Polysaccharides


(You can find in this post the answers to the Questions C-06, C-o7 and C-O8)

 

As discussed in a former post Polysaccharides are carbohydrates formed by more than 9 monosaccharides linked by glycosidic bonds.

 

 When they are formed by the same kind of monosaccharides, they are called homopolysaccharides, like starch, glycogen and cellulose, formed each of them by hundreds of molecules of glucose linked by glycosidic linkages.

If the polysaccharides molecules are formed by different kinds of monosaccharides, they are considered heteropolysaccharides. Hyaluronic acid, formed by thousands of alternative units of N-acetyl glucosamine and glucuronic acid, is an example of heteropolysaccharide.  

 

HOMOPOLYSACCHARIDES:

 

Cellulose

 

Cellulose is a linear polymer of D-glucose residues bonded by b(1, 4)-O-glycosidic linkages. It is the most abundant carbohydrate in nature.

 

It is formed by glucose units, linked by Beta-1, 4 O-glycosidic linkages. We can say then that, if we consider the kind of linkage, the repeating unit in cellulose is cellobiose, the disaccharide formed by two molecules of glucose linked by Beta-D-O glycosidic bonds, (that is why some text books say that the monomer in cellulose is cellobiose).

 

The long fibers of cellulose are held together by intermolecular hydrogen bonds. Hydrogen bonding continues in the same plane with other chains as well as in planes above and below this plane to form strong, fibrous bundles. It made cellulose very appropriate for its structural function in plants

 

Since cellulose is formed by glucose molecules, it can be a source of energy for certain species. The lack in human beings of appropriate enzymes for digesting cellulose make this polysaccharide unsuitable for human nutrition (Have you though about how hunger in the world could disappear if we had enzymes for digesting cellulose?). Cellulose and derivatives are used as a component of laxatives for humans.

 

 

Starch:

 

Starch is the second most abundant carbohydrate in nature.

The biological functions include, in plants, the main way of storage of sugar, and consequently, of energetic sources; in humans, the first supply of glucose on diet (Answer to C-O7)

Starch is not really a molecule, but a grain formed by two different kinds of molecules:  Amylose and Amylopectin

 

Amylose

 

Amylose is a linear molecule formed by glucose units linked by alpha-1, 4 O glycosidic linkages. Taking in account the kind of linkage we can say that the repeating unit in amylose is maltose. (It explains that some books indicate that the monomeric unit in amylose is maltose).

 

Amylose molecule is helicoidal

 

Amylopectin

 

Amylopectin is the second type of molecule that forms starch. It is a branched molecule, formed also by glucose. Amylopectin contains D-glucose residues bonded together by a(1, 4)-O-glycosidic linkages with branching through a(1      6)-O-glycosidic linkages.

The disaccharides that can be obtained from the digestion of amylopectin are maltose and isomaltose.

 

Amylopectin shows a branch each 24-30 units of glucose,

 

Glycogen

 

The structure of glycogen is very similar to amylopectin but more branched, with one branch every 8 to 12 glucose unit

 

Glycogen is the way in which glucose is stored in animals. Glycogen is stored mainly in liver (to release glucose to blood when necessary) and in muscle, where it is used as a reserve of energy for muscular contraction (Answer to C-o8)

 

HETEROPOLYSACCHARIDES

 

Heteropolysaccarides contain two or more different kind of monosaccharides. Usually they provide extracellular support for organisms of all kingdoms:  the bacteria cell envelope, or the matrix that holds individual cells together in animal tissues, and provides protection, shape and support to cells, tissues and organs.

 

Heteropolysaccharides provide extracellular support to very different organisms, from bacteria to humans; together with fibrous proteins, like collagen, elastin, fibronectin, laminin and others, heteropolysaccharides are the most important components of the extracellular matrix.  Hyaluronic acid, condroitin sulfates and dermatan sulfates are important heteropolysaccharides in the extracellular matrix. These heteropolysaccharides usually are formed by the repetition of a disaccharide unit of an aminosugar and an acid sugar. 

 

A typical example

 

Other common constituents are sulfate groups linked to certain monosaccharides. Usually heteropolysaccharides are associated with proteins forming proteoglycans, glycosaminoglycans or mucopolysaccharides (since they are abundant in mucous secretions).  As a group, they perform diverse functions: structural, water metabolism regulation (as a reservoir of water), cellular cement, biological sieve, biological lubricant, docking sites for growth factors, among other functions.

 

Established specific functions of some glycosaminoglycans are:

 

Hyaluronic Acid (Hyaluronate): It is a lubricant in the synovial fluid of joints,

give consistency to vitreous humor, contributes to tensile strength and elasticity of cartilages and tendons (Answer to C-O6)

 

Chondroitin Sulfates: contributes to tensile strength and elasticity of cartilages, tendons, ligaments and walls of aorta.

