Glycogen: Chemistry & Metabolism | Polyose | Organisms | Biology

In this article we will discuss about:- 1. Chemistry of Glycogen 2. Amount and Distribution of Glycogen 3. Mobilization 4. Formation 5. Metabolism.

Chemistry of Glycogen:

Glycogen is called animal starch; because it is in this form that glucose remains stored in the liver and muscles. Glycogen is branched polysaccharides (amylopectin type) consisting of hundreds of glucose units linked together by glucosidic linkages, i.e., α-1, 4′ linkage and 1, 6′ linkage which are formed by specific enzymes—uridine diphosphate glucose (UDPG)—pyrophosphorylase, glycogen synthetase and amylo-(1, 4′ —1, 6′)- transglucosidase respectively.

Glycogen is soluble in water and makes an opalescent solution and gives red colour with iodine. Glycogen liberates more energy than the corresponding weight of glucose. It does not diffuse into the intracellular fluid, as it exerts no osmotic pressure. It may be easily broken down into glucose by enzymes present in the liver.

Amount and Distribution of Glycogen:

In a normal adult about 700 gm of glycogen is present in the body, about 300 gm in liver and 400 gm in muscles. Liver and muscles are the chief storehouses. All growing tissues can store glycogen. Consequently, they are present in large amounts in the placenta in its early stage, the foetal muscles, and the yeast, etc. In the foetal muscles it may be as much as 40% of the total dried solids. Oyster is very rich in glycogen and is a good source for its manufacture.

Glycogen in any tissue is not a static quantity. It is being constantly used up and re-synthesised. So that at any time the glycogen of the tissue should be considered as a balance between the constant production and loss. Liver glycogen is most mobile. It is the first to be formed and is also the first to be mobilized. Muscle glycogen is much slower to move. There are remarkable differences between the metabolism of liver glycogen and muscle glycogen.

Mobilization of Glycogen:

Glycogen is formed both in the liver and muscles (Fig. 10.8).

When blood sugar tends to fall, liver glycogen is converted into glucose and mobilized in the blood stream (Fig. 10.9).

Thus blood sugar is maintained. In muscular exercise, starvation, exposure to cold and such other conditions, in which extra energy is demand­ed, liver glycogen is mobilized. This action is helped by certain hormones such as adrenaline (epinephrine), glucagon, thyroxine, growth or somatotrophic hormone (STH) of anterior pituitary, etc. Stimulation of the sympathetic has same function. It is antagonised by insulin. Insulin helps glycogenesis in liver and prevents glycogenolysis.

The former process is the breakdown of glycogen to glucose whereas the latter is the process of break­down of glycogen or glucose to pyruvic acid (anaerobic) which is further oxidized to CO₂ and H₂O (aer­obic) through TCA cycle. In both the processes, glycogen is converted to glucose-6-phosphate and in the process of glycogenolysis glucose-6-phosphate is splitted into glucose and Pi by phosphatase whereas in the process of glycolysis glucose-6-phosphate is converted further into fructose-6-phosphate by phosphohexose isomerase.

Glycogen is broken down to glucose-1-phosphate, catalysed by the enzyme phosphorylase-a. (active form). Phosphorylase exists in an inactive form, phosphorylase. b. Cyclic AMP (CAMP or 3′-5′-AMP) donates a phosphate group and converts it into an active form, phosphorylase- a. An enzyme, adenyl cyclase, helps in the formation of cyclic AMP from ATP which is accelerated by glucagon and adrenaline (epinephrine). The glucose-l-phosphate is converted into glucose-6-phosphate, catalyzed by the enzyme phosphoglucomutase. The enzyme phosphohexo isomerase converts glucose-6-phosphate to fructose-6-phosphate.

Formation of Glycogen (Glycogenesis):

In the process of glycogenesis, glucose is phosphorylated to glucose-6-phosphate by hexokinase (glucokinase) in presence of a phosphate donor, ATP a common to the first reaction in the glycolytic path of glucose metabolism. Glucose-6 phosphate is transformed into glucose-1-phosphate, catalysed by the enzyme phosphoglucomutase.

In the next step glucose-1-phosphate reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (activated glucose units as UDPG) and inorganic pyrophosphate (PPi). This reaction is catalysed by enzyme UDPG – pyrophosphorylase.

An enzyme UDPG – glycogen transglucosylase (glycogen synthetase) helps in the addition of glucose residue present in its activated form (UDPG) to a pre-existing glycogen chain at non-reducing outer end of the molecule (glycogen) so that glycogen tree is elongated successively due to the 1, 4′ linkage formation. Thus uridine diphosphate (UDP) is liberated and re-synthesised with the help of ATP –  UDP + ATP ↔ ADP + UTP.

A second enzyme, called branching enzyme [amylo-(1, 4′-1,6′) – transglucosidase] transfers a part of the 1, 4′-chain to adjacent chain to form α-1, 6′ linkage and helps in glycogen synthesis by forming a branch point (1, 6′ linkage ) in the molecule.

