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LET'S TALK LIFE-SCIENCE BIOCHEMISTRY

Suraj Prakash Sharma | Ekta Chotia

GLUCONEOGENESIS
62

10.6.      Formation of glucose from glucose-6-phosphate

Glucose-6-phosphatase enzyme, found only in the endoplasmic reticulum of liver and kidney, catalyzes the irreversible hydrolysis of glucose-6-phosphate to form glucose and Pi. Subsequently this glucose is released into the blood and taken by cells.

Each set of such paired reactions is referred to as a substrate cycle. Because they are coordinately regulated (an activator of the enzyme catalyzing the forward reaction serves as an inhibitor of the enzyme catalyzing the reverse reaction), very little energy is wasted, even though both enzymes may be operating at some level at the same time.

Flux control (regulation of the flow of substrate and removal of product) is more effective if transient accumulation of product is funneled back through the cycle. The catalytic velocity of the forward enzyme will remain high if the concentration of the substrate is maximized. The gain is more in catalytic efficiency than the small energy loss in recycling the product.

10.7.      Energy Balance :

Gluconeogenesis is an energy-consuming process. Instead of generating ATP (as in glycolysis), gluconeogenesis requires the hydrolysis of six high energy phosphate bonds.

Patients with von Gierke’s disease lack glucose-6-phosphatase activity in the liver. This resulted into accumulation of excess glucose in the form of Glycogen. Upon fasting the patients are not able to convert this glycogen into glucose. Thus  fasting hypoglycemia and lactic acidosis are two prominent symptoms of this disorder.

10.8.      Gluconeogenesis Substrates

1.            Lactate

Lactate is released by red blood cells and other cells that lack mitochondria or during low oxygen concentrations. During exercise lactate is released by skeletal muscle. This lactate is converted into pyruvate and subsequently into glucose by gluconeogenesis. This cycle is known as Cori cycle.

2.            Glycerol

In adipose tissue the store fat is in the form of triacylglycerol. TAG yields glycerol and fatty acid upon metabolism. Glycerol is transported to the liver and then converted to glycerol-3-phosphate by glycerol kinase. Oxidation of glycerol-3-phosphate to form DHAP occurs when cytoplasm NADconcentration is relatively high.

10.9.      The Glucose-Alanine Cycle

Alanine is formed from pyruvate in muscle. During starvation, it is transported to the liver, alanine is reconverted to pyruvate by alanine transaminase in liver. Eventually pyruvate is used in the synthesis of new glucose by gluconeogenesis process. The glucose-alanine cycle is used to transfer amino nitrogen to the liver. Of all the amino acids that can be converted to glycolytic intermediates (molecules referred to as glucogenic), alanine is the most important amino acid. When exercising muscle produces large quantities of pyruvate, some of these molecules are converted to alanine by a transamination reaction involving glutamate. After it has been transported to the liver, alanine is reconverted to pyruvate and then to glucose.

The glucose-alanine cycle serves several purposes.

In  the recycling of  the  alpha Keto acids between muscle and liver.

It is the mechanism for transporting amino nitrogen to the liver. Because muscle cannot synthesize urea from amino nitrogen, so the amino nitrogen is transported to liver for urea synthesis. Once alanine reaches the liver, it is reconverted to pyruvate. The amino nitrogen of alanine is then incorporated into urea or transferred to other a-keto acids to restore the amino acid balance in the liver.

10.10.    Gluconeogenesis Regulation

Like any other metabolic pathways, the rate of gluconeogenesis is regulated. Three parameters that affects the rate of gluconeogenesis are  substrate availability, allosteric effector, and hormones.

  1. Gluconeogenesis is stimulated by high concentrations of lactate, glycerol, and amino acids.
  2. A high-fat diet, starvation, and prolonged fasting make large quantities of these molecules available.
  3. The four key enzymes in gluconeogenesis (pyruvate carboxylase, PEP carboxykinase, fructose-1, 6-bisphosphatase, and glucose-6-phosphatase) are affected to varying degrees by allosteric modulators.
  • Fructose-1,6-bisphosphatase is activated by citrate and inhibited by AMP and fructose-2,6-bisphosphate.
  • Pyruvate carboxylase is activated by Acetyl-CoA ( produce during Fatty acid oxidation and Acetyl-CoA concentration is high during starvation).

