Mono- and disaccharides

Transcription

1 Seminar 6

2 Mono- and disaccharides

3 Definition Saccharides (glycids) are polyhydroxyaldehydes, polyhydroxyketones, or substances that give such compounds on hydrolysis 3

4 Classification Basal units Give monosaccharides when hydrolyzed MONOSACCHARIDES polyhydroxyaldehydes polyhydroxyketones OLIGOSACCHARIDES 2 10 basal units POLYSACCHARIDES polymeric GLYCOSES (sugars) water-soluble, sweet taste GLYCANS Don't use the historical misleading term carbohydrates, please. It was primarily derived from the empirical formula C n (H 2 O) n and currently is taken as incorrect, not recommended in the IUPAC nomenclature (even though it can be found in numerous textbooks till now) 4

5 occur widely in the nature, present in all types of cells the major nutrient for heterotrophs energy stores (glycogen, starch) Saccharides components of structural materials (glycosaminoglycans) parts of important molecules (nucleic acids, nucleotides, glycoproteins, glycolipids) signalling function (recognition of molecules and cells, antigenic determinants) 5

6 are simple sugars that cannot be hydrolyzed to simpler compounds tetroses pentoses hexoses heptoses Monosaccharides Aldoses Ketoses Simple derivatives (polyhydroxyaldehydes) (polyhydroxyketones) are further classified according to the deoxysugars number of carbon atoms in their chains: amino sugars glyceraldehyde (a triose) uronic acids dihydroxyacetone tetruloses pentuloses hexuloses heptuloses modified monosaccharides other simple derivatives alditols glyconic acids glycaric acids Trivial names for stereoisomers glucose (i.e. D-glucose) fructose (i.e. D-fructose) L-idose L-xylulose, etc. Systematic names (not used in biochemistry) comprise trivial prefixes according to the configuration: e.g., for glucose D-gluco-hexose, for fructose D-arabino-hexulose 6

7 Stereoisomerism in monosaccharides Secondary alcoholic groups CH-OH in monosaccharides are stereogenic centres. Monosaccharides are chiral compounds and, therefore, most of them are optically active Stereogenic centres are mostly carbon atoms that bind four different groups; those atoms are often called "asymmetric" carbon atoms If there are more (n) stereogenic centres in the given molecule, the maximal number of stereoisomers equals 2 n Each of those stereoisomers has its enantiomer (mirror image) so that there will be a maximum of 2 n / 2 pairs of enantiomers Stereoisomers that differ from the particular pair of enantiomers are diastereomers of the pair In contrast to enantiomers, diastereomers differ in their properties and exhibit different values of specific optical rotation 7

8 Fischer projections formulas are structural formulas that describe the configuration of particular stereoisomers When a plane formula of an aldose with four stereogenic centres is drawn anywhere it is necessary to see a spatial arrangement of the atoms and assess it according to the established rules: an hexose the least number carbon (carbonyl group in monosaccharides) is drawn upwards the carbon chain is directed downwards then on each stereogenic centre the bonds to neighbouring carbon atoms written above and below are projected from beneath the plane of drawing (the carbons are behind the plane) the horizontal bonds written to the left and right are projected from above the plane of drawing, they are in front of plane 8

9 Without changing the configuration, Fischer formulas may only be turned 180 in the plane of the paper. Assigning configurations D- and L- (from Latin dexter and laevus) at stereogenic centres is carried out by comparison with the configurations of D- and L-glyceraldehyde (see optical isomerism, lecture 5-A). Monosaccharides are classified as D- or L-sugars according to configuration at the configurational carbon atom the chiral carbon with the highest numerical locant (i.e. the assymetric carbon farthest from the aldehyde or ketone group): D-aldose L-ketose 9

10 What is that? Enantiomers, diatereomers, epimers L-Glucose is enantiomer of D-glucose because of having opposite configuration at all centres of chirality. Are there, among the following sugars, some diastereomers of D-allose that are not epimers of it? Is there any epimer of D-mannose? D-allose D-glucose L-glucose D-mannose 10