Pathway of Formation of Pyruvic Acid:

Fructose-6-phosphate accepts another phosphate group from ATP and is transformed into fructose-1-6-diphosphate. This reaction is influenced by the enzyme 6-phosphofructokinase. Another enzyme aldolase breaks down the above hexose diphosphate into dihydroxyacetone phosphate and glyceral dehyde-3-phosphate each con­taining 3 carbon atoms (triosephosphate).

Enzyme triosephosphate isomerase keeps the above two triosephosphates in equilibrium. Glyceraldehyde-3-phosphate is then dehydrogenated by triosephosphate dehydrogenase into 1-3-diphosphoglycerate, the hydrogen being accepted by NAD. Phosphorylation also takes place at this stage and requires inorganic phosphate (Pi). Diphosphoglycerate then donates one high energy phosphate to ADP to convert it into ATP and it itself is transformed into 3-phosphoglycerate.

This reaction is catalysed by the en­zyme, ATP phosphoglyceric transphosphorylase (phosphoglyceric acid kinase). Phosphoglyceromutase then transforms 3-phosphoglycerate to 2-phosphoglycerate and enolase converts it into 2-phosphoenolpyruvate. Phosphoenolpyruvate is spontaneously converted to pyruvate which is oxidised further to CO₂ and H₂O through TCA cycle if aerobic condition exists or otherwise reduced to lactic acid.

ATP-phosphopyruvic transphosphorylase (py­ruvic acid kinase) then transfers one energy-rich (∼) phosphate bond from phosphoenolpyruvate to ADP to form ATP and pyruvic acid. Other monosaccharides (galactose, fructose, and mannose) gain their entrance in the glycolytic pathway as indicated in the Figure 10.10. Citric Acid Cycle or Krebs Cycle:

The citric acid cycle is one of the most important biochemical mechanisms of oxidation of the activated metab­olites and it is perhaps the major terminal pathway of biological oxidation in all animal tissues. The activated metabolites, which are few in number derived from carbohydrate, protein, and fat, are oxidised by the elec­tron-transport chain and most of the utilisable energy (ATP) are produced for the organism.

The activated metabolites, which are derived from different foodstuffs (Fig. 10.11), are given below:

The components, included in this cycle, are interrelated by oxidation and reduction, and other reactions which produce 2CO₂, H₂O and energy ATP. In case of carbohydrate, the pyruvic acid which is formed by glycolytic path of oxidation enters this cycle by first being transformed into acetyl CoA.

This cycle is known as Krebs (citric acid) cycle after the English biochemist H.A. Krebs who first formulated and proposed the mechanism. Citric acid being one of the member of the cycle and some of the members contains these carboxylised groups so this cycle is also known as citric acid cycle and tricarboxylic acid (TCA) cycle.

Acetyl CoA or Active Acetate Formation:

In presence of six factors, i.e., Mg⁺⁺, NAD, thiamine pyrophosphate, lipoic acid, FAD and coenzyme A, the pyruvic oxidase along with enzyme complex converts pyruvate to active acetate as a result of oxidative decarboxylation and as a result the NADH₂ is formed which is reconverted to NAD by electron-transport chain. It enters into the TCA cycle.

A condensing enzyme, citrate synthetase, helps in the condensation of acetyl CoA with oxalo-acetate to form citrate. Citrate first by a process of dehydration is converted into cis-aconitate which again by a process of rehydration is transformed into iso-citrate. The enzyme aconitase catalyses the reaction at both the two steps, so-citrate in presence of the enzyme iso-citrate dehydrogenase is then dehydrogenated to oxalosuccinate. NAD or NADP acts as a hydrogen-acceptor and is converted into NADH₂ or NADPH₂.

An enzyme oxalosuccinate decarboxylase in presence of Mn⁺⁺ removes CO₂ from oxalosuccinate which is thus converted into α-ketoglutarate. A process of oxidative decarboxylation, similar to that in the conversion of pyruvate to acetyl CoA, transforms a-ketoglutarate to succinyl CoA catalysed by α-ketoglutaric oxidase which also requires coenzyme A, lipoic acid and NAD acting as hydrogen-acceptor.

Succinyl CoA, while it being converted into succinate, provides energy for synthesis of GTP (guanosine-5′-triphosphate) from GDP (guanosine-5′-diphosphate). So GTP in turn supplies energy for synthesis of ATP from ADP while it is reconverted to GDP. Thus succinyl CoA supplies ultimately energy for the synthesis of ATP.

[The enzyme thiophorase present in tissues, other than liver, can help in the conversion of succinyl CoA → succinate.] Enzyme succinate dehydrogenase converts succinate to fumarate, the hydrogen is transferred directly to flavoprotein (FAD) converting it into FADH₂. Fumarase helps in the addition of water to fumarate, malate is formed in this process. Oxaloacetate is regenerated from malate under the influence of malate dehydrogenase, NAD again is the hydrogen-acceptor (Fig. 10.12).

