into urine.

Dimer (homocystine) forms spontaneously in tissue

(iii) 4 types of homoCYS ( see table)

Type I = defect in cystathionine synthase (enzyme homoCYS  CYS: first step) Also with less homoCYS  MET therefore increase homoCYS

Type II: defect in methylene THF reductase decrease [5 methyl THF] which is necessary to methylate homoCYS

Type III: Decrease in B12

Type IV: malabsorption of B12

type i homocystinuria
Type I Homocystinuria

B6 responsive - (responsive to vitamin therapy)

- 50% Type I

- doses B6 up to 1 g / day

Remember defect in cystathionine synthase

enzyme that converts homoCYS  CYS (Step I)

pyridoxal phosphate is a cofactor

and that B6 Ppal

 Km mutants: do not bind cofactor as avidly therefore need much more cofactor to increase enzyme activity

Note: overly large dose (4-5 g / day)  nervous system dysfunction.

type i homocystinuria14
Type I Homocystinuria

B6 unresponsive

- enzyme mutation that does not involve cofactor binding site

therefore  dietary therapy

(i) add betaine  Why? Enhance alternate pathway

(ii) keep MET (use plant P like soybean/lentil which has half the MET of animal P)

(iii) CYS  conditionally essential because MET cannot be converted to CYS

(iv) Start therapy early due to serious clinical symptoms


- Mental defects

- Skeletal malformations (osteoporosis) due to defective collagen formation (homoCYS interferes with corsslinking collagen)

-Dislocation ocular lens(abnormal lens ligaments)

- Thromboembolism and vascular occlusion (decreased life expectancy) with damage to lining of blood vessels

 major cause morbidity and mortality.

Note:Increased homoCYS is a recognized risk factor for heart attack / stroke in adults

TREATMENT:Dietary folic acid which decreases homoCYS (via trans-sulfuration pathway)


- much rarer than Type I

- due to a defect in cystathion(in)ase (Step 2 CYS synthesis)

- less clinical abnormalities than Type I

- accumulation cystathionine in blood/urine (not detectable normally)

- responds to B6 supplementation in some cases (B6  Ppal  cofactor to enzyme) which also suggests a Km mutant

4 sulfur containing amino acids homocystinuria case discussion
#4 Sulfur-Containing Amino Acids: Homocystinuria Case Discussion

A 6-year-old girl was brought to the hospital with vision problems. She was found to have a downward dislocation of the left lens. Her mother indicated that the girl’s birth was normal, but that she lagged in development. She was unable to crawl until 1-year-old and did not walk until 2 years. Speaking was also delayed. She had long, thin bones; on roentgenographic examination the lower femur showed signs of osteoporosis. An older brother had similar symptoms, but had been diagnosed as having Marfan’s syndrome. A simple cyanide-nitroprusside test of the patient’s urine was positive, suggesting homocystinuria. This was confirmed by amino acid analysis of the plasma, which revealed homocystine, an abnormally high methionine level, and other sulfur-containing compounds that were derivatives of homocysteine. The patient was treated with a low-methionine diet supplemented with folic acid and pyridoxine.

symptoms clinical characteristics
Symptoms / clinical characteristics

1. Downward dislocation left lens

Slow development - crawling / walking / speaking.

Osteoporosis, long thin bones

2. Cyanide/nitro prusside urine test = +ve

3. Plasma AA   homoCYS, MET, homoCYS derivatives

Suggests that homoCYS  due to decrease conversion to CYS. MET also  therefore no problem in conversion homoCYS MET

  • 1. What is the origin of the homocystine excreted in this disease?
  • 2. What are some of the metabolic substances formed by the enzymatic reactions that use S-adenosylmethionine as the methylating agent?

2.These include RNA, DNA, amino terminal groups P’s, precursors of melatonin, creatine, epinephrine, phosphatidylcholine, methyl cobalamin (B6).

1. Origin of homocystine: dimer of homoCYS, product of excess homoCYS, overflows into urine

  • 3. What are some causes of homocystinuria in humans?
  • 4. How would one test for a deficiency of cystationine βsynthase in this patient?

3. Any part of pathway that impedes MET  homoCYS pathway  homoCYS

- decrease cystathionine B synthase (Step 1 for CYS)

- decreased syn of MET from homoCYS (5 MeTHF or B12 or enzyme ) genetic or nutritional

- Also 6 azauridine administration: anticancer agent which inh PPal enzymes therefore decreases both step 1 and 2

- bacterial action on cystathionine in urine

4. Test of enzyme: Measure enzyme in cells (human skin fibroblasts)to define hetero or complete mutation. Test addition of pyridoxal phosphate in vitro since  with effectiveness of therapy. (ie B6 sensitivity)

  • 5. Explain why pyridoxine is useful in the treatment of some patients with homocystinuria.
  • 6. What effect would a diet low in folate have on this patient?

5. (i) pyridoxine and/or B6  improvement in behaviour and IQ

(ii) Diet decreased MET, add smaller meals to prevent MET overload

(iii) add Vitamin B12 and folic acid

6. Diet decrease folate: Good or Bad? BAD Seriously effect 5 MeTHF rxn therefore  homoCYS even worse (no alternate pathway)

  • 7. What might account for the homocystinuria of an apparently normal infant (not in this case) with severe megaloblastic anemia and who was exclusively breast-fed by a strict vegetarian mother?
  • 8. Describe the genetics of homocystinuria (cystathionine βsynthase deficiency).

7. HomoCYS  B12 deficiency

- vegetarians: no eggs, no dairy, scrubbed vegetables  decrease cobalamin therefore not enough vitamin B12  synthesize cofactor

- therefore no homoCYS  MET

Can result in permanent neurological damage

8. Autosomal Recessive (1:45,000), Defects in gene chromosome 21, Heterogeneous