Metabolism of Sulfur Containing Amino Acids

(Cysteine, Cystine and Methionine)

Cysteine (Cys or C) and Cystine
Synthesis
Cysteine is a nonessential amino acid being synthesized by trans-sulfuration pathway
of homocysteine with serine to give homoserine and cysteine.
Carbon & nitrogen atoms of Cysteine comes from Serine while sulfur comes from
methionine.

CH2-OH CH2-SH CH2 S CH2 CH2-OH CH2-SH

Cystathionine Cystathionase
CHNH2 CH2 Synthase CH2 CHNH2 CH2 CHNH2
COOH + CHNH2 PLP H2O CHNH2 COOH PLP CHNH2 + COOH
H2O
Serine COOH COOH COOH Cysteine
Homocysteine Cystathionine Homoserine

Catabolic Fate
Cysteine is glucogenic being converted to pyruvate by desulfhydrase (PLP-dependent)
in which cysteine is converted to pyruvate, hydrogen sulfide (H2S) and ammonia
(NH3).

Metabolic Pathways of Cysteine Derivatives

CH2-SH CH3 CH3
Desulfhydrase H2O NH3
CHNH2 PLP C = NH C=O
NAD+ COOH COOH Spontaneous COOH
H2S
Cystine Cysteine -Iminopropionate Pyruvate
reductase
CH2-SO2H CH2-SO2H
+ Dioxygenase Decarboxylase
NADH,H CHNH2
PLP CH2NH2
CH2 S S CH2 O2 COOH CO2 Hypotaurine
CHNH2 CHNH2 Decarboxylase Cysteine sulfinate
COOH COOH PLP [O]
Oxidase
Cystine CO2

CH2-SH
CH2-SO3H
CH2NH2
CH2NH2
Thioethanolamine
Taurine
III- Metabolic Derivatives of Cysteine
1- Two molecules of cysteine are oxidized to form cystine with disulfide bond. The
disulfide bond is important for stabilization of the structure of many proteins, as
insulin.
2- Synthesis of glutathione (γ-glutamylcysteinylglycine or GSH) which is a
biologically active tripeptide, very powerful antioxidant.
3- Cysteine is decarboxylated to thioethanolamine which is the active part in 4`-
phosphopantetheine which is a component of both CoA and fatty acid synthase
complex.
4- Cysteine is oxidized and then decarboxylated to form hypotaurine then taurine
mainly in liver cells. Taurine is conjugated (like glycine) with bile acids and excreted
in bile in the form of bile salts. Taurine is an inhibitory neurotransmitter in CNS.
5- Cysteine provides the sulfate group of phosphoadenosyl-phosphosulfate (PAPS), or
active sulfate. PAPS is the sulfate donor for synthesis of sulfate containing
compounds e.g. GAGs and sulfolpids and detoxification (mentioned later).

N.B Cysteine is present in large quantities Keratin of hair and nails.

 Methionine (Met or M)
Synthesis
Methionine is an essential amino acid containing sulfur.

Activation of Methionine, transmethylation and its conversion to

HomoCysteine

Role of Methionine as Methyl Donor

Ribose A
CH2 – S – CH3 CH2 – S ~ CH3
CH2 +
ATP 2 H2O PPi + Pi CH2
CHNH2
CHNH2
COOH Methionine
Adenosyl transferase COOH
Methionine S-adenosyl-methionine (SAM)active
(G-SH)
methionine
a
Cobalamin Methyl-FH4 Methyl acceptor

Methionine Methyl transferase

synthase
Methylated product
FH4
Methylcobalamin
Ribose A
CH2 – S
CH2 – S H Hydrolase
CH2
CH2
CHNH2
CHNH2 Adenosine H2O
COOH
COOH
S-adenosyl-homocysteine (SAH)
Homocysteine

1- The active form of methionine, S-adenosyl methionine (SAM), is the main source of
methyl groups in the body. Trans-methylation reactions are catalyzed by different
methyl transferases.

SAM is used in many transmethylation reactions as follows:

- Guanidoacetate Creatine
- Ethanolamine Choline
- Nor-epinephrine Epinephrine
- N-acetyl serotonin Melatonin
- Nicotinamide N-methylnicotinamide
2- Methionine is involved in the synthesis of protein and polyamines (spermine and
spermidine).
Spermine and spermidine have multiple positive charges that can bind with DNA and
RNA helping their stabilization. They play an important role in the process of gene
expression.

Catabolic Fate
It is a glucogenic amino acid, HOW?
Being converted to homocysteine, and then homocysteine is conjugated to serine to
form cystathionine by cystathionine synthase then by cystathionase forming cysteine
and homoserine. Homoserine is deaminated then decarboxylated to propionyl-CoA
which enters TCA as succinyl Co-A to be converted to Glucose.
Metabolic disorders of sulfur containing compounds
Metabolic Disorders of Sulfur Containing Amino Acids

1- Hyperhomocysteinemia: is a high level of homocysteine in blood (but

methionine level is normal).

Cause: It is due to defect in remethylation of homocysteine caused by:

a- Nutritional deficiency of pyridoxine (vitamin B6), folic acid or/and vitamin B12.
b- Genetic disorders affecting
i. The activity of methylene tetrahydrofolate reductase (MTHFR), essential for
the formation of methyltetrahydrofolate.
ii. Methionine synthase
iii. Cystathionine synthase (Homocystinuria) (methionine is high)

Effects of hyperhomocysteinemia:
a- A high level of homocysteine causes a modification in LDL and collagen
leading to:
i. Endothelial injury, which leads atherogenesis, which can result in ischemic
injury, Hyperhomocysteinemia is therefore a risk factor for coronary artery
disease, thromboembolic disorders and hypertension.
ii. Osteoporosis and dislocation of the eye lens.
b- Cysteine becomes essential.

2- Homocystinuria:
Incidence: 1 in 200,000 births
Cause: lack of cystathionine synthase (PLP dependent). Transsulfuration cannot be
achieved, and homocysteine and methionine accumulate in tissues, blood
(homocysteinemia) and excreted in urine (homocystinuria). Cysteine, in this
condition is also considered an essential amino acid.
Effects: During childhood the patient of homocystinuria presents with
atherogenesis, thrombo-embolic manifestations, osteoporosis, mental
retardation and in addition dislocation or complete detachment of the eye lens
due to lack of adequate cysteine.
3- Cystathioninuria:
Cause: decreased activity of cystathionase.
Effects: excretion of excess amount of cystathionine in urine.
Treatment: The above conditions (1,2 and 3) are treated by:
Diet rich in cysteine, but poor in methionine.
Some cases respond to high doses of vitamin B6.

4- Cystinuria ( Cystine-Lysinuria):
Prevelance: Cystinuria occurs at a frequency of 1 in 7000 individuals, making it the
most common genetic error of amino acid transport.
Cause: a genetic defect in the transporter of dibasic amino acids leading to failure
of transport of these amino acids (cystine, arginine, ornithine and lysine) across the
renal proximal tubules and are excreted in urine. Cystine precipitates in renal
tubules, crystallizes (hexagonal shape crystals in urine) and forms cystine stones.
Treatment:This process could be interrupted with alkalinization of urine and
ingestion of plenty of fluids that makes cystine more soluble and washed off urinary
tract

Cystine crystals