Pentose Phosphate Pathway (PPP) or Pentose Cycle or Hexose Monophosphate (HMP) Shunt or Phosphogluconate Oxidative path or Warburg-Dickens-Lipmann Path:

This pathway of glucose metabolism takes place in liver, mammary gland, testis, adrenal cortex and leucocytes. Glucose-6-phosphate derived from different sources is dehydrogenated by glucose-6-phosphate dehydrogenase into 6-phospho-gluconolactone which, through several steps described in the Figure 10.10, is ultimately con­verted into sedoheptulose-7-phosphate and enters again into the main glycolytic pathway at fructose-6-phosphate and glyceraldehyde-3-phosphate.

The formation of sedoheptulose-7-phosphate is catalysed by transketolase whereas the breakdown is catalysed by the enzyme transaldolase. The transketolase and transaldolase reactions are important in this path which is responsible for conversion of aldehydes to ketones and vice versa, as well as lower sugars to higher sugars and vice versa.

The physiological benefits in the cycle are as follows:

i. Synthesis of pentose to be required for the synthesis of nucleotides.

ii. Pentoses can enter into the glycolytic path and it itself may be oxidized in pentose phosphate pathway (PPP).

iii. Hexose (glucose-fructose) may be burnt in this PPP or may supply pentoses.

iv. NADPH₂ formed in the PPP, is utilized in the fat and steroid synthesis.

v. Energy formed in this path is 36 ATP per molecule of glucose if all the NADPH, are oxidized in the mitochondria to NADP.

vi. The oxidation of glucose (Fig. 10.13) in this path is independent of TCA cycle components.

vi. Components of PPP may enter into the path of formation of glucuronic acid an ascorbic acid (vitamin C).

Metabolism of Glycogen:

I. Metabolism of Glycogen in Liver:

Sources of Liver Glycogen:

Glycogenesis (formation of glycogen) in the liver can take place from the following:

i. From Carbohydrates and the Related Substances:

For instance, glucose, ga­lactose, fructose, mannose, lactic acid (from muscles or otherwise), pyruvic acid, methyl glyoxal, etc. Lactic acid of muscles is carried through blood stream to the liver where it is converted into glycogen very readily. It is believed that pentose does not form glycogen.

ii. From Proteins:

The antiketogenic amino acids (e.g., glycine, alanine, aspartic acid and glutamic acid, etc.) can read­ily form glucose through TCA cycle or reversible glycolytic path or both, as the case may be, as seen in diabetes mellitus. In diabetes mellitus the G: N ratio increased indicating the glucose is formed from protein (neoglucogenesis). It is reasonable to believe that this glucose may be available for glycogen formation.

iii. From Fats:

The glycerol part of fats is converted into glucose from which glycogen may be derived.

Functions of Liver Glycogen:

i. Liver glycogen is a ready source of glucose supply in the blood.

ii. It helps in the de-toxicating mechanism in the liver.

iii. It protects the liver from the toxic effects of arsenic, carbon tetrachloride, etc.

iv. If the liver glycogen level is high, ketone body formation and rate of deamination of amino acids are depressed.

II. Metabolism of Glycogen in Muscles:

Muscle contains about 0.5%-1.0% of glycogen as opposed to 5% in the liver. But due to greater amount of muscles in the body, the total quantity is higher and is about 400 gm or approximately equal depending on the total muscle mass of the body.

1. Glycogenesis in Muscles:

Source:

Muscle glycogen can be derived from the following sources:

i. From Glucose:

Which is obviously taken from the blood stream?

ii. From Lactic Acid:

Which is produced in the muscle during muscular contraction? The major part (4/5ths) of the lactic acid produced during exercise is reconverted into glycogen. A small part of it (1/5th) is oxidised into carbon dioxide and water through TCA cycle.

The conversion of lactic acid into glycogen in the muscle is comparatively much slower than in the liver. So that during heavy muscular exercise, a large amount of lactic acid is produced in the muscles. A good part of it diffuses into the blood stream and is brought to liver where it is readily reconverted into glycogen. Probably glycogen is not produced in the muscles from proteins and carbohydrates.

2. Glycolysis in Muscles:

Glycolysis is the process of breakdown of glycogen or glucose in muscles and other tissues into pyruvic and lactic acids (Embdert-Meyerhof glycolytic pathway). Glyco­gen leaves the liver in the form of glucose, but it leaves the muscles in the form of pyru­vic and lactic acids. The difference is proba­bly due to the fact that, the enzyme systems and the chemical reaction in the liver and muscles are not the same.

Lactic acid that emerges from the muscles is carried to liver through blood stream where it is reconvert­ed into glycogen. This glycogen is again mo­bilised in the form of glucose which enters into the blood stream. Muscles take up this glucose from the blood stream and recover its lost glycogen. This cyclic process of cir­culation of carbohydrate in different forms in different tissues is known as Cori cycle through which muscle and liver glycogens become readily interchangeable (Fig. 10.16).

Glycogen, in other tissues excepting liver, exhibits the same pattern of breakdown as in the muscles.