Gluconeogenesis chem.com pdf

What is Gluconeogenesis?

Introduction

Glucose is a key metabolite in human metabolism, but it is not always available at sufficient levels in the diet. Therefore, a pathway exists that converts other foodstuffs into glucose. This pathway is called gluconeogenesis. Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. From breakdown of proteins these substrates include glycogenic amino acids (although not ketogenic amino acids from breakdown of lipids (such as triglycerides they include glycerol odd-chain fatty acids (although not even chain fatty acids, see below) and from other steps in metabolism they include pyruvate and lactate. Although most gluconeogenesis occurs in the liver, the relative contribution of gluconeogenesis by the kidney is increased in diabetes and prolonged fasting. Gluconeogenesis is one of several main mechanisms used by humans and many other animals to maintain blood glucose levels avoiding low levels (hypoglycemia). Other means include the degradation of glycogen gluconeogenesis and fatty acid catabolism.

Step and Reactions involved in Gluconeogenesis:

 Lactate alanine and some other amino acids produce pyruvate which is first converted by pyruvate carboxylase (a mitochondrial enzyme that requires ATP and Biotin) into oxaloacetate.

 Oxaloacetate is converted into malate or aspartate as it cannot directly cross the mitochondrial membrane after crossing membrane it is reconverted into oxaloacetate in cytosol.

 Oxaloacetate is decarboxylase to form phosphoenolpyruvate by phosphoenolpyruvate carboxykinase. This reaction requires GTP.

 By reversal of the glycolytic reactions phosphoenolpyruvate is converted to fructose 1- 6-bisphosphate.

 Fructose-1- 6-bisphosphate is converted to fructose-6-phosphate in a reaction that release inorganic phosphate, fructose-1- 6-bisphosphatase is used as catalyst.

 Using same isomerize as uses in glycolysis Fructose-6-phosphate is converted to glucose 6-phosphate.

 Glucose-6-phosphate releases inorganic phosphate which produces free glucose that enters the blood. The enzyme involved is glucose 6-phosphat

 

The pyruvate carboxylase reaction

With the pyruvate carboxylase reaction we are able to metabolically fix CO2—just like plants! Before we try to claim Kyoto treaty credits for this ability however it is necessary to consider that the very same molecule of CO2 gets released again in the next step. The whole purpose of transient CO2 fixation is to enable this subsequent reaction.

The pyruvate carboxylase response happens in two separate advances, which in human digestion are completed in two particular dynamic destinations of a solitary protein particle. In E. coli the two exercises are found on independent protein particles. The main chemical action is biotin carboxylase which appends CO2 to the coenzyme biotin. 

 just as of a few key amino corrosive buildups, inside the dynamic site of the E. coli compound. The response includes bicarbonate and ATP the terminal phosphate gathering of ATP would fit into the space between ADP arginine 292 and bicarbonate. The jobs of arginine 338 and glutamate 296 are outlined in the following slide. 

Enactment of bicarbonate and carboxylation of biotin 

Glutamate 296 in the dynamic site starts the procedures by deprotonating bicarbonate, which thus assaults the terminal phosphate of ATP. This yields carboxyphosphate which thus deprotonates biotin; arginine 338 balances out the anionic biotin middle of the road that structures briefly at this stage

The carboxylation of pyruvate 

Stage 2 

The subsequent dynamic site—or, in the E. coli pathway, the subsequent compound—moves the carboxyl gathering from biotin to pyruvate. The response starts with pyruvate receiving the enroll setup. The electrons of the C=C twofold security at that point play out a nucleophilic assault on the carboxyl gathering, to which biotin promptly yields. The item is oxaloacetate. 

Cycles in glycolysis and gluconeogenesis 

Every one of these short cycles consolidates one chemical from glycolysis (blue bolts) with a couple of compounds from gluconeogenesis (red bolts). For each situation, the net consequence of the cycle is basically the utilization of ATP or GTP and the arrival of warmth. 

