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Substrates of Gluconeogenesis – (Lecture -2)
(For lactate, glycerol and propionate– check lecture-1)
Glucogenic amino acids- Amino acids are derived from the dietary proteins, tissue proteins or from the breakdown of skeletal muscle proteins during starvation. After transamination or deamination, glucogenic amino acids yield either pyruvate or intermediates of the citric acid cycle. Amino acids that are degraded to acetyl CoA or Acetoacetyl CoA are termed ketogenic amino acids because they can give rise to ketone bodies or fatty acids. Acetyl co A cannot be termed glucogenic, since the conversion back to pyruvate is not possible due to irreversible nature of the reaction and in TCA cycle Acetyl co A loses both of its carbons as carbon dioxide, hence there is nothing left to contribute to glucose production.
Amino acids that are degraded to pyruvate, α-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate are termed glucogenic amino acids. The net synthesis of glucose from these amino acids is feasible because these citric acid cycle intermediates and pyruvate can be converted into phosphoenolpyruvate. The entry point of these glucogenic amino acids in to the pathway of gluconeogenesis is as follows-
1) Pyruvate is the point of entry for alanine, serine, cysteine, glycine, threonine, and tryptophan (Figure-1). The transamination of alanine directly yields pyruvate.
Glucose Alanine cycle
The glucose-alanine cycle is used primarily as a mechanism for skeletal muscle to eliminate nitrogen while replenishing its energy supply. Glucose oxidation produces pyruvate which can undergo transamination to alanine. This reaction is catalyzed by alanine transaminase, ALT (ALT used to be referred to a serum glutamate-pyruvate transaminase, SGPT). Additionally, during periods of fasting, skeletal muscle protein is degraded for the energy value of the amino acid carbons and alanine is a major amino acid in protein. The alanine then enters the blood stream and is transported to the liver. Within the liver alanine is converted back to pyruvate which is then a source of carbon atoms for gluconeogenesis. The newly formed glucose can then enter the blood for delivery back to the muscle. The amino group transported from the muscle to the liver in the form of alanine is converted to urea in the urea cycle and excreted (Figure-1)
Figure-1- Glucose alanine cycle serves two purposes, firstly ammonia disposal (as amino group of alanine and secondly transport of pyruvate(carbon skeleton of alanine) for glucose production.
Role of Muscle in wasting conditions, starvation or in Anorexia nervosa
Gluconeogenesis requires a coordinated supply of precursors from muscle and adipose tissue to the liver (and kidneys).
Plasma glucose concentrations are normally maintained within a relatively narrow range, roughly 70–110 mg/dL (3.9–6.1 mmol/L) in the fasting state with transient higher excursions after a meal, despite wide variations in exogenous glucose delivery from meals and in endogenous glucose utilization by, for example, exercising muscle. Between meals and during fasting, plasma glucose levels are maintained by endogenous glucose production, hepatic glycogenolysis, and hepatic (and renal) gluconeogenesis. Although hepatic glycogen stores are usually sufficient to maintain plasma glucose levels for approximately 8 h, this time period can be shorter if glucose demand is increased by exercise or if glycogen stores are depleted by illness or starvation.
Muscle provides lactate, pyruvate, Alanine, glutamine, and other amino acids. Triglycerides in adipose tissue are broken down into fatty acids and glycerol, which is a gluconeogenic precursor. Fatty acids provide an alternative oxidative fuel to tissues other than the brain (which requires glucose).
This glucose-alanine cycle thus provides an indirect way of utilizing muscle glycogen to maintain blood glucose in the fasting state. The ATP required for the hepatic synthesis of glucose from pyruvate is derived from the oxidation of fatty acids. Thus by interplay of glycolysis and Gluconeogenesis, the energy requirements of different cell types are fulfilled.
