Kwame Nkrumah University of

Science & Technology, Kumasi, Ghana

CATABOLISM OF SULFUR
CONTAINING AMINO ACIDS

Dr Max Efui Annani-Akollor

Dept of Molecular Medicine

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 Lecture Outline
• Metabolism of Methionine
Homocysteinuria
Cystathionuria
• Metabolism of Cysteine
• One carbon Metabolism
Biotin
Tetrahydrofolate

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 Lecture Objectives
• Identify key intermediates and end products in the catabolism of
sulfur containing amino acids.
• Know some clinical outcomes of errors in catabolism of methionine
and cysteine
• Explain how Biotin and Tetrahydrofolate are involved in one carbon
metabolism

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METABOLISM OF SULPHUR AMINO ACIDS
MET, CYS,HCys

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 Methionine
Synthase NH3+
NH3+ (Vit. B12-dep.) -
- + FH4 HSCH 2CH 2CHCO 2 + 5-Methyl
CH 3SCH 2CH 2CHCO 2 FH4
Methionine L-Homocysteine
(Essential) CO 2 -

Cystathionine H C NH3 +
Serine
b-synthase CH2OH
(PLP-dep.)

Cystathionine NH3 +
NH3+ lyase -
OH SCH 2CH 2CHCO 2
CH 3CHCH 2CO 2 +
- -
HSCH 2CHCO 2 CH2CHCO2 -
Cystathionine
b-Hydroxy- Cysteine NH3 +

butyrate (Non-essential)

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METHIONINE METABOLISM: METHYL DONATION
NH2
N
N

S-Adenosyl methionine N N
NH3+
synthase +
- -O
2 CCHCH2 CH2 -S-H2 C
CH 3SCH 2CH 2CHCO 2
O

ATP NH3+ CH3

Methionine
OH OH
SAM
Decarboxylase
S-Adenosyl
NH2
NH2 Methionine
N
N N (SAM)
Decarboxylated N
CO2 R-H
SAM N N
N N Methyl-
- transferases
+ + O2 CCHCH2CH2 -S-H2C O
H3NCH2CH2CH2-S-H2C O NH3 + R-CH3
CH3
S-Adenosyl
OH OH
OH OH
homocysteine
•The major metabolic fate of methionine are:
•Its conversion to S-adenosyl methionine, the principal methyl group donor in
biosynthetic reactions
•Its conversion through the trans-sulfuration pathway leads to synthesis of
cystathionine, cysteine and other biosynthetic intermediates
•These two metabolic fates are however related since methionine may be
converted sequentially to:
– S-adenosyl methionine
– S-adenosyl homocysteine
– homocysteine

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•Homocysteine is then converted
irreversibly to cystathionine by a PLP
requiring cystathionine-β synthase
•Cystathionine is then converted to
cysteine and α-ketobutyric acid by a
PLP requiring γ-lyase
•α-ketobutyric acid is then oxidatively
decarboxylated to propionyl CoA.
•Cysteine suppresses the synthesis of
cystathionine β synthase The net effect of these
reactions is the transfer
of the sulfhydryl group
•It is also an allosteric inhibitor of of homocysteine to the
carbon chain of serine
cystathionine γ lyase

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 HOMOCYSTINURIA
•Rare - deficiency of cystathionine β synthase
•Accumulation of homocysteine in the blood and their excretion in the urine
•Accumulation of methionine in the blood of affected persons.
•Accumulated homocysteine reacts with lysyl semialdehydes and thus interferes
with cross-linking of collagen - Dislocated optical lenses
•The accumulated homocysteine may be converted to homocysteinethiolactone
•Homocysteine thiolactone modified LDL leads to their aggregation and
atheroma formation – CVD and death

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 HOMOCYSTINURIA
Affected individuals present with severe mental retardation and connective
tissue defects such as:
• Deformation of the spine
• Dimineralisation of bone
• Dislocation of joints
• Aortic aneurysms

They may also present with:

• Bilateral dislocation of the lenses
• Fair complexion with blue eyes
• Hepatomegaly
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 HOMOCYSTINURIA
•Management entails the provision of extra cysteine in the diet of patients
•Restrict the intake of methionine containing diets but feed with betaine or its
precursor choline
•Some subjects may respond favorably to pyridoxine therapy

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 METABOLISM OF CYSTEINE
•Cysteine - several metabolic fates
•The pathway of degradation is
determined by the needs of the cell.
•The major route for cysteine
catabolism is a three step pathway
leading to pyruvate.
•It may be converted to hypotaurine
and taurine