These cycles have been appeared to run in living cells at obvious levels, conceivably for heat creation; and as brought up in part 2, such substrate cycles likewise hone up administrative reactions. In any case, their movement must be maintained within proper limits in control to stay away from over the top wastage of ATP. A few however not the entirety of the administrative components that activity this control are comprehended. 

 

 

Significance of Gluconeogenesis Pathway

• Gluconeogenesis meets the needs of the body for glucose when sufficient carbohydrate is not available from the diet or glycogen reserves.

• Glycogen stored in adipose tissue and in skeletal muscle is converted to glucose by        Gluconeogenesis.

• However the stored glycogen may not be sufficient during heavy exercise, diabetic conditions, or during fasting etc. so during shortage glucose is synthesized by gluconeogenesis process.

• A continual supply of glucose is necessary as a source of energy especially for the nervous system and erythrocytes.

• Gluconeogenesis mechanism is used to clear the products of the metabolism of other tissues from the blood, eg: Lactate produced by muscle and erythrocytes and glycerol, which is continuously produced by adipose tissue.

Connections of gluconeogenesis with different pathways 

 Substrate carbon for gluconeogenesis collects generally from amino corrosive debasement and is gathered at the degree of pyruvate or of TCA cycle intermediates. Pyruvate carboxylase, which transforms pyruvate into a TCA cycle moderate, is significant in gluconeogenesis; yet in addition in the renewal of TCA cycle intermediates which may get drained through redirection to the biosynthesis of amino acids or of home. Along these lines, this compound is communicated not just in the organs that perform gluconeogenesis (liver and kidneys) however pervasively.

Regulation of gluconeogenesis

The movement of proteins in gluconeogenesis is controlled by a few systems as indicated by the metabolic needs of the cell and those of the whole body. Deficiency in any of the gluconeogenic enzymes leads to hypoglycemia.

Uria introduction:  

                                     The urea cycle is a biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). This cycle occurs in ureotelic organisms. The urea cycle converts highly toxic ammonia to urea for excretion This cycle was the first metabolic cycle to be discovered five years before the discovery of the TCA cycle. This cycle was described in more detail later on by Ratner and Cohen. The urea cycle takes place primarily in the liver and to a lesser extent in the kidneys. 

 

Overall reaction equations:

In the first reaction, NH+4 + HCO−3 is equivalent to NH3 + CO2 + H2O

Thus, the overall equation of the urea cycle is:

• NH3 + CO2 + aspartate + 3 ATP + 2 H2O → urea + fumarate + 2 ADP + 2 Pi + AMP + PPi

Since fumarate is obtained by removing NH3 from aspartate (by means of reactions 3 and 4), and PPi + H2O → 2 Pi, the equation can be simplified as follows:

• 2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP+ 4 Pi + AMP

Note that reactions related to the urea cycle also cause the production of 2 NADH so the overall reaction releases slightly more energy than it consumes. The NADH is produced in two ways:

• One NADH molecule is produced by the enzyme glutamate dehydrogenase in the conversion of glutamate to ammonium and α-ketoglutarate. Glutamate is the non-toxic carrier of amine groups. This provides the ammonium ion used in the initial synthesis of carbamoyl phosphate.

• The fumarate released in the cytosol is hydrated to malate by cytosolic fumarate. This malate is then oxidized to oxaloacetate by cytosolic malate dehydrogenase generating a reduced NADH in the cytosol. Oxaloacetate is one of the keto acids preferred by transaminases and so will be recycled to aspartate maintaining the flow of nitrogen into the urea cycle.

We can summarize this by combining the reactions:

• CO2 + glutamate + aspartate + 3 ATP + 2 NAD++ 3 H2O → urea + α-ketoglutarate + oxaloacetate + 2 ADP + 2 Pi + AMP + PPi + 2 NADH

The two NADH produced can provide energy for the formation of 5 ATP a net production of two high-energy phosphate bond for the urea cycle. However if gluconeogenesis is underway in the cytosol the latter reducing equivalent is used to drive the reversal of the GAPDH step instead of generating ATP.