11 Configurations at stereogenic centres other than configurational carbon cannot be deduced from the assignment to D- or L-sugars. Unfortunately, configurations of several most important monosaccharides have to be remembered Stereogenic centres in molecules of monosaccharides are the cause of their optical activity Solutions of mono- and oligosaccharides turn the plane of polarized light Optical activity is measured by using polarimeters and usually expressed as specific optical rotation [α] D 20. Dextrorotatory substances are marked (+), laevorotatory ( ) There is no obvious relation between the assignment D- or L- and either the values or direction of optical activity 11

12 D- Aldoses stereochemical relations D-glyceraldehyde D-erythrose D-threose D-ribose D-arabinose D-xylose D-lyxose D-allose D-altrose D-glucose D-mannose D-gulose D-idose D-galactose D-talose 12

13 D- Aldoses optical rotation (+) dextrorotatory ( ) laevorotatory D-(+)-glyceraldehyde D-( )-erythrose D-( )-threose D-( )-ribose D-( )- arabinose D-(+)-xylose D-( )-lyxose D-(+)-glucose D-(+)-mannose D-(+)-galactose D-(+)-allose D-(+)-altrose D-( )-gulose D-( )-idose D-(+)-talose 13

14 D- Ketoses stereochemical relations dihydroxyacetone D-( )-erythrulose D-( )-ribulose D-(+)-xylulose D-( )-fructose D-(+)-psicose D-(+)-sorbose D-(+)-tagatose 14

15 Cyclic forms of monosaccharides Monosaccharides (polyhydroxyaldehydes and polyhydroxyketones) undergo rapid and reversible intramolecular addition of some properly located alcoholic group to carbonyl group so that they form cyclic hemiacetals Monosaccharides exist mainly in cyclic hemiacetal forms, in solutions the acyclic aldehydo- or keto-forms are in minority. al-d-glucose a hemiacetal, pyranose ring 15

16 In this way, six- or five-membered rings can originate. In pyranoses, there is the tetrahydropyran (oxane) ring, tetrahydrofuran (oxolane) ring in furanoses. In the acyclic forms, carbon of the carbonyl group is achiral, but this carbon becomes chiral in the cyclic forms. Two configurations are possible on this new stereogenic centre called anomeric (or hemiacetal) carbon so that the cyclization results in two epimers called α or β anomers: α-anomer β-anomer 16

17 The hemiacetal hydroxyl group is called the anomeric hydroxyl the configuration of - anomer is the same as the configuration at anomeric reference carbon in monosaccharides comprising five and six carbon atoms (pentoses and hexoses, pentuloses and hexuloses), the anomeric reference carbon is the configurational carbon α-anomers in Fischer formulas of D-sugars have the anomeric hydroxyl localized on the right the configuration of β-anomers is opposite, the anomeric hydroxyl is written on the left in Fischer formulas of D-sugars 17

18 In solutions, all five forms of a hexose or hexulose occur; the cyclic forms usually prevail E.g., in the aqueous solution of D-glucose equilibrated at 20 C, there is approximately 62 % -D-glucopyranose, 36 % -D-glucopyranose, < 0.5 % -D-glucofuranose, < 0.5 % -D-glucofuranose, and < % aldehydo-d-glucose. If D-glucose is crystallized from methanol or water, the pure α-d-glucopyranose is obtained; crystallization of D-glucose from acetic acid or pyridine gives the β-d-glucopyranose. These pure forms exhibit mutarotation, when dissolved: α-d-glucopyranose just after dissolution exhibits [α] D 20 = + 112, the β-form [α] D 20 = After certain time period, [α] D 20 of both solutions will settle at the same equilibrium value of This change can be explained by opening of the cyclic homicidal to the acyclic aldehyde. which can then recyclize to give either the α or the β form till an equilibrium is established. 18

19 Don't confuse: Enantiomers (optical antipodes) stereoisomers that are not superimposable mirror images of each other, the configurations at all stereogenic centres are exactly opposite. All their chemical and physical properties are the same but the direction of optical rotation. Diastereomers stereoisomers that are not enantiomers of one another. They have different physical properties (melting points, solubility, different specific optical rotations) so that they are viewed as different chemical substances. Epimers are those diastereomers that differ in configuration at only one centre of chirality, they have the same configuration at all stereogenic centres except one. Anomers (α or β) represent a special kind of epimers, they have identical configuration at every stereogenic centre but they differ only in configuration at anomeric carbon atom. 19

