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Gluconeogenesis
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Gluconeogenesis (GNG) is a metabolic pathway that results in the
generation of glucose from non-carbohydrate carbon substrates such
as pyruvate, lactate, glycerol, and glucogenic amino acids. While
primarily odd-chain fatty acids can be converted into glucose, it is
possible for at least some even-chain fatty acids.
It is one of the two main mechanisms used by humans and many other
animals to maintain blood glucose levels, avoiding low blood glucose
level (hypoglycemia). The other means of maintaining blood glucose
levels is through the degradation of glycogen (glycogenolysis).
Gluconeogenesis is a ubiquitous process, present in plants, animals,
fungi,
bacteria,
and
other
microorganisms.
In
vertebrates,
gluconeogenesis takes place mainly in the liver and, to a lesser extent,
in the cortex of the kidneys. In ruminants, this tends to be a
continuous process. In many other animals, the process occurs during
periods of fasting, starvation, low-carbohydrate diets, or intense
exercise. The process is highly endergonic until it is coupled to the
hydrolysis of ATP or GTP, effectively making the process exergonic.
For example, the pathway leading from pyruvate to glucose-6phosphate requires 4 molecules of ATP and 2 molecules of GTP to
proceed spontaneously. Gluconeogenesis is often associated with
ketosis. Gluconeogenesis is also a target of therapy for type 2
diabetes, such as the antidiabetic drug, metformin, which inhibits
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glucose formation and stimulates glucose uptake by cells. In
ruminants, because metabolizable dietary carbohydrates tend to be
metabolized by rumen organs, gluconeogenesis occurs regardless of
fasting, low-carbohydrate diets, exercise, etc.
In humans the main gluconeogenic precursors are lactate, glycerol
(which is a part of the triacylglycerol molecule), alanine and
glutamine. Altogether, they account for over 90% of the overall
gluconeogenesis. Other glucogenic amino acids as well as all citric
acid
cycle
intermediates,
the
latter
through
conversion
to
oxaloacetate, can also function as substrates for gluconeogenesis. In
ruminants, propionate is the principal gluconeogenic substrate.
Lactate is transported back to the liver where it is converted into
pyruvate by the Cori cycle using the enzyme lactate dehydrogenase.
Pyruvate, the first designated substrate of the gluconeogenic pathway,
can then be used to generate glucose. Transamination or deamination
of amino acids facilitates entering of their carbon skeleton into the
cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric
acid cycle.
Whether even-chain fatty acids can be converted into glucose in
animals has been a longstanding question in biochemistry. It is known
that odd-chain fatty acids can be oxidized to yield propionyl-CoA, a
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precursor for succinyl-CoA, which can be converted to pyruvate and
enter into gluconeogenesis. In plants, specifically seedlings, the
glyoxylate cycle can be used to convert fatty acids (acetate) into the
primary carbon source of the organism. The glyoxylate cycle
produces
four-carbon
dicarboxylic
acids
that
can
enter
gluconeogenesis.
In 1995, researchers identified the glyoxylate cycle in nematodes. In
addition, the glyoxylate enzymes malate synthase and isocitrate lyase
have been found in animal tissues. Genes coding for malate synthase
have been identified in other metazoans including arthropods,
echinoderms, and even some vertebrates. Mammals found to possess
these genes include monotremes (platypus) and marsupials (opossum)
but not placental mammals. Genes for isocitrate lyase are found only
in nematodes, in which, it is apparent, they originated in horizontal
gene transfer from bacteria.
The existence of glyoxylate cycles in humans has not been
established, and it is widely held that fatty acids cannot be converted
to glucose in humans directly. However, carbon-14 has been shown to
end up in glucose when it is supplied in fatty acids. Despite these
findings, it is considered unlikely that the 2-carbon acetyl-CoA
derived from the oxidation of fatty acids would produce a net yield of
glucose via the citric acid cycle - however, acetyl-CoA can be
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converted into pyruvate and lactate through the ketogenic pathway.
Put simply, acetic acid (in the form of acetyl-CoA) is used to partially
produce glucose; acetyl groups can only form part of the glucose
molecules (not the 5th carbon atom) and require extra substrates (such
as pyruvate) in order to form the rest of the glucose molecule. But a
roundabout pathway does lead from acetyl-coA to pyruvate, via
acetoacetate, acetone, acetol (hydroxyacetone) and then either
propylene glycol or methylglyoxal.
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