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

IV. Metabolism of Absorbed Carbohydrates
53
shunt pathway. This reaction requires NAD as a cofactor
and the products of the reaction are uridine diphosphoglucuronic
acid (UDPGA) and NADH. This UDPGA is
involved in a large number of important conjugation reactions
in animals (e.g., bilirubin glucuronide formation, synthesis
of mucopolysaccharides [chondroitin sulfate], which
contain glucuronic acid, and generally in detoxification
reactions). UDPGA is cleaved to release D-glucuronate
and UDP.
D-glucuronate is next reduced to L-gulonate in a reaction
catalyzed by the enzyme gulonate dehydrogenase (GUD),
with NADPH as the hydrogen donor. The L-gulonate
may be converted to a pentose, L-xylulose, or to vitamin C.
When converted to L-xylulose, the C-6 carbon of L-gulonate
is oxidatively decarboxylated and evolved as CO 2 . The
L-xylulose is then reduced to xylitol, catalyzed by the
enzyme L-xylulose reductase. This is the enzyme that is
deficient in pentosuria of humans. As shown in Figure 3-7 ,
xylitol is converted to D-xylulose, which is then phosphorylated
to D-xylulose-5-P and a cyclical pathway involving
the HMP shunt pathway may occur. L-gulonate is also
converted by enzyme-catalyzed reactions to L-ascorbate in
those species that can synthesize their own vitamin C (i.e.,
all domestic animals). The enzyme, L-gulonolactone oxidase
(GLO), is lacking in humans, nonhuman primates, and
guinea pigs, and therefore vitamin C must be supplied in
their diets. The enzyme is present only in the liver of the
mouse, rat, pig, cow, and dog. In the dog, the liver GLO
activity is low and the ascorbate hydrolytic activity is high
so dogs may have additional needs for vitamin C during
stress (e.g., wound healing, postsurgical stress). For vitamin
C synthesis, D-galactose may be an even better precursor
than D-glucose. This pathway is also included in Figure 3-7 .
2 . Terminal Oxidation: Aerobic Glycolysis
The metabolic pathways described thus far are those of the
carbohydrates. In analogous fashion, the breakdown of fats
and of proteins also follows independent pathways leading
to the formation of organic acids. Among the organic acids
formed from lipids are acetyl-CoA (AcCoA), acetoacetate
(AcAc), and 3-OH-butyrate (3-OH-B) from the β -oxidation
of fatty acids. From proteins, pyruvate, oxaloacetate
(OAA), and α -ketoglutarate ( α -KG) are formed from transamination
of their corresponding α -amino acids. Direct
deamination of amino acids is also a route of formation of
organic acids. These organic acid intermediate metabolites
are indistinguishable in their subsequent interconversions.
Thus, the breakdown of the three major dietary constituents
converges into a final common pathway, which also
serves as a pathway for the interconversions between them.
a . Pyruvate Metabolism
The pathway for breakdown of glucose to pyruvate has
been described in Section IV.D.1. Pyruvate, if it is not
Aspartate
Threonine
Proline
Glutamate
Histidine
Valine
Propionate
Fumarate
Succinate
Oxaloacetate
Malate
CO 2
CO 2
Glucose
Phospho-enol-pyruvate
Pyruvate
Acetyl CoA
Acetylations
Cholesterol
CO2
Fatty acids
Ketone bodies
FIGURE 3-8 Pathways of acetate and pyruvate metabolism.
Alanine
Serine
Cysteine
Lactate
reduced to lactate, is oxidatively decarboxylated in a complex
enzymatic system requiring the presence of lipoic
acid, thiamine pyrophosphate (TPP), coenzyme A (CoA),
NAD , and pyruvate dehydrogenase (PD) to form AcCoA
and NADH. Pyruvate may follow a number of pathways as
outlined in Figure 3-8 . The conversion of pyruvate to lactate
was described in Section IV.D.1. By the mechanism of
transamination or amino group transfer, pyruvate may be
reversibly converted to alanine. The general reaction for an
amino group transfer is
R1-C-COO- R2-C-COO- → R1-C-COO-
R2
-C-COO-
|| |transferase| ||
ONH2 NH2O
α-keto acid α-amino acid α-amino acid α-keto acid
where the amino group of an amino acid is transferred to
the α position of an α -keto acid and as a result, the amino
acid is converted to its corresponding α -keto acid. This
reaction requires the presence of vitamin B 6 as pyridoxal
phosphate and is catalyzed by a specific transferase, in
this case alanine aminotransferase (ALT). Serum levels of
several of these transferases (e.g., ALT and aspartate aminotransferase
[AST]) have been particularly useful in the
diagnosis and evaluation of liver and muscle disorders,
respectively. These aspects are discussed in the individual
chapters on liver and muscle function.
The energetics of the reaction from phosphoenolpyruvate
(PEP) to form pyruvate and catalyzed by pyruvate
kinase (PK) are such that this is an irreversible reaction,
as is the PD catalyzed conversion of pyruvate to AcCoA.
A two-step separate pathway to reverse this process is
present at this step so this is a fourth site of directional
metabolic control. Through a CO 2 fixation reaction in the
presence of NADP -linked malate dehydrogenase (MD),
malate is formed from pyruvate. Malate is then oxidized to
OAA in the presence of NAD -linked MD. OAA may also
be formed directly from pyruvate by the reaction catalyzed