The figure rendered from 3G8C. The roles of arginine and glutamate are illustrated in the next slide. Glutamate in the active site initiates the proceedings by deprotonating bicarbonate, which in turn attacks the terminal phosphate of ATP.
This yields carboxyphosphate, which in turn deprotonates biotin; arginine stabilizes the anionic biotin intermediate that forms transiently at this stage. The biotin anion finally attacks the carboxyphosphate, producing phosphate and carboxybiotin. Figure simplified after a scheme given in [ 29 ]. Beyond its role in biotin-dependent carboxylation reactions, carboxyphosphate or carbonic-phosphoric anhydride also occurs as an intermediate in the carbamoylphosphate synthetase reaction, which is the first step in the urea cycle see slide The second active site—or, in the E.
The reaction begins with pyruvate adopting the enol configuration. The product is oxaloacetate. In the phosphoenolpyruvate carboxykinase reaction, the CO 2 that just had been attached to the substrate leaves again. This gives rise to an enolpyruvate anion intermediate that attacks and acquires the terminal phosphate group of GTP. The product is phosphoenolpyruvate, which is an intermediate of glycolysis. All of the reactions between phosphoenolpyruvate and fructose-1,6-bisphosphate are reversible; we can therefore skip ahead to the latter metabolite.
These reactions revert the substrate phosphorylations that occur in the first and the third step of glycolysis, which are catalyzed by hexokinase and phosphofructokinase, respectively. In gluconeogenesis, the phosphate groups are simply hydrolyzed off, which is not a very difficult sort of reaction. In glycolysis, there was a net gain of only two molecules of ATP per molecule of glucose. The expenditure of an extra four equivalents of ATP in gluconeogenesis reverts the energy balance of the pathway, so that it actually proceeds in the opposite direction.
Formation of no more than two ATP molecules makes it exergonic to turn glucose into pyruvate, whereas expenditure of six ATP equivalents makes it exergonic to turn pyruvate back into glucose. As pointed out above section 7. Pyruvate carboxylase, which turns pyruvate into a TCA cycle intermediate, is important not only in gluconeogenesis, but also in the replenishment of TCA cycle intermediates, which may become depleted through diversion to the biosynthesis of amino acids or of heme.
Therefore, this enzyme is expressed not only in the organs that perform gluconeogenesis liver and kidneys but ubiquitously. Gluconeogenesis is also part of two interorgan cycles, namely, the Cori cycle and the glucose-alanine cycle.
These will be discussed after several other participating pathways have been introduced see slides 8. In keeping with its role in replenishing TCA cycle intermediates, pyruvate carboxylase resides inside the mitochondria. The next step in gluconeogenesis, catalyzed by phosphoenolpyruvate carboxykinase, occurs in the cytosol; therefore, oxaloacetate must in some way be exported from the mitochondria again.
We had already seen that the mitochondrial concentration of oxaloacetate is low, and that the malate dehydrogenase equilibrium favors malate section 5. It turns out that substrate export occurs indeed at the level of malate, which is exchanged for phosphate by a mitochondrial transport protein known as the dicarboxylate carrier. The malate dehydrogenase reaction is then reversed in the cytosol; the NADH produced can be used in the reversal of the glyceraldehydedehydrogenase reaction see slide 3.
The phosphate that entered the mitochondrion in exchange for malate can be used by ATP synthase, and the ATP be exchanged for cytosolic ADP, which balances the entire transport cycle and supplies one ATP to the cytosol, where it may for example be used by phosphoglycerate kinase in gluconeogenesis.
The dicarboxylate carrier that exports malate to the cytosol is susceptible to inhibition by methylmalonate. The coenzyme A thioester of methylmalonate occurs in the metabolic utilization of fatty acids with uneven numbers of carbon atoms see slide Those two hepatic ducts join to form the common hepatic duct that drains all bile away from the liver. The common hepatic duct finally joins with the cystic duct from the gallbladder to form the common bile duct , carrying bile to the duodenum of the small intestine.
Most of the bile produced by the liver is pushed back up the cystic duct by peristalsis to arrive in the gallbladder for storage, until it is needed for digestion. The blood supply of the liver is unique among all organs of the body due to the hepatic portal vein system.
Blood traveling to the spleen , stomach , pancreas , gallbladder, and intestines passes through capillaries in these organs and is collected into the hepatic portal vein. The hepatic portal vein then delivers this blood to the tissues of the liver where the contents of the blood are divided up into smaller vessels and processed before being passed on to the rest of the body.
Blood leaving the tissues of the liver collects into the hepatic veins that lead to the vena cava and return to the heart. The liver also has its own system of arteries and arterioles that provide oxygenated blood to its tissues just like any other organ.
The internal structure of the liver is made of around , small hexagonal functional units known as lobules. Each lobule consists of a central vein surrounded by 6 hepatic portal veins and 6 hepatic arteries. These blood vessels are connected by many capillary-like tubes called sinusoids , which extend from the portal veins and arteries to meet the central vein like spokes on a wheel.
Each sinusoid passes through liver tissue containing 2 main cell types: Kupffer cells and hepatocytes. The liver plays an active role in the process of digestion through the production of bile. Bile is a mixture of water, bile salts, cholesterol, and the pigment bilirubin. Hepatocytes in the liver produce bile, which then passes through the bile ducts to be stored in the gallbladder.
When food containing fats reaches the duodenum , the cells of the duodenum release the hormone cholecystokinin to stimulate the gallbladder to release bile.
Bile travels through the bile ducts and is released into the duodenum where it emulsifies large masses of fat. The emulsification of fats by bile turns the large clumps of fat into smaller pieces that have more surface area and are therefore easier for the body to digest. Kupffer cells in the liver catch and destroy old, worn out red blood cells and pass their components on to hepatocytes. Hepatocytes metabolize hemoglobin, the red oxygen-carrying pigment of red blood cells, into the components heme and globin.
Globin protein is further broken down and used as an energy source for the body. The iron-containing heme group cannot be recycled by the body and is converted into the pigment bilirubin and added to bile to be excreted from the body. Bilirubin gives bile its distinctive greenish color.
Intestinal bacteria further convert bilirubin into the brown pigment stercobilin, which gives feces their brown color. When you have diabetes, these processes can be thrown off balance, and if you fully understand what is happening, you can take steps to fix the problem. It is important for individuals with type 2 diabetes to understand these concepts, because some of the high morning blood sugars commonly seen in type 2 diabetes are a result of excessive gluconeogenesis overnight.
Too much ketone formation is a less common problem, but can be dangerous, and needs emergency medical attention. Self assessment quizzes are available for topics covered in this website. To find out how much you have learned about Facts about Diabetes , take our self assessment quiz when you have completed this section.
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