20 Haworth projection formulas the rings are projected as planes perpendicular to the plane of drawing, carbon atoms of the rings and hydrogens attached to them are not shown, each of the formulas can be drawn in four positions, one of which is taken as the basal position (used preferentially) α-d-glucopyranose Fischer projection Haworth projetion (the usual basal position) 20

21 Rules for drawing Haworth projection formulas (the basal position): The anomeric carbon atom (C-1, in ketoses C-2) on the right; oxygen atom in the ring is "behind", i.e. carbon atoms are numbered in the clockwise sense; Then, hydroxyl groups and hydrogens on the right in the Fischer projection are down in the Haworth projection (below the plane of the ring), and conversely, hydroxyls on the left in Fischer formulas means up in Haworth formulas; the terminal CH 2 OH group is up for D-sugars (for L-sugars, it is down). C C C C 1 OH 1 OH 2 OH pyranose ring of a hexose furanose ring of a hexose furanose ring of a hexulose 21

22 α-d-glucopyranose can be drawn in four different positions: The basal position: Position obtained by rotation of the "model" round a vertical axis O Positions obtained by tilting the model over: because the numbering of carbons is then counter-clockwise, the groups on the right in Fischer projection as well as the terminal CH 2 OH are up in those Haworth formulas: or 22

23 Four different cyclic forms of glucose (all are depicted in the basal position) al-d-glucose β-d-glucopyranose α-d-glucopyranose β-d-glucofuranose α-d-glucofuranose 23

24 Four different cyclic fructose forms (all are depicted in the basal position) keto-d-fructose β-d-fructofuranose α-d-fructofuranose β-d-fructopyranose α-d-fructopyranose 24

25 Conformation of pyranoses The chair conformation of six-membered rings is more stable than the boat one. From two possible chair conformations, that one prevails, in which most of the voluminous groups (-OH, -CH 2 OH) are attached in equatorial positions. E.g., conformations of β-d-glucopyranose: steric hindrance boat conformation 4 C 1 -chair conformation 1 C 4 -chair conformation α-d-glucopyranose- 4 C 1 β-d-glucopyranose- 4 C 1 25

26 Physical properties of simple sugars Multiple hydrophilic alcoholic groups in the molecules, therefore non-electrolytes generally crystalline solids with a high melting temperature very soluble in water most of them exhibit optical activity More or less sweet to the taste Sweetness related to the sweetness of sucrose Saccharides Synthetic sweeteners Sucrose 1.0 Glucitol 0.5 Glucose 0.5 Aspartame a) 180 Fructose 1.5 Saccharin b) 550 Lactose 0.3 Neotame c) 8000 a) methyl ester of the dipeptide aspartyl-phenylalanine b) 2-sulfobenzoic imide c) methyl ester of the dipeptide N-(3,3-dimethylbutyl)aspartyl-phenylalanine 26

27 Common reactions of monosaccharides Carbonyl group is responsible for formation of cyclic forms (intramolecular hemiacetals) the hemiacetal (anomeric) hydroxyl may form acetals called glycosides in reactions with alcohols, phenols, thiols, and amines gives sugar alcohols called alditols by reduction (hydrogenation), aldoses can give glyconic acids by oxidation can take part in the aldol condensation that gives rise to -C C- bond. 27

28 Common reactions of monosaccharides Alcoholic groups give ethers by alkylation, form esters in reactions with acids, primary alcoholic group gives glycuronic acid by oxidation, as polyhydric alcohols, monosaccharides undergo oxidative cleavage. 28

29 Other reactions of saccharides monosaccharides are unstable in alkaline solutions, at ph < 9 may form epimers or other isomers, at ph > 9, when heated, they are cleaved in strongly acidic solutions, pentoses and hexoses are dehydrated to derivatives of furan-2-carbaldehyde (2-furaldehyde); in oligosaccharides and polysaccharides, acids cleave glycosidic bonds by hydrolysis all monosaccharides and some of oligosaccharides are reducing sugars; they are easily oxidized, e.g. in Benedict s test, if they have a free aldehyde group or an hemiacetal hydroxyl (see Practicals) 29