As stated above many vertebrates use the urea cycle to create urea out of ammonium so that the ammonium does not damage the body. Though this is helpful there are other effects of the urea cycle. For example; consumption of two ATP production of urea generation of H+ the combining of HCO3- and NH4+ to forms where it can be regenerated and finally the consumption of NH4+  .

Steps of urea cycle ?

• Carbamoyl phosphate is converted to citrulline. With catalysis by ornithine transcarbamoylase the carbamoyl phosphate group is donated to ornithine and releases a phosphate group. 

• A condensation reaction occurs between the amino group of aspartate and the carbonyl group of citrulline to form argininosuccinate This reaction is ATP dependent and is catalyzed by argininosuccinate synthetase. 

• Argininosuccinate undergoes cleavage by argininosuccinate to form arginine and fumarate. 

• Arginine is cleaved by arginase to form urea and ornithine. The ornithine is then transported back to the mitochondria to begin the urea cycle again.

Formation of citruline 

•Ornithine and citrulline are fundamental amino acids that take an interest in the urea cycle. •They are not joined into cell proteins, in light of the fact that there are no codons for these amino acids

• Ornithine is recovered with each turn of the urea cycle, much similarly that oxaloacetate is recovered by the responses of the citrus extract cycle

Synthesis of Argininiosuccinate

Citrulline gathers with aspartate to frame argininosuccinate. The α-amino gathering of aspartate gives the second nitrogen that is eventually fused into urea. ATP to adenosine monophosphate (AMP) and pyrophosphate. This is the third and last particle of ATP devoured in the development of urea.

Cleavage of Argininosuccinate

Argininosuccinate is severed to yield arginine and fumarate. The arginine shaped by this response fills in as the quick antecedent of urea. Cleavage of argininosuccinate •Fumarate delivered in the urea cycle is hydrated to malate, giving a connection a few metabolic pathways.

For instance, the malate can be shipped into the mitochondria through the malate transport and reappear the tricarboxylic corrosive cycle. On the other hand, cytosolic malate can be oxidized to oxaloacetate, which can be changed over to aspartate.

Cleavage of Arginine to ornithine and urea

Arginase cuts arginine to ornithine and urea, and happens only in the liver

Fate of urea

Urea diffuses from the liver, and is moved in the blood to the kidneys, where it is sifted and discharged in the pee. A bit of the urea diffuses from the blood into the digestive tract, and is divided to CO2 and NH3 by bacterial urease

This smelling salts is halfway lost in the defecation, and is somewhat reabsorbed into the blood. In patients with kidney disappointment, plasma urea levels are raised, advancing a more prominent exchange of urea from blood into the gut

 

Role of Kidneys:

  Urea  is a waste product of many living organisms and is the major organic component of human urine. This is because it is at the end of chain of reactions which break down the amino acids that make up proteins. These amino acids are metabolised and converted in the liver to ammonia CO2 water and energy. But the ammonia is toxic to cells, and so must be excreted from the body. Aquatic creatures such as fish can expel the ammonia directly into the water but land-based animals need another disposal method. So the liver converts the ammonia to a non-toxic compound urea which can then be safely transported in the blood to the kidneys where it is eliminated in urine.

  Urea

An adult typically excretes about 25 grams of urea per day. As urea goes stale bacteria convert it back into ammonia which gives the familiar pungent smell of lavatories. Any condition which impairs the elimination of urea by the kidneys can lead to uremia a buildup of urea and other nitrogen wastes in the blood that can be fatal. To reverse the condition either the cause of the kidney failure must be removed or the patient must undergo blood-dialysis to remove the wastes from the blood.

Significance of Urea cycle:

The main purpose of the urea cycle is to eliminate toxic ammonia from the body. About 10 to 20 g of ammonia is removed from the body of a healthy adult every day. A dysfunctional urea cycle would mean excess amount of ammonia in the body, which can lead to hyperammonemia and related diseases. The deficiency of one or more of the key enzymes catalyzing various reactions in the urea cycle can cause disorders related to the cycle. Defects in the urea cycle can cause vomiting, coma and convulsions in new born babies.