Gluconeogenesis

Gluconeogenesis ( Latinized spelling of gluconeogenesis, a compound word from ancient Greek γλυκύς glykys "sweet", νέος neos "new" and γένεσις genesis " generation ") is a new synthesis of D- glucose from non-carbohydrate organic precursors such as pyruvate, oxaloacetate and dihydroxyacetone phosphate. This pathway is ubiquitous. Plants can also be produced also from acetyl -CoA, and bacteria from the ethylmalonyl CoA pathway by glucose but the glyoxylate cycle.

• 3.1 Energy balance in comparison to the reversal of glycolysis
• 3.2 gluconeogenesis and glycolysis - reciprocal regulation

Necessity of gluconeogenesis in humans

The daily need of an adult glucose is in the idle state about 200 g, of which only 75 % of the brain, the majority of the remainder of the erythrocytes are used. The amount of glycogen, which is stored in the body, is about 400 to 450 g of which about two-thirds of the muscle, and stored in approximately one-third in the liver. The available amount of glucose in the blood is about 5 mM, which corresponds to about 90 mg per 100 ml.

The red blood cells are completely dependent on the supply of glucose. Therefore, these cells must obtain their energy from glycolysis. The brain covers its enormous need for quick energy mainly also by glucose. Above all, therefore, begins gradually at relatively short periods of starvation a synthesis of glucose, which, skeletal and cardiac muscle takes place mainly in the liver and in the renal cortex and less in the brain. By building glucose in gluconeogenesis glucose level never drops below 3.5 mM (= 60 mg / dl). About 180 to 200 g of glucose can be made per day.

Expiry of gluconeogenesis

Cellular Localization

The process of gluconeogenesis is distributed in eukaryotes three compartments of a cell. The vast majority takes place in the cytosol. A reaction step occurs in the mitochondrion, in the smooth endoplasmic reticulum, a further, as necessary in each case for the enzyme ( pyruvate carboxylase and glucose-6- phosphatase) is present here.

Reaction steps

The starting materials of gluconeogenesis are either in the form of pyruvate or oxaloacetate, as products of amino acid degradation and lactic acid fermentation ( from lactate ), or in the form of dihydroxyacetone phosphate, a derivative of glycerol from the fat loss, introduced into the metabolic pathway. In bacteria can also act as a starting material propionate in gluconeogenesis. This is converted via propionyl -CoA to succinyl -CoA, formed from the citric acid cycle in the course of oxaloacetate.

Next, the structure of L-lactate from glucose is shown:

Gluconeogenesis is only partly in the reverse reaction of glycolysis. Here, there are three reactions in which the chemical equilibrium is almost exclusively on the side of the reaction products. These steps, all catalyzed by kinases, are:

• The conversion of glucose to glucose -6-phosphate,
• Fructose -6-phosphate to fructose -1 ,6- bisphosphate and
• The reaction of phosphoenolpyruvate (PEP) to pyruvate.

To reverse the reaction, the cell should be able to establish extreme concentration ratios. Therefore, these three steps in the glycolysis in fact irreversibly and are bypassed in the gluconeogenesis in the reverse order as follows:

• The carboxylation of pyruvate to oxaloacetate consumption of ATP ( pyruvate carboxylase ) and the subsequent phosphorylating decarboxylation of oxaloacetate to PEP under GTP consumption ( phosphoenolpyruvate carboxykinase );
• Fructose-1 ,6- bisphosphatase, the reaction of fructose -1 ,6 -bisphosphate to fructose catalyzed 6-phosphate;
• Glucose -6-phosphate is converted from glucose to glucose -6-phosphatase ( in the glycolysis catalyzes a hexokinase or glucokinase ( hexokinase IV), the reverse reaction ).

The other conversion processes are in equilibrium, which is why they play a role in gluconeogenesis. Typical of glycolysis reactions are:

Another important difference from glycolysis is the reaction site. While this occurs exclusively in the cytosol, gluconeogenesis is divided into three compartments. The conversion of pyruvate to oxaloacetate is carried in the lumen of the mitochondria. Oxaloacetate, the inner membrane of the mitochondrion but not freely pass and must be back transformed. But there are two ways to do this. Either mitochondrial oxaloacetate into PEP is converted by mitochondrial PEP carboxykinase. PEP then leaves the mitochondrion by a specific anion shuttle system. In the cytoplasm PEP is implemented as a result of gluconeogenesis to glucose.