30 Reduction of monosaccharides results in formation of alditols (sugar alcohols): D-glucose D-glucitol D-fructose D-mannitol 30

31 Oxidation of monosaccharides a glyconic acid (aldonic) an aldose a glycaric acid (aldaric) a glycuronic acid (uronic acid) 31

32 Important monosaccharides D-Glucose (dextrose, grape sugar) is in the form of polysaccharides (cellulose, starch, glycogen) the most abundant sugar in the nature 32

33 D-Galactose is the 4-epimer of glucose. It occurs as component of lactose in milk and in dairy products (hydrolysis of lactose in the gut yields glucose and galactose), and as a component of glycoproteins and glycolipids. D-Galactose β-d-galactopyranose 33

34 D-Ribose is the most important pentose a component of nucleotides and nucleic acids: β-d-ribofuranose β-d-ribopyranose 34

35 D-Fructose (laevulose, fruit sugar) is the most common ketose, present in many different fruits and in honey. A considerable quantities of this sugar are ingested chiefly in the form of sucrose D-fructose β-d-fructofuranose β-d-fructopyranose 35

36 Simple derivatives of monosaccharides Esters with phosphoric acid are intermediates in metabolism of saccharides, constituents of nucleotides, etc- glucose 6-phosphate glucose 1-phosphate base fructose 1,6-bisphosphate nucleoside 5 -phosphate 36

37 Deoxysugars Deoxyribose (2-deoxy-β-D-ribose) is a constituent of nucleotides in DNA L-Fucose (6-deoxy-L-galactose) is, e.g., present in some determinants of blood group antigens, and in numerous glycoproteins 37

38 Amino sugars are important constituents of saccharidic components of glycoproteins and glycosaminoglycans. The basic amino groups NH 2 of amino sugars are nearly always "neutralized by acetylation in the reaction with acetyl-coenzyme A, so that they exist as N-acetylhexosamines. Unlike amines, amides (acetamido groups) are not basic. CH 2 OH C=O HO CH CH OH CH OH CH 2 OH fructose CH=O CH NH 2 HO CH CH OH CH OH CH 2 OH glucosamine (2-amino-2-deoxy-D-glucose) α-d-glucosamine N-acetylglucosamine N-acetylgalactosamine 38

39 Neuraminic acid is an aminononulose (ketone) as well as glyconic acid, 5-amino-3,5-dideoxynonulosonic acid. It originates in the cells by condensation of pyruvate (in the form of phosphoenolpyruvate) with mannosamine: C=O CH 3 HC=O NH 2 CH HO CH pyruvate COOH HC OH HC OH CH 2 OH mannosamine COOH C=O C H 2 HC OH NH 2 CH HO CH HC OH HC OH CH 2 OH neuraminic acid 39

40 Sialic acids is the group name used for various acylated derivatives of neuraminic acid (N- as well as O-acylated) The most common sialic acid is N-acetylneuraminic acid: neuraminic acid sialic acid N-acetylneuraminic acid Sialic acids are constituents of saccharidic components of glycolipids (gangliosides) and glycoproteins 40

41 Glycuronic acids (uronic acids) D-Glucuronic acid originates in human bodies by oxidation of activated glucose (UDP-glucose). It is a component of glycosaminoglycans in connective tissue and some hydrophobic waste products and xenobiotics are eliminated from the body after conjugation with glucuronic acid. D-glucuronic acid D-galacturonic acid D-Galacturonic and L-iduronic acids occur also as components of numerous glycoproteins and proteoglycans. 41

42 Glyconic acids are polyhydroxycarboxylic acids obtained by oxidation of the aldehyde group of aldoses. E.g., glucose gives gluconic acid: 1/2 O 2 D-gluconic acid gluconate In the body, glucose (activated to glucose 6-phosphate) is dehydrogenated in the enzyme-catalyzed reaction to phosphogluconolactone that gives phosphogluconate by hydrolysis. This reaction (the initial reaction of the pentose phosphate pathway) is very important as a source of NADPH. P NADP + NADPH+H + P P glucose 6-phosphate D-glucono-1,5-lactone D-glucono-1,4-lactone 42