2) Oxalo acetate- Aspartate and asparagine are converted into oxaloacetate, a citric acid cycle intermediate (Figure-2). Aspartate, a four-carbon amino acid, is directly transaminated to oxaloacetate.The reaction is catalyzed by AST (Aspartate transferase also called SGOT- Serum glutamate oxaloacetate transaminase)
3) α-Ketoglutarate is the point of entry of several five-carbon amino acids that are first converted into glutamate (Figure-2) . Arginine, histidine , proline, glutamate and glutamine enter the pathway as α-Ketoglutarate which is eventually converted to oxaloacetate to proceed further in to the main pathway of glucose production.
All the intermediates of TCA cycle beyond α-Ketoglutarate are considered glucogenic.
4) Succinyl CoA is a point of entry for some of the carbon atoms of methionine, isoleucine, and valine. Propionyl CoA and then Methylmalonyl CoA are intermediates in the breakdown of these three nonpolar amino acids.
5) Fumarate is the point of entry for Aspartate, Phenyl alanine and Tyrosine.
The TCA intermediates either directly form pyruvate from Malate by the activity of Malic enzyme or are converted to oxaloacetate by the activity of Malate dehydrogenase so as to be converted to phosphoenol pyruvate by the activity of phospho enol pyruvate carboxy kinase enzyme.
Figure- 2- Amino acids forming Acetyl co A or Acetoacetyl co A are not considered glucogenic, they are called ketogenic amino acids since acetyl co A is a precursor for ketone bodies. All other amino acids which form pyruvate or intermediates of TCA cycle are considered glucogenic.
Role of kidney in gluconeogenesis
Although the liver has the critical role of maintaining blood glucose homeostasis and therefore, is the major site of gluconeogenesis, the kidney plays an important role. During periods of severe hypoglycemia that occur under conditions of hepatic failure, the kidney can provide glucose to the blood via renal gluconeogenesis. In the renal cortex, glutamine is the preferred substance for gluconeogenesis.
During fasting (starvation) or acidosis, cortisol acts to induce muscle protein degradation. Muscle glutamine synthetase activity is induced.
Glutamine is produced in high amounts by skeletal muscle during periods of fasting as a means to export the waste nitrogen resulting from amino acid catabolism. Alanine and glutamine account for approximately 50% of all amino acids that leave muscle. Through the actions of transaminases, a mole of waste ammonia is transferred to α-ketoglutarate via the glutamate dehydrogenase catalyzed reaction yielding glutamate (Figure-3).
Figure-3- The reaction catalyzed by glutamate dehydrogenase is reversible. The enzyme is unique in the sense that it can utilize either of NAD + or NADP+
Glutamate is then a substrate for glutamine synthetase, which incorporates another mole of waste ammonia generating glutamine (Figure-4) .
Figure-4- Muscle Glutamine synthetase activity increase during conditions of starvation and stress. The activity of Brain isoenzyme increase in conditions of ammonia intoxication in order to detoxify ammonia.
The glutamine is then transported to the kidneys where the reverse reactions occur liberating the ammonia and producing α-ketoglutarate which can enter the TCA cycle and the carbon atoms diverted to gluconeogenesis via oxaloacetate (Figure-5).This process serves two important functions. The ammonia (NH3) that is liberated spontaneously ionizes to ammonium ion (NH4+) and is excreted in the urine effectively buffering the acids in the urine. In addition, the glucose that is produced via gluconeogenesis can provide the brain with critically needed energy.
Figure-5- Reaction 1 and 2 show the reversible reactions catalyzed by glutamate dehydrogenase enzyme. Reaction 3 for the formation of glutamine is catalyzed by Glutamine synthetase while the reaction 4 for the formation of glutamate from glutamine is catalyzed by glutaminase enzyme. Glutamine in kidney is converted first to glutamate and then to alpha ketoglutarate so as to be converted to oxaloacetate and that is converted to glucose by a series of steps.
The secretion of cortisol hormone, increases in response to a variety of stresses, including fasting and acidosis.
Revision of steps of gluconeogenesis – figure-6
Figure-6- steps of gluconeogenesisPlease help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!