N-carbamoylglutamate, activates CPSI, does not share the
undesirable properties of NAG, and has been effective in
management of this deficiency.
The most common cause of hyperammonemia in adults
is disease of the liver (e.g., due to ethanol abuse, infection,
or cancer). The ability to detoxify ammonia is decreased
in proportion to the severity of the damage. In advanced
disease (e.g., cirrhosis), hyperammonemia is augmented
by shunting of portal blood that carries ammonia from the
intestinal tract and other splanchnic organs to the systemic
blood circulation (bypassing the liver) and leads to portal-
systemic encephalopathy. In addition to dietary protein
restriction, colonic growth of bacteria must be suppressed
by antibiotics (e.g., neomycin) and administration of lac-
tulose (Chapter 9), a nonassimilable disaccharide. Enteric
bacteria catabolize lactulose to organic acids that convert
NH3 to NH^ , thereby decreasing absorption of NH3 into
the portal circulation. Catabolism of lactulose also leads to
formation of osmotically active particles that draw water
into the colon, produce loose, acid stools, and permit loss
of ammonia as ammonium ions.
17.3 Metabolism of Some Individual Amino Acids
Mammalian tissues synthesize the nonessential amino
acids from carbon skeletons derived from lipid and car-
bohydrate sources or from transformations that involve
essential amino acids. The nitrogen is obtained from
NHj or from that of other amino acids. Nonessential
amino acids (and their precursors) are glutamic acid
(a-ketoglutaric acid), aspartic acid (oxaloacetic acid),
serine (3-phosphoglyceric acid), glycine (serine), tyro-
sine (phenylalanine), proline (glutamic acid), alanine
(pyruvic acid), cysteine (methionine and serine), arginine
(glutamate-y-semialdehyde), glutamine (glutamic acid),
and asparagine (aspartic acid).
Amino acids may be classified as ketogenic, glucogenic,
or glucogenic and ketogenic, depending on whether feed-
ing of a single amino acid to starved animals or animals
with experimentally induced diabetes increases plasma or
urine levels of glucose or ketone bodies (Chapter 18).
Leucine and lysine are ketogenic; isoleucine, phenylala-
nine, tyrosine, and tryptophan are glucogenic and keto-
genic; and the remaining amino acids are glucogenic.
Points of entry of amino acids into the gluconeogenic path-
way are discussed in Chapter 15.
participates in a number of metabolic pathways
depending on the cell type. It is synthesized as an inter-
section 17.3
Metabolism of Some Individual Amino Acids
mediate in the urea cycle pathway and is also obtained
from dietary proteins. A number of key metabolites such
as nitric oxide, phosphocreatine, spermine and ornithine
are derived from arginine. During normal growth and de-
velopment, under certain pathological conditions (e.g., en-
dothelial dysfunction) and if the endogenous production
of arginine is insufficient, a dietary supplement of arginine
may be required. Thus, arginine is considered a semiessen-
tial amino acid.
Metabolism and Synthesis of Nitric Oxide
Nitric oxide (NO)
is a reactive diatomic gaseous molecule
with an unpaired electron (a free radical). It is lipophilic
and can diffuse rapidly across biological membranes. NO
mediates a variety of physiological functions such as en-
dothelial derived relaxation of vascular smooth muscle,
inhibition of platelet aggregation, neurotransmission, and
cytotoxicity. The pathophysiology of NO is a double-
edged sword. Insufficient production of NO has been im-
plicated in the development of hypertension, impotence,
susceptibility to infection, and atherogenesis. Excessive
NO production is linked to septic shock, inflamma-
tory diseases, transplant rejection, stroke, and carcino-
NO is synthesized from one of the terminal nitrogen
atoms or the guanidino group of arginine with the con-
comitant production of citrulline. Molecular oxygen and
NADPH are cosubstrates and the reaction is catalyzed
by nitric oxide synthase (NOS). NOS consists of sev-
eral isoforms and is a complex enzyme containing bound
FMN, FAD, tetrahydrobiopterin, heme complex, and non-
heme iron. A calmodulin binding site is also present. NO
formation from arginine is a two-step process requiring
five-electron oxidations. The first step is the formation of
№-hydroxylarginine (NG denotes guanidinium nitrogen
Arginine + O
+ NADPH + H+ —>
HO-NG-Arg + NADP+ + H20
This step is a mixed-function oxidation reaction simi-
lar to the one catalyzed by cytochrome P-450 reduc-
tase and there is considerable homology between NOS
and cytochrome P-450 reductase. In the second step, fur-
ther oxidation of №-hydroxyl arginine yields NO and
HO-NG-Arg + 0 2 + ^ (NADPH + H+)
citrulline + NO + H20 + -NADP+
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