43 L- Ascorbic acid (2,3-dehydro-L-gulono-1,4-lactone, vitamin C) is derived from L-gulonic acid. It is a weak diprotic acid (endiols are acidic), which has outstanding reducing properties. It can be very easily oxidized, to dehydroascorbic acid, namely in alkaline solutions. Ascorbate acts as a cofactor of several enzymes and a powerful hydrophilic antioxidant. It is essential only for humans, primates, and guinea pigs. Deducing of the structure of ascorbate: 2H 2H L-gulose L-gulonic acid L-gulono-1,4-lactone L-ascorbic acid dehydro-l-ascorbic acid 43

44 Glycosides Cyclic forms of saccharides, relatively unstable hemiacetals, can react with alcohols or phenols to form acetals called glycosides. The hemiacetal hydroxyl group (the anomeric hydroxyl) on the anomeric carbon is replaced by an alkoxy (or aryloxy) group. The bond between the anomeric carbon and the alkoxy group is called the glycosidic bond or O-glycosidic bond, at need. Similarly, glycosidic bonds can be formed by reaction with an amino group, N- glycosidic bonds, or with a sulfanyl group, S-glycosidic bonds Example: glycosidic bond + HO-CH 3 H 2 O α-d-glucopyranose methanol methyl-α-d-glucopyranoside 44

45 Names of glycosides are formed in two different ways. Both kinds of names have to denominate the type of glycosidic bond (α or β). Formation of a glycosidic bond disables anomerization on the anomeric carbon atom that takes part in the glycosidic bond. 1 The name of only the alkyl or aryl is used instead of the name of alkoxy or aryloxy group that replaces anomeric hydroxyl and the suffix e in the following name of the saccharide is changed to ide. Examples: phenyl-α-d-glucopyranoside, propyl-β-d-fructofuranoside. 2 The name of a respective glycosyl is placed before the name of a compound that gives its alcoholic or phenolic hydroxyl, sulfanyl or amino group,. The group that remains after taking off the anomeric hydroxyl is called glycosyl. E.g., α-d-glucopyranosyl (α-glucosyl): Examples: 9-β-D-ribosyl-adenine, O-β-D-galactosyl-5-hydroxylysine. 45

46 Classification of glycosides Hologlycosides are glycosides that give only monosaccharides by hydrolysis - O-glycosidic bonds bind various number of monosaccharides. Oligosaccharides consist of as much as approximately ten monosaccharides; the most common are disaccharides. Polysaccharides comprise up to many thousands monosaccharide units bound through glycosidic bonds. Those units are either of the same kind in homopolysaccharides, or may be of several kinds in heteropolysaccharides. Heteroglycosides in which nonsaccharidic components called aglycones or genins are linked to saccharides through glycosidic bond This bond may be not only O-glycosidic but also N-glycosidic or S-glycosidic. 46

47 Disaccharides are the most common disaccharides, in which two monosaccharides are linked through glycosidic bond. There are two types of these sugars reducing and nonreducing disaccharides. Reducing disaccharides are formed by a reaction between the anomeric hydroxyl of one monosaccharide and a alcoholic hydroxyl group of another, so that this second monosaccharide unit retains its anomeric hydroxyl, the reducing properties, it may anomerize and exhibits mutarotation. Their names take the form D-glycosyl-D-glycose (with specification of the glycoside bond). Nonreducing disaccharides Both anomeric hydroxyl are linked in the glycosidic bond (called anomeric bond), neither unit has its anomeric hydroxyl. They cannot reduce Benedict's reagent and cannot mutarotate. Their names have the form D-glycosyl-D-glycoside. 47

48 Reducing disaccharides Maltose (4-O- -D-glucopyranosyl-D-glucopyranose, malt sugar) is obtained by the partial hydrolysis of starch or glycogen. Two molecules of glucose are linked through (1 4) glycosidic bond, further hydrolysis results in only glucose. Maltose is laevorotatory. Crystalline maltose is the β-anomer and exhibits mutarotation, when dissolved.. β-maltose 4-O- -D-glucopyranosyl-β-D-glucopyranose 48

49 Isomaltose may be viewed as a constituent of glycogen and amylopectin placed at branching points of the long chains connected through α(1 4) bonds. (1 6) glycosidic bond 6 α-isomaltose 6-O- -D-glucopyranosyl-α-D-glucopyranose 49