4.            Hormonal Regulation

  1. Glucagon hormone decrease the synthesis of fructose-2,6-bisphosphate. Fructose- 2,6-bisphosphate is positive allosteric regulator of PFK1. So PFK 1 is inhibited. Inhibition results into less synthesis of fructose-1,6-bisphosphatase. And eventually less synthesis of PEP. Hence PEP is no longer available for glycolytic enzyme pyruvate kinase. So the activity of pyruvate kinase is inhibited.
  2. Cortisol hormone increase the expression of  gluconeogenic enzymes.
  3. Insulin hormone increase the synthesis of new molecules of glucokinase, PFK-1 (SREBP1c- induced) and PFK-2 (glycolysis favored). Insulin Hormone also decrease the synthesis of of PEP carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase.
  4. Glucagon action leads to the synthesis of additional molecules of PEP carboxykinase, fructose-1, 6-bisphosphatase, and glucose-6-phosphatase.

10.11.    Catabolism of sugars other than glucose

Starch is the most abundant carbohydrate in our diet. Lactose and sucrose are disaccharides.

Fructolysis

Fructose degradation, also called fructolysis, runs mostly in the liver.

  1. Fructokinase phosphorylates fructose and converted into fructose-1-phosphate.
  2. Aldolase cleaves it into  dihydroxyacetone phosphate and and glyceraldehydes. dihydroxyacetone phosphate enter into glycolysis. Glyceraldehydes also enter into glycolysis after phosphorylation by glyceraldehyde kinase.
  3. Glyceraldehyde can alternatively be utilized by conversion to glycerol and then to glycerol-1-phosphate. glycerol-1-phosphate is involved in  synthesis of triacylglycerol (Fat).

Fructose and sucrose promote obesity more strongly than equivalent amounts of starch or glucose this is because of the above reason as the intermediate is involved in fat synthesis.

10.12.    Fructose intolerance

Fructose intolerance is due to mutation in aldolase B gene. In this condition, fructose is still phosphorylated by fructokinase. The product fructose-1-phosphate, is not processed further, and therefore the phosphate tied up in it cant be reused. Since phosphate is required for the regeneration of ATP from ADP, this means that ATP will be lacking too, which will sooner or later damage or even destroy the cell. The disease is characterized by potentially severe liver failure.

Fructosuria is increased in fructose concentration in Urine. This is due to  defect in the gene encoding fructokinase. In this disease fructose levels are increased both in the blood and the urine. Since fructose is not phosphorylated, no phosphate depletion occurs, and the liver cells do not occur any damage. The disease is therefore quite benign.

10.13.    The Leloir pathway for galactose utilization

This is a galactose utilization cycle mainly occur in liver.

Step:

  1. Galactokinase transfer the phosphate group to galactose and convert galactose into galactose-1-phosphate.
  2. Galactose-1-phosphate uridyltransferase catalyses the exchange reaction in which the galactose-1-phosphate undergoes an exchange reaction with UDP-glucose and releases glucose-1-phosphate and UDP-galactose.

10.14.    Lactose intolerance

It is due to deficiency of lactase enzyme in the small intestine. Lactose is cleaved by lactase enzyme in small intestine. If lactose is not cleaved, it cannot be absorbed by brush border epithelial of small instestine. It enters into large intestine where lactose is metabolised by intestinal bacteria like E.coli. Escherichia coli has a pathway called mixed acid fermentation which produce acids( formic acid) and gas. Formic acid lyases converts formic acid into H2 and CO2. Treatment consists in emission of lactose in the diet.

10.15.    Galactosemia means “galactose in the blood”

                Galactosemia is due to defect in the following enzymes

10.16.    Sorbitol

Sorbitol is not a sugar, since it lacks a keto or aldehyde group.

It is normally a minor component of dietary carbohydrates. Sorbitol  is also formed by metabolism from glucose in the polyol pathway. Sorbitol converted into fructose. NADPH is used in the first step and NAD+ is  used in the second.

Aldose reductase can reduce galactose into galactitol. Elevated level of galactose in the blood causes galactitol to accumulate in the lens and causes cataract. Conversion of glucose to fructose via the polyol pathway occurs in the seminal Vesicles in male. Fructose is found in the sperm fluid. Sperm cells require fructose to sustain their motility

10.17.    Mannose

Mannose is the C2 epimer of glucose. Mannose is a substrate for hexokinase which converts it into Mannose 6-phosphate. An enzyme similar to phosphoglucose isomerase, phosphomannose isomerase isomerizes mannose 6-phosphate into fructose-6-phosphate. Fructose 6-phosphate is the substrate for PFK-1.

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