348
chapter 17
Protein and Amino Acid Metabolism
Glycine is also oxidized by D-amino acid oxidase, an
FAD protein:
NHj -CHz-COO
+ 0 2 + H20
glycine
CHO-COO
+ NH+ + H20 2
glyoxalate
Glyoxalate can be transaminated to glycine, reduced to
glycolate, converted to o'-hydroxy-/3-ketoadipate by reac-
tion with «-ketoglutaratc, or oxidized to oxalate and ex-
creted in urine. The first three reactions require pyridoxal
phosphate, NADH, and thiamine pyrophosphate, respec-
tively. In humans, ascorbic acid (vitamin C) is a precursor
of urinary oxalate (Chapter 38). Since calcium oxalate is
poorly soluble in water, it can cause nephrolithiasis and
nephrocalcinosis due to
hyperoxaluria.
Disorders o f Glycine Catabolism
Nonketotic hyperglycinemia
is an inborn error due to a
defect in the glycine cleavage enzyme complex in which
glycine accumulates in body fluids and especially in cere-
brospinal fluid. It is characterized by mental retardation
and seizures. Glycine is an inhibitory neurotransmitter
in the central nervous system, including the spinal cord.
Strychnine, which produces convulsions by competitive
inhibition of glycine binding to its receptors, gives mod-
est results in treatment but not very effective. Sodium
benzoate administration reduces plasma glycine levels but
does not appreciably alter the course of the disease. Ex-
change transfusion may be useful.
Ketotic hyperglycine-
mia
also occurs in propionic acidemia but the mechanism
has not been established.
Primary hyperoxaluria type I
is due to a deficiency of
cytosolic o'-ketoglutarate-glyoxylate carboligase, which
catalyzes the following reaction:
O
II
CHO— COO" + "OOC— CH
2
— CH
2
— C — COO"
Glyoxalate
a-K etoglutarate
Carboligase
Thiamine pyrophosphate
O
OH
Il
I
C 0 2 + "OOC— CH
2
— CH
2
— C — CH— COO"
a-Hydroxy-/?-ketoadipate
The
glyoxylate
that
accumulates
is
converted
to
oxalate.
Creatine and Related Compounds
Phosphocreatine serves as a high-energy phosphate
donor for ATP formation (e.g., in muscle contraction; see
Chapter 21). Synthesis of
creatine
(methyl guanidinoac-
etate) requires transamidination, i.e., transfer of a guani-
dine group from arginine to glycine, to form guanidinoac-
etate (glycocyamine) by mitochondrial arginine-glycine
amidinotransferase
n h
2
1
n h
2
c =
n h 2+
1
1
NH3+
C = N H 2+
NH3+
1
NH
1
1
(CH
2 ) 3
1
+
+
X
z
11
X
0
1
(CH
2 ) 3
1
1
1
COO"
CH
2
CHNH
3
1
CHNH3+
1
1
C
0 0
"
COO"
COO"
Arginine
G lycine
G uanidinoacetate
Ornithine
(glycocyam ine)
In the next step guanidinoacetate is methylated by S-
adenosylmethionine by cytosolic S-adenosylmethionine
guanidinoacetate-N-methyltransferase to form creatine.
C H
3
1
n h
2
1
n h
2
1
S-Adenosyl
S + -Adenosyl
1
c — n h 2+
1
c =
n h 2+
1
1
(C H
2)2
(C H
2)2
1
+
N H
------>
1
N — C H
3
1
+
1
+
C H N H
3
+
C H N H
3
+
1
C H
2
1
C H
2
1
1
C O O "
C O O "
C O O "
C O O "
S-A denosyl-
G u a n id in o -
C reatin e
S-Adenosyl-
m ethio nin e
acetate
hom ocysteine
These reactions occur in liver, kidney, and pancreas, from
which creatine is transported to organs such as muscle
and brain. Creatine synthesis is subject to negative modu-
lation of amidinotransferase by creatine. Phosphocreatine
production is catalyzed by creatine kinase:
n h
2
1
NH— P 0 32"
1
c =
n h 2+
1
1
C = N H
2
+
N— CH
3
+ ATP4-
1
1
* = i
N— CH
3
+ ADP:
-
O -X
ro
1
CH
2
1
COO"
1
COO"
Creatine
P hosp h ocreatine
This kinase is a dimer of M and B (M = muscle, B =
brain) subunits produced by different structural genes.
Three isozymes are possible: BB (CK-1), MB (CK-2),
and MM (CK-3). Another isozyme differs immunologi-
cally and electrophoretically and is located in the inter-
membrane space of mitochondria. Tissues rich in CK-1
