section 17.1
Essential and Nonessential Amino Acids
335
O U T S ID E
M E M B R A N E IN S ID E
lAm ino acid|-
A -G lu tam yP '
vtransferasey
Y -Glutam yl-am ino acid
"
" v Y-G Iutam ylcyclotransferase
■
[Am ino acidl
5-Oxbproline
J > A T P
o u . / M 5-Oxoprolinase
f —A D P + P,
J3i peptidase G lutam ate
* C y s t e in e - 'i'- A T P
A Y -G O synthetase
-A D P + P,
Y -Glutam ylcysteine
''G S H synthetase^
A D P + P,
A T P
FIGURE 17-2
The /-glutamyl cycle for the transport of amino acids. GSH =
Glutathione; /-GC = /-glutamylcysteine.
and ATP (three ATP molecules are required for each
amino acid translocation). In this cycle, there is no net
consumption of GSH, but an amino acid is transported
at the expense of the energy of peptide bonds of GSH,
which has to be resynthesized. Translocation is initi-
ated by membrane-bound
y
-glutamyltransferase (y-GT,
y
-glutamyl transpeptidase), which catalyzes formation of
a
y
-glutamyl amino acid and cysteinylglycine. The lat-
ter is hydrolyzed by dipeptidase to cysteine and glycine,
which are utilized in resynthesis of GSH. The former is
cleaved to the amino acid and 5-oxoproline (pyroglutamic
acid) by y-glutamylcyclotransferase. The cycle is com-
pleted by conversion of 5-oxoproline to glutamate and by
resynthesis of GSH by two ATP-dependent enzymes, y-
glutamylcysteine synthetase and glutathione synthetase,
respectively. GSH synthesis appears to be regulated by
nonallosteric inhibition of y-glutamylcysteine synthetase.
GSH has several well-established functions: it provides
reducing equivalents to maintain -SH groups in other
molecules (e.g., hemoglobin, membrane proteins; Chap-
ter 15); it participates in inactivation of hydrogen perox-
ide, other peroxides, and free radicals (Chapter 14); it par-
ticipates in other metabolic pathways (e.g., leukotrienes;
Chapter 18); and it functions in inactivation of a variety
of foreign compounds by conjugation through its sulfur
atom. The conjugation reaction is catalyzed by specific
glutathione S-transferases and the product is eventually
converted to mercapturic acids and excreted.
Inherited deficiency of GSH synthetase, y-glutamy-
lcysteine synthetase y-glutamyltransferase, and 5-oxopro-
linase have been reported. Red blood cells, the central
nervous system, and muscle may be affected. In GSH
synthetase deficiency, y-glutamylcysteine accumulates
from lack of inhibition of y-glutamylcysteine synthetase
by glutathione, and it is converted to 5-oxoproline and
cysteine by y-glutamylcyclotransferase. 5-Oxoproline
is excreted so that GSH synthetase deficiency causes
5-oxoprolinuria (or
pyroglutamic aciduria).
Measurement of serum y-GT activity has clinical signi-
ficance. The enzyme is present in all tissues, but the highest
level is in the kidney; however, the serum enzyme orig-
inates primarily from the hepatobiliary system. Elevated
levels of
serum y-GT
are found in the following disorders:
intra- and posthepatic biliary obstruction (elevated serum
y-GT indicates cholestasis, as do leucine aminopeptidase,
5'-nucleotidase, and alkaline phosphatase); primary or
disseminated neoplasms; some pancreatic cancers, es-
pecially when associated with hepatobiliary obstruc-
tion; alcohol-induced liver disease (serum y-GT may be
exquisitely sensitive to alcohol-induced liver injury); and
some prostatic carcinomas (serum from normal males has
50% higher activity than that of females). Increased ac-
tivity is also found in patients receiving phénobarbital or
phenytoin, possibly due to induction of y-GT in liver cells
by these drugs.
General Reactions of Amino Acids
Some general reactions that involve degradation or in-
terconversion of amino acids provide for the synthesis
of nonessential amino acids from a-kcto acid precursors
derived from carbohydrate intermediates.
Deamination
Removal of the a-amino group is the first step in
catabolism of amino acids. It may be accomplished ox-
idatively or nonoxidatively.
Oxidative deamination
is stereospecific and is cat-
alyzed by L- or D-amino acid oxidase. The initial step is
removal of two hydrogen atoms by the flavin coenzyme,
with formation of an unstable a-amino acid intermediate.
This intermediate undergoes decomposition by addition
of water and forms ammonium ion and the correspond-
ing a-keto acid: L-Amino acid oxidase occurs in the liver
H
•
L-Amino acid
I
oxidase
R — C — C O O "
I
N H 3 +
a-A m in o
a cid
H
2
O
2
O
2
and kidney only. It is a flavoprotein that contains flavin
mononucleotide (FMN) as a prosthetic group and does not
attack glycine, dicarboxylic, or /3-hydroxy amino acids. Its
activity is very low.
High levels of D-amino acid oxidases are found in the
liver and kidney. The enzyme contains flavin adenine din-
ucleotide (FAD) and deaminates many D-amino acids and
