Page 191 - Color Atlas of Biochemistry

P. 191

182 Metabolism

Urea cycle [1] In the first step, carbamoyl phosphate is
formed in the mitochondria from hydrogen
–
+
Amino acids are mainly brokendowninthe carbonate (HCO 3 )and NH 4 ,with two ATP
liver. Ammonia is released either directly or molecules being consumed. In this com-
indirectly in the process (see p. 178). The deg- pound, the carbamoyl residue (–O–CO–NH 2 )
radation of nucleobases also provides signifi- is at a high chemical potential. In hepatic
cant amounts of ammonia (see p. 186). mitochondria, enzyme [1] makes up about
Ammonia (NH 3 ) is a relatively strong base, 20% of the matrix proteins.
and at physiological pH values it is mainly [2] In the next step, the carbamoyl residue
present in the form of the ammonium ion is transferred to the non-proteinogenic amino
+
+
NH 4 (see p. 30). NH 3 and NH 4 are toxic, and acid ornithine,convertingitinto citrulline,
at higher concentrations cause brain damage which is also non-proteinogenic. This is
in particular. Ammonia therefore has to be passed into the cytoplasm via a transporter.
effectively inactivated and excreted. This can [3] The second NH 2 group of the later urea
be carried out in various ways. Aquatic ani- molecule is provided by aspartate,which
+
mals can excrete NH 4 directly. For example, condenses with citrulline into argininosucci-
+
fish excrete NH 4 via the gills (ammonotelic nate. ATP is cleaved into AMP and diphos-
animals). Terrestrial vertebrates, including phate (PP i ) for this endergonic reaction. To
humans, hardly excrete any NH 3 ,and instead, shift the equilibrium of the reaction to the
most ammonia is converted into urea before side of the product, diphosphate is removed
excretion (ureotelic animals). Birds and rep- from the equilibrium by hydrolysis.
tiles, by contrast, form uric acid, which is [4] Cleavage of fumarate from argininosuc-
mainly excreted as a solid in order to save cinate leads to the proteinogenic amino acid
water (uricotelic animals). arginine, which is synthesized in this way in
The reasons for the neurotoxic effects of animal metabolism.
ammonia have not yet been explained. It [5] In the final step, isourea is released
may disturb the metabolism of glutamate from the guanidinium group of the arginine
and its precursor glutamine in the brain (see by hydrolysis (not shown), and is immedi-
p. 356). ately rearranged into urea. In addition, orni-
thine is regenerated and returns via the orni-
thine transporter into the mitochondria,
A. Urea cycle
whereitbecomes availablefor thecycle
Urea (H 2 N–CO–NH 2 ) is the diamide of car- once again.
bonic acid. In contrast to ammonia, it is neu- The fumarate produced in step [4] is con-
tral and therefore relatively non-toxic.The verted via malate to oxaloacetate [6, 7], from
reason for the lack of basicity is the molecule’s which aspartate is formed again by transami-
mesomeric characteristics. The free electron nation [9]. The glutamate required for reac-
pairs of the two nitrogen atoms are delocal- tion [9] is derived from the glutamate dehy-
ized over the whole structure, and are there- drogenase reaction [8], which fixes the sec-
+
fore no longer able to bind protons. As a small, ond NH 4 in an organic bond. Reactions [6]
uncharged molecule, urea is able to cross bio- and [7] also occur in the tricarboxylic acid
logical membranes easily. In addition, it is cycle. However, in urea formation they take
easily transported in the blood and excreted place in the cytoplasm, where the appropriate
in the urine. isoenzymes are available.
Urea is produced only in the liver, in a cyclic The rate of urea formation is mainly con-
sequence of reactions (the urea cycle)that trolled by reaction [1]. N-acetyl glutamate,as
starts in the mitochondria and continues in an allosteric effector, activates carbamoyl-
the cytoplasm. The two nitrogen atoms are phosphate synthase. In turn, the concentration
+
derived from NH 4 (the second has previously of acetyl glutamate depends on arginine and
been incorporated into aspartate; see below). ATP levels, as well as other factors.
The keto group comes from hydrogen carbo-
–
nate (HCO 3 ), or CO 2 that is in equilibrium
–
with HCO 3 .

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