section 17.3
Metabolism of Some Individual Amino Acids
355
il
S u lfate
O__c _ Q-
adenyjyltraosferase,
||
f
o
A T P
PF>
Q
O
o — s — o — P — o — CH
2
o
o"
o
o
_
Il
II
o —
s—
o — P — O — CH;
Il
L
o
o
H O
O H
A d e n o sin e 5 '-p h o sp h o su lfa te
n
0
O H
_
I
o =
p —
c r
1
C T
P A P S
F I G U R E 1 7 -1 7
Formation of 3'-phosphoadenosine-5'-phosphosulfate (PAPS).
the méthylation of homocysteine to methionine using
N5-methyltetrahydrofolate (N5-methyl-FH4) catalyzed by
a vitamin Bi
2
-dependent enzyme. The second is the
transsulfuration pathway where homocysteine condenses
with serine to form cystathionine; this is catalyzed by
cystathionine /3-synthase (CBS) which is a pyridoxal-
5'-phosphate enzyme. End products of the transsul-
furation
pathway
are
cysteine,
taurine,
and
sulfate
(Figure 17-18). The methyl donor N5-methyl-FH4 is syn-
thesized from N5,N10-methylene-FH4 and the reaction is
catalyzed by N5,N10-methylenetetrahydrofolate reductase
(MTHFR). MTHFR is a FAD-dependent enzyme. Thus,
the metabolism of homocysteine involves four water sol-
uble vitamins, folate, vitamin Bi2, pyridoxine, and ri-
boflavin. Any deficiencies or impairment in the conversion
of the four vitamins to their active coenzyme forms will
affect homocysteine levels. Severe cases of
hyperhomo-
cysteinemia
occur due to deficiencies of enzymes in the
homocysteine remethylation or transsulfuration pathways.
Individuals with a homozygous defect in cystathionine
/3-synthase have severe hyperhomocysteinemia (plasma
concentrations >50 /xM/L) and their clinical manifes-
tations are premature atherosclerosis, thromboembolic
complications, skeletal abnormalities, ectopia lentis and
mental retardation.
In plasma, homocysteine is present as both free (< 1%)
and oxidized forms (>99%). The oxidized forms include
protein (primarily albumin)-bound homocysteine mixed
disulfide (80-90%), homocysteine-cysteine mixed disul-
fide (5-10%), and homocystine (5-10%). Several studies
have shown the relationship between homocysteine and
altered endothelial cell function leading to thrombosis.
Thus, hyperhomocysteinemia appears to be an indepen-
dent risk factor for occlusive vascular disease. Five to ten
percent of the general population have mild hyperhomo-
cysteinemia.
It has been shown that a thermolabile form of MTHFR
is a major cause of mildly elevated plasma homocys-
teine levels, which have been associated with coronary
heart disease. The thermolabile MTHFR gene has a
