section 17.3
Metabolism of Some Individual Amino Acids
357
D IET
N H Î
C H — C H — C O O
Phenylalanine
(essential)
-coo-
Tyrosine (essential
in the event of
inadequate
phenylalanine
supply)
Body
protein
Thyroxine
(thyroid gland)
Neurotransmitters and
adrenal medullary hormones
Oxidation
(liver)
Melanin
(skin pigment)
Norepinephrine
+
Epinephrine
FIGURE 17-19
Overview of the metabolism of phenylalanine and tyrosine.
(Figure 17-19). The conversion of phenylalanine to tyro-
sine and its degradation to acetoacetate and fumarate are
shown in Figure 17-20.
The phenylalanine hydroxylase reaction is complex,
occuring principally in liver but also in kidney. The hy-
droxylating system is present in hepatocyte cytosol and
contains phenylalanine hydroxylase, dihydropteridine re-
ductase, and tetrahydrobiopterin as coenzyme. The hy-
droxylation is physiologically irreversible and consists of
a coupled oxidation of phenylalanine to tyrosine and of
tetrahydrobiopterin to a quinonoid dihydroderivative with
molecular oxygen as the electron acceptor:
phenylalanine hydroxylase
Phenylalanine + O
2
+ tetrahydrobiopterin------------------------ >■
tyrosine + H
2
O + quinonoid-dihydrobiopterin
The tetrahydrobiopterin is regenerated by reduction of the
quinonoid dihydrobiopterin in the presence of NAD(P)FI
by dihydropteridine reductase:
Quinonoid dihydrobiopterin + NAD(P)H +
dihydropteridine reductase
H+----------------------►
NAD(P)+ + tetrahydrobiopterin
NADH
exhibits
a lower
Km
and
higher
Vmax
for
the reductase than NADPH. Thus, the pterin coen-
zyme functions stoichiometrically (in the hydroxylase
reaction) and catalytically (in the reductase reaction).
Deficiency
of
dihydropteridine
reductase
causes
a
substantial decrease in the rate of phenylalanine hy-
droxylation. Dihydropteridine reductase and tetrahydro-
biopterin are involved in hydroxylation of tyrosine and
of tryptophan to yield neurotransmitters and hormones
(dopamine, norepinephrine, epinephrine, and serotonin).
Unlike
phenylalanine
hydroxylase,
dihydropteridine
reductase is distributed widely in tissues (e.g., brain,
adrenal medulla).
Human liver phenylalanine hydroxylase is a multimeric
homopolymer whose catalytic activity is enhanced by
phenylalanine and has a feed-forward metabolic effect.
Phosphorylation of phenylalanine hydroxylase by cAMP-
dependant kinase leads to increased enzyme activity and
dephosphorylation has an opposite effect. Thus, glucagon
and insulin have opposing effects on the catalytic activity
of phenylalanine hydroxylase.
Quinonoid dihydrobiopterin is an extremely unstable
compound that can rapidly rearrange (by tautomerization)
to 7,8-dihydrobiopterin (Figure 17-21) and be reduced to
the tetrahydro form by dihydrofolate reductase:
dihydrofolate reductase
7,8-Dihydrobiopterin + NADPH + H+-------------------->
NADP+ + tetrahydrobiopterin
This enzyme also catalyzes conversion of dihydrofolate
(FH2) to tetrahydrofolate (FH4), and folic acid contains a
pteridine ring system (see the discussion of one-carbon
metabolism in Chapter 27). However, regeneration of
tetrahydrobiopterin by the dihydrofolate reductase reac-
tion, however, is too slow to support normal rates of pheny-
lalanine hydroxylation.
Tetrahydrobiopterin is synthesized starting from GTP
and requires at least three enzymes. The first committed
step is GTP-cyclohydrolase, which converts GTP to dihy-
droneopterin triphosphate. 6-Pyruvoyltetrahydrobiopterin
synthase
transforms
dihydroneopterin
triphosphate
into 6-pyruvoyltetrahydrobiopterin. The latter is reduced
to
tetrahydrobiopterin
by
NADPH-dependent
sepi-
apterin reductase. Deficiency of GTP-cyclohydrolase and
