352
chapter 17
Protein and Amino Acid Metabolism
of histamine). Its effect on secretion of hydrochloric acid
is mediated by H2 receptors. H
2
-receptor antagonists are
cimetidine and ranitidine (Chapter 12), which are useful
in treatment of gastric ulcers. Histamine is rapidly inacti-
vated by méthylation from S-adenosylmethionine of one
of the nitrogen atoms of the imidazole ring (catalyzed by
N-methyltransferase) or of the terminal amine group (cat-
alyzed by methyltransferase). Ring-methylated histamine
is deaminated by monoamine oxidase to methyl imidazole
acetic acid, which is readily excreted. Inactivation also re-
sults from deamination of histamine by diamine oxidase.
The imidazole acetic acid formed is then excreted as 1-
ribosylimidazole-4-acetic acid. This reaction is the only
known reaction in which ribose is used for conjugation.
Branched-Chain Amino Acids
Leucine, isoleucine, and valine are essential amino acids
but can be derived from their respective a-keto acids. A
single enzyme may catalyze transamination of all three.
The a-keto acids, by oxidative decarboxylation, yield
the acyl-CoA thioesters, which, by a,/1-dehydrogenation,
yield
the
corresponding
a,/3-unsaturated
acyl-CoA
thioesters. The catabolism of these thioesters then di-
verges. Catabolism of leucine yields acetoacetate and
acetyl-CoA via /?-hydroxy-/3-methylglutaryl-coenzyme
A (HMG-CoA)—also an intermediate in the biosynthe-
sis of cholesterol and other isoprenoids (Chapter 19).
Catabolism of isoleucine yields propionyl-CoA (a gluco-
genic precursor) and acetyl-CoA. Catabolism of valine
yields succinyl-CoA (Figure
17-14). Thus, leucine is
ketogenic and isoleucine and valine are ketogenic and
glucogenic.
Oxidative decarboxylation of the a-keto acids is cat-
alyzed by a branched-chain keto acid dehydrogenase
(BCKADH) complex analogous to that of the pyru-
vate dehydrogenase and a-ketoglutarate dehydrogenases
complexes. BCKADH is widely distributed in mam-
malian tissue mitochondria (especially in liver and kid-
ney). It requires Mg2+, thiamine pyrophosphate, CoA-SH,
lipoamide, FAD, and NAD+ and contains activities of a-
keto acid decarboxylase, dihydrolipoyl transacylase, and
dihydrolipoyl dehydrogenase. Like the pyruvate dehydro-
genase complex, BCKADH is regulated by product in-
hibition and by phosphorylation (which inactivates) and
dephosphorylation (which activates).
The a,^-dehydrogenation is catalyzed by an FAD pro-
tein and is analogous to the dehydrogenation of straight-
chain acyl-CoA thioesters in /1-oxidation of fatty acids
(Chapter 18). Methylenecyclopropylacetyl-CoA derived
from the plant toxin hypoglycin (Chapters 15 and 18),
which inhibits this step in /1-oxidation, also inhibits
it in the catabolism of branched-chain amino acids.
FIGURE 17-14
Overview of the catabolism of branched-chain amino acids. TPP = thiamin
pyrophosphate.
Hypoglycin produces hypoglycemia and metabolic aci-
dosis, which frequently are fatal.
Branched-chain ketoaciduria
(maple syrup urine dis-
ease),
an autosomal recessive disorder characterized by
ketoacidosis starts early in infancy and is due to a de-
fect in the oxidative decarboxylation step of branched-
chain amino acid metabolism. The name derives from
the characteristic odor (reminiscent of maple syrup) of
the urine of these patients. Five different variants (clas-
sic, intermittent, intermediate, thiamine-responsive, and
dihydrolipoyl dehydrogenase deficiency) are known, of
which the first, which is due to deficiency of branched-
chain a-keto acid decarboxylase, is the most severe. The
incidence of
maple syrup urine disease
in the U.S. popu-
lation is 1
in 250,000-400,000 live births. In Mennonite
populations the incidence is extremely high (1 in 760).
Neonatal screening programs consist of measuring leucine
levels in dried blood spots using a bacterial inhibition as-
say. Neonatal screening programs usually include testing
for a number of other treatable metabolic disorders such
as
hypothyroidism, phenylketonuria, galactosemia,
and
others. If the screening test is positive for a given metabolic
disease, a confirmatory test is performed. For maple syrup
urine disease, the confirmation requires quantitation of
the serum levels of branched-chain amino acids and urine
levels of both the branched-chain amino acids and their
ketoacids. Long-term management includes dietary re-
striction of the branched-chain amino acids. Frequent
measurement of plasma concentrations of these amino