 

Dermatan sulfate (former chondroitin sulfate B) is found mainly in skin, but also is in vessels, heart, lungs. It may be related to coagulation and vascular diseases and other conditions.

 

Keratan sulfate: Present in cornea, cartilage bone and a variety of other structures as nails and hair.

 

Heparin

 

It is a potent natural anticoagulant produced in the Mast Cells that causes antithrombin bind to thrombin and produce inhibition of blood coagulation.

 

Glycosaminoglycans are synthesized in the ER and Golgi. They are degraded by lysosomal hydrolases. A deficiency of one of the hydrolases results in a mucopolysaccharidosis. These are hereditary disorders in which glycosaminoglycans accumulate in tissues, causing symptoms such as skeletal and extracellular matrix deformities, and mental retardation.

Examples of these genetic diseases are Hunter and Hurler syndromes.

These diseases, caused by different enzyme deficits, are characterized by physical deformities, mental retardation and disturbances in the degradation of heparan sulfate and dermatan sulfate.

 

Cellulose as laxative


Answer to C-05

 

Original Question

 

 

Answer (a)

 

   

   

Cellulose is a polymer of hundreds to thousands of Beta-D-glucose molecules linked by beta-1,4 O-glycosidic linkages (the OH of the Beta anomeric carbon of the glucose residues is linked to the OH in carbon 4 of the adjacent residue of glucose). The repeated dimer (Beta-D-glucose linked to another D-glucose through a Beta  1,4-O-glycosidic linkage) is called cellobiose.  

 

Cellulose is the most abundant organic compound in nature, since it forms around 30 % of plants,  but unfortunately, what could be an abundant source of glucose, can not be used by human beings, since we lack, as other animals, the enzyme necessary for hydrolyzing the beta 1,4 O-glycosidic linkages between molecules of glucose. In fact, ruminants and termites do not produce the necessary enzymes for digestion of cellulose, but they have in the gastrointestinal tract some bacteria that produce the required enzymes, that is why they can take advantage of the glucose in cellulose.

 

Since cellulose can not be digested by human beings and it is a very hydrophilic compound,  it can absorb water in the intestines producing a softer and bulkier stool that stimulates peristalsis.

 

Cellulose derivatives as methylcellulose, ethylcellulose and others are used in Medicine as components of laxatives, artificial tears, tablet coating, etc.

 

 

Answer to Carbohydrate Question (C-04)


 

Original Question C-04 

 

 

 

 

 

 

Answer: (d)

 

Heparin is a heteropolysaccharide (a polysaccharide formed by different kinds of monosaccharides).

 

In fact, Heparin is a family of molecules that are usually composed by the repetition of a sulfated amino sugar and an acid sugar. The most abundant pair of monosaccharides whose repetition forms heparin is this one                                               

 

 

The physiological function of heparin is subject of discussion:  it is related to the inflammation process and not to coagulation in physiological conditions.

 

Heparin inhibits the coagulation process by inhibiting, indirectly, the action of Thrombin.

 

Normally, during the coagulation process, Thrombin (factor II), a proteolytic enzyme, (as many coagulation factors), catalyzes the conversion of fibrinogen to fibrin, activates factors V, VIII and XI and also promotes platelet activation.

 

Antithrombin is an antiprotease protein with an important role in the regulation of normal coagulation. It inhibits mainly the proteases of the intrinsic pathway of coagulation, but also affects other factors or the extrinsic and the complement pathways.

 

Heparin increases the inhibitory action of antithrombin in thousands of times. Heparin can act through two mechanisms:

 

1.- An allosteric mechanism, in which Heparin provokes conformational changes in antithrombin that increases its ability to inhibit some of the coagulation factors,

 

 2.- By forming ternary complexes Heparin-antithrombin-Thrombin.

 

Since it is necessary that the heparin molecule be big enough to bind properly to antithrombin and thrombin for forming the ternary complex (Heparin molecule should have more than 18 monosaccharides for allowing the simultaneous binding), small molecules of Heparin have no effect on Thrombin but maintain anticoagulant activity affecting other factors, mainly factor X. Because of this fact and that natural Heparin molecules are very heterogeneous, Low Molecular Weight Heparins (LMWHs), that show better pharmacokinetics properties, have been developed in order to achieve a better medical regulation of the anticoagulant therapy.

 

The medical uses and indications of Heparins and LMWH are discussed in detail in this article of the American Heart Association.

 

AHA Scientific Statement

 

Guide to Anticoagulant Therapy: Heparin: a Statement for Healthcare Profession

    

 

 

Answer to Carbohydrate Question C-03


Original Question

 

(b) lactose

 

Lactose is the milk sugar.

