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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

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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-6-

phosphate 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

glucose formation and stimulates glucose uptake by cells. In

ruminants, because metabolizable dietary carbohydrates tend to be

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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

precursor for succinyl-CoA, which can be converted to pyruvate and

enter into gluconeogenesis. In plants, specifically seedlings, the

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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

converted into pyruvate and lactate through the ketogenic pathway.

Put simply, acetic acid (in the form of acetyl-CoA) is used to partially

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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.