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• Deficiency of sulfite oxidase results in the excretion of large amounts of
thiosulfate and sulfite
• Affected subjects present with neurological abnormalities at birth which
deteriorates progressively and results in early death
• Cysteine may be metabolised to thiocysteine and thiosulfate which may be
converted to thiocyanate

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• Cysteine may be metabolised to sulfite and pyruvate

• Sulfite may be converted to sulfate under the catalysis of mitochondrial

sulfite oxidase
• Sulfate, subsequently metabolised to 3’-phosphoadenosine 5’-
phosphosulfate (PAPS), the source of sulfate groups in biological systems

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 CYSTATHIONURIA
•A rare metabolic defect characterized by the deficiency of cystathionine γ lyase
•Imbalance between the synthesis and degradation of cystathionine
•The condition may also be associated with either the reduced affinity of the γ
lyase or the deficiency of PLP
•Affected subjects accumulate cystathionine in the blood and excrete high levels
in their urine
Most affected subjects are asymptomatic
– Some subjects may present with the following;
– Small liver
– Pale liver
– Fibrotic liver
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 CYSTATHIONURIA
•Taurine appears to play a role in brain development
•Taurine may form a conjugate with bile acids to enhance the clearance of
cholesterol by the liver
•Taurine participates in the clearance of xenobiotics and toxins
•It is probably involved in the regulation of intracellular [calcium]
•It may be involved in osmoregulation

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 ONE CARBON METABOLISM
•One carbon transfers involve one of three cofactors:
–Biotin - pyruvate carboxylase reaction
– Tetrahydrofolate - can transfer single c units in a number of different oxidation states
–Or s-adenosyl methionine - as a methylating agent, cytosine methylation of CpGs In gene promoter
regions

•These cofactors are used for the transfer of one carbon groups in different
oxidation states
The various oxidation states of carbon encountered in metabolism are:
– Carbon dioxide - Formyl (-CHO)
– Formimino (-CHNH-) - Methenyl (-CH=)
– Methylene (-CH2-) - Methyl (-CH3)
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 BIOTIN
• This is a human vitamin obtained from the diet
• It is also synthesized by the intestinal flora
• It is involved in the carboxylation reactions
• Biotin may be sequestered by avidin which is found in uncooked egg white

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BIOTIN

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 TETRAHYDROFOLATE
•It is otherwise known as tetrahydropteroyl glutamate
•It consists of a substituted pteridine, para amino benzoate and glutamate
•It is a human vitamin obtained from the diet
•It may be synthesized by the intestinal flora

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 TETRAHYDROFOLATE
• Review structure
– focus on heterocyclic ring structure
• 2-amino-4-oxo-6-methylpterin
• Notice the numbering of the atoms
• Look At N5
– PABA joins to 2-amino-4-oxo-6-methylpterin to form pteroic acid
• Find N10
• Covalent attachment of c1 units at
– N5
– N10
– Both

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 TETRAHYDROFOLATE
• Three different oxidation states
– Methanol at N5
• Methyl (-CH3)
– Formaldehyde at N5,N10
• Methylene (-CH2-)
– Formate
• Formyl (-CH=O) at N5 or N10
• Formimino (-CH=NH) at N5
• Methenyl ( -CH=) at N5,N10
• Look again at the 2 reactions for synthesis of Gly
– Serine hydroxymethyltransferase
– Glycine synthase
• THF is involved in each
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 TETRAHYDROFOLATE

• C1 units enter the THF pool mainly from these two reactions
– as N5,N10 –Methylene-THF
Oxidation States Of C1 units attached To THF are interconvertible
Via enzymatic redox reactions
• We will see THF in:
– Methionine synthesis
– His synthesis
– Purine synthesis
– DTMP (thymidylate) synthesis

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 TETRAHYDROFOLATE
• THF is derived from folic acid
– Mammals cannot synthesize it
– Deficiency during early pregnancy can lead to neural tube defects
• Anencephaly   Spina Bifida
• Bacteria synthesize folic acid
– Sulfonamides competitively inhibit
• Structural analogs of PABA
• Good antibacterial agents
• Why are mammals unaffected?

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 TETRAHYDROFOLATE
•Tetrahydrofolate is a highly versatile carrier of activated one carbon units
•The one carbon units may be bonded to its N5, N10 nitrogen atom or both (N5,
N10)
•The one carbon atoms carried by tetrahydrofolate are interconvertible
•They serve as donors of one carbon units in a variety of biosynthetic reactions.
•The major source of one carbon units for tetrahydrofolate is the carbon
removed in the conversion of serine to glycine

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