 

It is formed by Beta-D galactose and D-glucose. The galactose is linked  to the glucose through a beta 1,4-O-glycosidic linkage.

 

                                   

 This linkage is hydrolyzed by a specific disaccharidase called Lactase, located in the brush border of the epithelial cells of the small intestine.  The glucose and galactose  are absorbed and transported through the portal system to the liver.

 

In spite of the common believe in developed countries, that consume great amounts of dairy products,  most of the humanity are glucose intolerant. Human beings show a decrease in the synthesis of lactase after the 4 years of age. In persons with primary lactose intolerance (the “physiological” one we are talking about), this decrease is usually evident after 6 years of age, in some cases after puberty, and most of the lactose contained in the ingested food remain undigested and continue to the large intestine. where it is fermented by intestinal bacteria, producing gases, organic acids and a decrease in the pH.

 

It can be manifested with cramps, abdominal pain, and other gastrointestinal disorders, that begin 1 to 2 hours after the ingestion of dairy products. This condition is more frequent among Afro American than among white Americans.

 

Another kinds of Lactose intolerance are a congenital form, very rare, and lactose intolerance secondary to intestine diseases, including infections.

 

In fact, primary lactose intolerance can be hardly considered a disease, since there is a genetic programmed decrease in the synthesis of lactase (Humans were not ‘supposed” to drink milk after a few months of life!).  Since around 70 % of the whole population is lactose intolerant, it has been proposed that lactose intolerance should be considered the norm, and that the minority should be considered as a lactase persistent group, that appeared as mutation of the “normal” gen.

 

Anyway, for those persons living in a society where milk is an important componente of diet, to be intolerant to lactose convey certain minor problems.

The “treatment” consist mainly in avoiding lactose containing products (but recall to supplement calcium and other minerals usually associated to dairy products!)

 

More information about this condition can be found in:

 

National Digestive Diseases Information Clearinghouse.

 

Policy of the American Academy of Pediatrics about Lactose Intolerance (2006)

 

Marks, J.W.: Lactose intolerance (Lactase deficiency)

 

Swagerty, D.L.; Walling, A.D.; Klein, R.M.: Lactose Intolerance

 

Guandalini, S.: Lactose Intolerance

 

A: About a baby with Fructose Intolerance (C-02)


Original question 

 

Short answer: (f)

 

Sucrose or table sugar is a disaccharide formed by glucose and fructose. When digested in the small intestine by the action of sucrose, glucose and fructose are released. For the patient, the effect is the same as consuming fructose.

(Usually the baby is asymptomatic during the first weeks of life, until he/she consumes fructose (in fruit juices) or milk sweetened with sucrose)

 

Extended answer:

 

Sucrose is formed by glucose linked by an alpha-1, beta-2 O-glycoside linkage to fructose.  Sucrose is hydrolyzed by the action of Sucrase, a disaccharidase of the epithelial brush border, to free glucose and fructose. These monosaccharides are absorbed in the small intestine and travel to the portal system up to the liver.

 

In the liver, glucose is phosphorylated to Glucose 6(P) by Glucokinase (present in the liver) or the Hexokinase (present in the liver and in most of the tissues). (See Kinases enzymes).

 

Fructose also needs to be phosphorylated to be metabolized. This phosphorylation can happens in a reaction catalyzed by Fructokinase, (yielding fructose 1 phosphate), or in a reaction catalyzed by Hexokinase (the specificity over substrate of Hexokinase is relative, so it can catalyzes the phosphorylation of different hexoses).

 

Fructose 6 (P) + ADP <—————-Fructose  + ATP ————-> Fructose 1 (P) + ADP

                                            Hexokinase                                   Fructokinase

 

The Fructose 6 (P) formed by the action of Hexokinase, can be degraded through the glycolysis pathway

 

Fructose 6 (P) + ATP ———————->fructose 1,6 bis (P) + ADP

                                      Phosphofructokinase

 

 

Fructose 1,6 bis (P) <—- ——–> 3 (P) glyceraldehyde + (P) dihydroxyacetone)

                                          Aldolases

 

…until completion.