50 Cellobiose (4-O-β-D-glucopyranosyl-D-glucopyranose) is obtained by the partial hydrolysis of cellulose. Two molecules of glucose are linked through β(1 4) glycosidic bond, further hydrolysis results in only glucose. Cellobiose is dextrorotatory. 4 β-cellobiose 4-O- -D-glucopyranosyl-β-D-glucopyranose 50

51 Lactose (4-O-β-D-galactopyranosyl-D-glucopyranose, milk sugar) is the major sugar in human and cow's milk. Equimolar mixture of glucose and galactose is obtained by hydrolysis of β(1 4) glycosidic bonds. Lactose is dextrorotatory. Crystalline lactose is the α-anomer and exhibits mutarotation, when dissolved. β 4 α-lactose 4-O- -D-galactopyranosyl-α-D-glucopyranose 51

52 Nonreducing disaccharides Sucrose (saccharose) ( -D-fructofuranosyl- -D-glucopyranoside, beet or cane sugar) is the ordinary table sugar. Both hemiacetal hydroxyl groups of fructose and glucose are involved in the (β2 α1) glycosidic bond (called occasionally anomeric glycosidic bond). 1 2 α β sucrose -D-fructofuranosyl- -D-glucopyranoside Sucrose is dextrorotatory and cannot mutarotate. When hydrolyzed, an equimolar mixture of glucose and fructose results that is laevorotatory (invert sugar), because the anomers of fructose are stronger levorotatory than the dextrorotatory anomers of glucose. 52

53 Real conformation of a sucrose molecule obtained X-ray structural analysis of crystalline table sugar 53

54 Pentose phosphate pathway

55 HMP pathway HMP pathway or HMP shunt is also called as pentose phosphate pathway or phosphogluconate pathway this is an alternative pathway to glycolysis and TCA cycle for the oxidation of glucose HMP shunt is more anabolic in nature

56 HMP pathway it is concerned with the biosynthesis of NADPH and pentoses about 10% of glucose enters this pathway/day the liver and RBC metabolize about 30% of glucose by this pathway

57 Location of the pathway the enzymes are located in the cytosol the tissues such as liver, adipose tissue, adrenal gland, erythrocytes, testes and lactating mammary gland, are highly active in HMP shunt most of these tissues are involved in biosynthesis of fatty acids and steroids which are dependent on the supply of NADPH

58 HMP shunt unique multifunctional pathway it starts with glucose-6-phosphate no ATP is directly utilized or produced in HMP shunt it is multifunctional pathway, several interconvertible substances are produced, which are proceed in different directions in the metabolic reactions

59 Reactions of the pathway Reactions of the pathway can be divided into two phases Oxidative phase Step:1 glucose-6-phosphate is oxidised by NADP-dependent glucose-6- phosphate dehydrogenase (G6PD), 6-phosphogluconolactone is formed NADPH is formed in this reaction and this is a rate limiting step

60 Reactions of the pathway Step:2 6-phosphogluconolactone is hydrolysed by glucono lactone hydrolase to form 6-phosphogluconate Step: 3 the next reaction involving the synthesis of NADPH and is catalysed by 6-phosphogluconate dehydrogenase to produce 3-keto-6 phosphogluconate which then undergoes decarboxylation to give ribulose 5-phosphate

61 Reactions of the pathway Non-oxidative phase Step: 4 the ribulose-5-phosphate is then isomerized to ribose- 5-phosphate or epimerised to xylulose-5-phosphate Step: 5 (Transketolase reaction) transketolase is a thiamine pyrophosphate (TPP) dependent enzyme

62 Transketolase it transfers two-carbon unit from xylulose-5-phosphate to ribose-5-phosphate to form a 7-carbon sugar, sedoheptulose-7-phosphate and glyceraldehyde-3- phosphate

63 Reactions of the pathway Step: 6 (Transaldolase reaction) transaldolase brings about the transfer of a 3-carbon fragment from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate to give fructose-6- phosphate and 4-carbon erythrose-4-phosphate