For hunger, a second way for transportation is taken. In the liver L- alanine is deaminated to pyruvate and thus serves as a source of oxaloacetate. In the fasting state, the amount of reducing agent in the form of NADH in the cytosol and in the mitochondrion low high. However, NADH is required in the cytosol for gluconeogenesis. To transport both NADH as well as oxaloacetate from the mitochondrion to the cytosol, known malate -aspartate shuttle system is used. Here, the generated oxaloacetate in the mitochondrion is reduced by mitochondrial malate dehydrogenase to L- malate, and can then be translocated across the membrane interior. For the transport stands beside the malate - aspartate shuttle in addition to the mitochondrial dicarboxylate carrier available. Oxidised in the cytosol of a cytosolic malate dehydrogenase malate to oxaloacetate, wherein the NAD is reduced to NADH and is used in the gluconeogenesis.

And the last reaction step in gluconeogenesis does not take place in the cytosol, but in the lumen of the endoplasmic reticulum (ER). Transport to the ER and the hydrolysis of glucose -6-phosphate worried a glucose- specific membrane - enzyme complex from glucose -6-phosphate translocase and glucose-6 - phosphatase (see also figure on the right ).

Pyruvate carboxylase

The pyruvate carboxylase is active only with their prosthetic group biotin. Biotin acts as a mobile carrier of carbon dioxide activated. The biotin is attached via its carboxyl group to the ε - amino group of a specific lysine residue. This creates a flexible arm, so that the biotin group can " swing " from one active site to the second. The carboxylation occurs in two steps:

.

The first part of the reaction is dependent on the presence of acetyl-CoA, without this is not possible carboxylation of biotin. This regulation is a form of allostery, since a high acetyl- CoA levels is a sign of more demand for oxaloacetate in the citric acid cycle. Acetyl-CoA is a potent and the only effector of the enzyme. Oxaloacetate can either be used for the Glucogenese or flows into the citric acid cycle. So that the catalyzed reaction of pyruvate carboxylase is an example of an anaplerotic reaction. In excess of the ATP is consumed in the gluconeogenesis oxaloacetate, thereby it will not be enriched. The second reaction step of the pyruvate carboxylase is acetyl-CoA independent.

Gluconeogenesis and glycolysis compared

Energy balance in comparison to the reversal of glycolysis

For the biosynthesis of one molecule of glucose four molecules of ATP and GTP and two molecules of NADH are starting from pyruvate needed.

Through the below- balance it is clear that the upper reaction is preferably run as a direct reversal of glycolysis is a thermodynamically unfavorable reaction:

This means that four ATP equivalents ( 2 GTP 2 ATP) necessary for gluconeogenesis can proceed to build glucose.

Gluconeogenesis and glycolysis - reciprocal regulation

The gluconeogenesis and glycolysis share several enzymatic reactions, but they are two completely running counter metabolic pathways. Therefore, there is the need for regulation. It takes place in two places:

The first reaction: the occurring in the glycolysis conversion of PEP to pyruvate is catalyzed by pyruvate kinase. The activity of this enzyme is 0.6 -bisphosphate increased by fructose -1 and inhibited by ATP and alanine. The enzymes of gluconeogenesis ( pyruvate carboxylase and PEP carboxykinase ) are activated by acetyl -CoA and inhibited by ADP. Since ATP is converted by hydrolysis into ADP, one can speak of this type of regulation of two opposing reactions of reciprocal regulation. Another example is for this reaction mentioned under 2. The involved in glycolysis, phosphofructokinase is stimulated by fructose -2 ,6 -bisphosphate and adenosine monophosphate (AMP ), but inhibited by citrate, among others. Reciprocal to find the regulation of those involved in gluconeogenesis, fructose-1 ,6- bisphosphatase place (activated by citrate and by fructose -2 ,6 -bisphosphate and AMP inhibited ).