 

 

The Fructose 1 (P) formed by the action of Fructokinase, will be split by the Aldolase B, aka fructose 1 (P) aldolase, to two trioses,  (just one of them is a phosphorylated triose):

 

Fructose 1 (P) ——————> Glyceraldehyde + (P) dihydroxiacetone

         

 

Errors in Fructose Metabolism:

 

These errors appears usually as a result of the deficit of the enzymes Fructokinase or Aldolase B

 

Fructokinase: Fructose +ATP  ———–> Fructose 1 (P) + ADP

 

Aldolase B: Fructose 1 (P)——> Glyceraldehyde + (P) dihydroxyacetone

 

If the deficitary enzyme is Fructokinase, the patient will present Benign Fructosuria, a disease that usually does not have consequences for the patient and sometimes is discovered by accident when fructose is detected in urine 

 

If the deficitary enzyme is Aldolase B, the disease that appears is Hereditary Fructose Intolerance, an autosomal  recessive disease with a frequency of 1:20 000 newborns.

The lack of this enzyme can produce deleterious consequences, apparently as a result of the trapping of (P) in form of fructose 1 (P) inside the cell, since fructose 1 (P) can not be hydrolyzed to fructose, or isomerized to fructose 6 (P) or glucose 1 (P), or be phosphorylated to Fructose 1,6 bisphosphate.

 

The increase of Fructose 1 (P) in the cell inhibits the action of fructokinase, causing fructosemia.  More dangerous, the decrease of availability of  phosphate inside the cell – since it is trapped as Fructose 1 (P) – causes a decrease in the formation of ATP.  It produces a decline in gluconeogenesis and consequently the patient presents hypoglycemia. It has been described that an important factor in decreasing gluconeogenesis is that aldolase B has also a similar effect to other Aldolases in the catalysis of the interconversion between phosphotrioses and fructose 1, 6 bisphosphate.

The lack of energy in the hepatocytes affects the synthesis of plasma proteins including coagulation factors and the patient can present hemorrhages.

 

Since the production of ATP is impaired, Adenine accumulates and its conversion to Uric acid increases (recall that in the catabolism of purines adenine and Guanine become Uric Acid), and the patient presents Hyperuricemia.

 

So, this patient can present sever hypoglycemia, vomiting, failure to thrive, jaundice, coagulopathy, hepatomegaly, sever metabolic acidosis and the ultimate consequence in a non treated patient is hepatic failure and death.

 

The long term treatment consists basically in the elimination of Fructose and Sucrose from the diet. Since many fruits are rich in fructose, and sucrose and High Fructose Corn Syrup (HFCS) are used for sweeter in the commercial production of many foods, the patient should follow the indications of an experienced nutritionist.

 

For more information about Hereditary Fructose Intolerance:

 

Roths, K.S.: Fructose 1 (P) Aldolase Deficiency (Fructose Intolerance)

  

  

 A good summary about Fructose metabolism can be found at:

The Medical Biochemistry page:  Metabolism of Major Non-glucose Sugars

 

A: Carbohydrates (C-01)


Answer: (e)

From the chemical point of view, carbohydrates can be classified based on the Polymerization degree (PD) in:

 Monosaccharides: formed by a single molecule; do not release more simple molecules when hydrolyzed, e.g. glucose, galactose, fructose.

 Oligosaccarides: Formed by 2-9 monomers linked by glycosidic bonds (release 2-9 monosaccharides when hydrolyzed).  The most important subgroup of oligosaccharides is the sub group of Disaccharides, formed by just two molecules of monosaccharides. Disaccharides that appear naturally are lactose or milk sugar, (formed by galactose and glucose), and sucrose or table sugar, formed by fructose and glucose. Other important disaccharides, products of the digestion of starch and glycogen, are maltose and isomaltose, formed both of them by two molecules of glucose, but linked in a different way. Cellobiose is a disaccharide formed in animals that can breakdown cellulose.

Polysaccharides are carbohydrates formed by more than 9 monosaccharides linked by glycosidic bonds. When they are formed by the same kind of monosaccharides, they are called homopolysaccharides, like starch, glycogen and cellulose, formed each of them by hundreds of molecules of glucose linked by glycosidic linkages. If the polysaccharides molecules are formed by different kinds of monosaccharides, they are considered heteropolysaccharides. Since Hyaluronic acid is formed by thousands of alternative units of N-acetyl glucosamine and glucuronic acid, it is a heteropolysaccharide.  

Heteropolysaccharides provide extracellular support to very different organisms, from bacteria to humans; together with fibrous proteins, like collagen, elastin and others, heteropolysaccharides are the most important components of the extracellular matrix.  Other important heteropolysaccharides in the extracellular matrix are condroitin sulfates and dermatan sulfates. These heteropolysaccharides are formed by the repetition of a disaccharide unit of an aminosugar and an acid sugar. 

Besides the rol of hyaluronic acid as an important component of extracellular matrix of skin and connective tissue, it also provides viscosity to the synovial fluid, lubricating joints, gives consistency to the vitreous humor and contributes to tensile strength and elasticity in cartilages and tendons.

Hyaluronic acid has received a big attention from the media as an important tool in the anti-aging process.