Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

IV. Plasma Proteins
121
NH 4 HCO 3
C-P-Syn
Carbamoyl-P
L-Ornithine
L-Ornithine
Urea
NH 2
CO
NH 2
ATP (2)
OCT
MITOCHONDRIA
ARG
L-Citrulline
CYTOSOL
MITOCHONDRIAL MEMRANE
L-Arginine
leaves the mitochondria and combines with aspartate to form
arginosuccinate, which separates into arginine and fumarate.
Urea is then released from arginine leaving ornithine, which
reenters the mitochondria and the cycle repeats. There is a
close link between the urea cycle and the tricarboxylic acid
(TCA) cycle as the fumarate released from arginosuccinate
is converted to malate and then oxaloacetate in reactions of
the TCA cycle. Aspartate transaminase catalyses the transfer
of an amino group for production of aspartate from the oxaloacetate,
thus providing the amino group for further urea
production. Division of the urea cycle between mitochondria
and cytoplasm aids in coordination between cycles. The urea
produced in the liver is transported in the circulation to the
kidney where it is excreted by the kidney tubules and eliminated
in urine. Other routes for the excretion of nitrogenous
material, such as uric acid or nucleic acid, are relatively
minor in mammalian species.
All animals are quite intolerant of free ammonia (NH 3 ),
but at physiological pH the protonated ammonium ion
form predominates:
NH 3 → NH
4
L-Citrulline
ATP
ArgS-Syn
L-Arginosuccinate
ArgSase
Fumarate
COO
C-NH 3
C
COO
L-Aspartate
FIGURE 5-1 The urea cycle. Formation of urea from precursors of
aspartate, NH 4
, and COO with part of the cycle taking place in the cytoplasm
and part in the mitochondria. Abbreviations: C-P-Syn, carbamoyl
phosphate synthase; OCT, ornithine citrulline transferase; ArgS-Syn,
argininosuccinate synthase; ArgSase, argininosuccinase; ARG, arginase.
The ammonium ion does not readily transfer across
membranes unlike free ammonia, which readily enters cells
where it is reconverted to the ammonium ion. Ammonia
is particularly toxic to cells of the central nervous system
where it acts by reducing the activity of the TCA cycle by
removing a critical intermediate, α -ketoglutarate. Increased
ammonia leads to the production of glutamate from
α -ketoglutarate by the action of glutamate dehydrogenase.
The α -ketoglutarate is lost to the TCA cycle, causing ATP
production in the neurons to be restricted. Ammonia may
also be directly toxic as it can decrease neurotransmitter
concentrations. Ammonia is associated with hepatic
encephalopathies of humans, horses ( Hasel et al. , 1999 ),
and dogs ( Reisdesmerie et al. , 1995 ), possibly by affecting
the expression of neuron proteins such as glial fibrillary
acidic protein, glutamate transporters, and peripheral-type
benzodiazepine receptors ( Butterworth, 2002 ).
IV . PLASMA PROTEINS
A . Sites of Synthesis
Apart from the immunoglobulins, produced by B-lymphocytes,
the major plasma proteins are synthesized and
secreted from hepatocytes. Control of secretion is exerted
by varied mechanisms. The secretion of albumin is stimulated
by a fall in osmotic pressure ( Evans, 2002 ) but can
also be affected by pathophysiological changes such as during
infectious or inflammatory disease when the secretion is
reduced. This is caused by proinflammatory cytokines such
as interleukin (IL)-1, IL-6, and tumor necrosis factor- α
(TNF). These cytokines are simultaneously responsible
for the increased synthesis and secretion of the APP (see
Section VI.B). The immunoglobulins are produced by
B-lymphocytes in the spleen, lymph nodes and bone
marrow following stimulation by the presence of pathogen
in the circulation or tissues.
Use of molecular biological techniques such as Northern
blots and the polymerase chain reaction (PCR) has revealed
that nonhepatic tissues have the capability to synthesize
some of the plasma proteins and that in certain circumstances
the expression of their mRNA is up-regulated.
Thus, in tissues such as intestine, lung, and adipose tissue,
the mRNA for the plasma proteins haptoglobin and serum
amyloid A are increased during infections and inflammation
( Friedrichs et al. , 1995 ; Vreugdenhil et al. , 1999 ; Yang
et al. , 1995 ). The proportion of the proteins in the circulation
derived from these nonhepatic sources has not been determined.
A further site of nonhepatic synthesis is the mammary
gland, which has been shown to produce a mammary
associated serum amyloid A and haptoglobin during mastitis.
However, the protein produced in the mammary gland
does not appear in plasma but is secreted in the milk during
the disease ( Eckersall et al. , 2001 ; Jacobsen et al. , 2005b ).
The origin of low-abundance plasma proteins is varied.
They may be made and secreted for specific functions such
as the protein and peptide hormones. For example, the
gonadotropins and adrenocorticotropin are released into the
circulation from the pituitary gland, insulin and glucagon