64 Reactions of the pathway Step: 7 (Second transketolase Reaction) in another transketolase reaction a 2-carbon unit is transferred from xylulose-5-phosphate to erythrose 4- phosphate to form fructose-6-phosphate and glyceraldehyde-3-phosphate fructose-6-phosphate and glyceraldehyde-3-phosphate are further metabolized by glycolysis & TCA cycle

65

66 Oxidative phase Glucose 6-phosphate NADP+ NADPH + H + Mg +2 Glucose 6Pdehydrogenase 6-phosphoglucanolactone 6-phosphogluconate Glucanolactone hydrolase NADP+ Mg +2 CO 2, NADPH + H + Phosphogluconate dehydrogenase Ribulose 5-phosphate

67 Non-oxidative phase Xylulose 5-phosphate Ribulose 5-phosphate Fructose 6- Phosphate Xylulose 5-phosphate Ribose 5-phosphate Transketolase, TPP Transketolase, TPP Sedoheptolose 7- phosphate Glyceraldehyde 3- phosphate Glyceraldehyde 3- phosphate Transaldolase Fructose 6- Phosphate Erythrose 4- Phosphate Fructose 6- Phosphate

68

69 Significance of HMP Shunt HMP shunt is unique in generating two important products: pentoses and NADPH Importance of pentoses: in HMP shunt, hexoses are converted into pentoses, the most important being ribose-5-phosphate this pentose or its derivatives are useful for the synthesis of nucleic acids (DNA & RNA), many nucleotides such as ATP, NAD +, FAD & CoA

70 Significance of HMP Shunt Importance of NADPH: NADPH is required for the bio synthesis of fatty acids and steroids NADPH is used in the synthesis of certain amino acids involving the enzyme glutamate dehydrogenase free radical Scavenging the free radicals (super oxide, hydrogen peroxide) are continuously produced in all cells

71 Significance of HMP Shunt Free radical Scavenging the free radicals (super oxide, hydrogen peroxide) are continuously produced in all cells these will destroy DNA, proteins, fatty acids and all biomolecules and in turn cells are destroyed the free radicals are inactivated by the enzyme systems containing SOD, POD and glutathione reductase Reduced GSH is regenerated with the help of NADH

72 Significance of HMP Shunt Erythrocyte membrane integrity NADPH is required by the RBC to keep the glutathione in the reduced state in turn, reduced glutathione will detoxify the peroxides and free radicals formed within the RBC NADPH, glutathione & glutathione reductase together will preserve the intigrity of RBC membrane

73 Significance of HMP Shunt Prevention of methemoglobinemia NADPH is also required to keep the iron of hemoglobin in the reduced (ferrous) state and to prevent the accumulation of methemoglobin methemoglobin cannot carry the oxygen

74 Significance of HMP Shunt Detoxification of drugs most of the drugs and other foreign substances are detoxified by the liver microsomal P450 enzymes, with the help of NADPH Lens of eye maximum concentration of NADPH is seen in lens of eye NADPH is required for preserving the transparency of lens

75 Significance of HMP Shunt Macrophage bactericidal activity NADPH is required for the production of reactive oxygen species (ROS) by macrophases to kill bacteria Availability of Ribose ribose and deoxyribose are required for DNA and RNA synthesis

76 Significance of HMP Shunt ribose is also necessary for nucleotide co-enzymes reversal of non-oxidative phase is present in all tissues, by which ribose could be made available ATP ATP is neither utilized nor produced by the HMP shunt cells do not use the shunt pathway for energy production

77 Regulation of HMP Shunt the entry of glucose-6-phosphate into the pentose phosphate pathway is controlled by the cellular concentration of NADPH NADPH is a strong inhibitor of glucose-6-phosphate dehydrogenase (G6PD) NADPH is used in various pathways, inhibition is relieved and the enzyme is accelerated to produce more NADPH

78 Regulation of HMP Shunt the synthesis of glucose-6-phosphate dehydrogenase is induced by the increased insulin/glucagon ratio after a high carbohydrate meal

79 Glucose-6-phosphate dehydrogenase deficiency (G6PD) it is an inherited sex-linked trait it is more severe in RBC decreased activity of G6PD impairs the synthesis of NADPH in RBC this results in the accumulation of methemoglobin and peroxides in erythrocytes leading to hemolysis