Glucose

D-glucose (file, molecular weight 180) is an aldohexose, often present as a component of polymeric and other complex structures,

Abbreviations

Co A coenzyme A

Fru D-fructose

Glc D-glucose

Gal D-galactose

GalNAc Gal N-acetylglucosamine

GLUT! glucose transporter 2 (SLC2A1 )

GLUT2 glucose transporter 2 (SLC2A2)

CLUT4 glucose transporter 2 (SLC2A4)

GLUTS glucose transporter 5 (SLC2A5)

Man D-mannose

MCT1 proton/monocarboxylic acid «transporter 1 (SLC16A1 )

M G macroglycogen

PG proglycogen

5GLT1 sodium/glucose Co transporter 1 (SLC5A1 )

SGLT2 sodium/glucose cotransporter 2 (SLC5A2)

Nutritional summary

Function: Glucose (Glc| is used as an energy fuel, for the synthesis of glycoproteins and glycolipids, and as a general precursor for most complex organic compounds in the body. Food sources; Glc is the exclusive constituent of starches, maltodextrin, maltose, isomaltose. and trehalose from plant foods, and glycogen from animal foods. It is combined with other monosaccharides in sucrose and lactose.

Requirements: A healthy diet should provide at least 130gd of carbohydrate, and that means some form of glucose (Food and Nutrition Board, 2002 >.

Hgur* 7.1 D-gluictic

Deficiency; Since Cilc constitutes the bulk of* carbohydrates in adults, the potential (disputed) health risk of low intake is that of low total carbohydrate intake. One obvious risk is due to overall low energy consumption (starvation, anorexia), A different situation concerns the long-term effects of an energy-balanced, low-carbohydrate diet with a correspondingly higher proportion of protein and fats. Concerns with such diets are largely about potential risks of the high protein and or fat intake, not the low carbohydrate content perse. Moderately low blood Glc concentration (hypoglycemia) induces hunger, sweating, tachycardia, dizziness. Severe hypoglycemia may cause loss of consciousness, coma, and organ damage.

Excessive intake: High Glc consumption is most likely to be harmful, if it causes total energy intake to exceed expenditure and body fatness to increase. The consequences of obesity are well known and include higher risk of hypertension, hyperlipidemia. diabetes mellitus, cardiovascular disease, and shortened life span, (ile intake needs to be most carefully balanced in people with diabetes mellitus because of the high potential for damage from high blood and tissue concentrations and the risks related to metabolic decompensation. Simple sugars promote dental canes and tooth loss, especially if dental hygiene is not meticulous.

Endogenous sources

Glc can be synthesized from a wide variety of intermediary metabolites in foods including glycolytic metabolites (glycerol, glyceraIdehydc-3-phosphate. 3-phosphoglycerate. 2,3-diphosphoglycerate, pyruvate, lactate), glucogenic amino acids (especially alanine), tricarboxylic cycle intermediates (oxaloacetate. «-keloglutarate. citrate, tsocitrate, succinate, fumarate, tnalate). fructose (Fru), galactose (Gal), mannose (Man), and other sugars can be convened mainly in the liver and kidney, into Glc.

Cluconeogenesis: The liver and the kidneys have the largest capacity for glucose synthesis from lactate, protein-derived precursors, or glycerol (from triglyceride hydrolysis). The Krebs cycle intermediate oxaloacetate is the common intermediate for Glc synthesis from lactate and amino acids. Glc synthesis from glycerol joins the shared pathway at the level of di hydroxy acetone phosphate. It should be noted that only about 9(1 g of Glc could be generated from I kg of fat.

NAD-dependent L-lactate dehydrogenase (ECl. 1.1.27) oxidizes lactate to pyruvate, which can be converted by the biotin-containing enzyme pyruvate carboxylase (EC64 II) into oxaloacetate. When protein is broken down in muscle and other tissues during times of need the llux of alanine and glutamine to the liver and kidneys increases. Alanine is tTansaminated to pyruvate, which gives rise to oxaloacetate as just described. Five of the Krebs cycle reactions convert the glutamate metabolite a-ketoglutarate into oxaloacetate.

The rate-limiting step then is the phosphorvlating decarboxylation of oxaloacetate by GTP-dependent phosphoenol pyruvate carboxykinasc (PEPCK; EC4.I.I.32). The isoenzymes in cytosol (PEPC'KI) and in mitochondria (PEPCK2) are genetically distinct. The mitochondrial enzyme requires manganese as a cofactor. All but two of the glutarnaie glulaffiine. argmirie, proline, rustidme methionine, valine threonine, obrt-chain tatty acids, cholesterol

Succinate

Keloglutarato

Fumarate phenylalanine, tyrosine

Malaie

COOK H-COH;POj

phosphoenolpy i uvale

(magnesium)

COOH

H-COHjPCb M-C-OM

2 - Phosphoglyce ralo

Pticsphoglyi tratfi mulaso

3-Phosphoglycerale

I _ ATP PrwsohogiyCiraipL'

tmayteiiumi ADP

COHjPO, H-C-OH H-COHjPOj H

1.3' Btsphosphoglycerale -NACH

OiFHiOC-H

O-Gtvceratdehyde-3-phospnale

Photphüenol'

pyruvate caitocxyfeiruuw

COOH

h COOH

asparíais aspflraginn

Oxaloaeetala

(Biolml ^aTP.COj.HjO

COOH

CHj Pyruvate

Lnctnto f Myatoaenau* fv. NAD

^OOH HO-C-H CHj Lactate alanine threonine glycine, senne. cysteine, moihionine

OH Glucose

OH Glucose

OiFHiOC-H

O-Gtvceratdehyde-3-phospnale

OHpPO; Fructose I .d-bisphosphale

Onydroicyacetone phosphate

Figur* 7,2 Gluconeogenesis from endogenous antt exogenous precursors remaining nine sicps arc the same as for Glc breakdown (glycolysis) and arc described in slightly more detail below, Synthesis of the Glc precursor glucose 6-phosphate proceeds \ia reactions catalyzed by phosphopyruvate hydratase (EC4.2.LI I), phosphoglyccrate muíase (F.C5.4.2.I), phosphoglycerate kinase (EC2.7.2.3), glyeeraldchyde 3-phosphate dehydrogenase (EC1.2.1.12). trióse isomera.se (EC5.3.1.1). fructose-bisphosphate aldolase (EC4.L2.I3). fructose 1,6-bisphosphatase (EC3.I.3.I1). and glucose 6-phos-phalc isomerasc (EC5.3.I.9). The key gluconeogenic enzyme fructose 1,6-bisphos-phatasc is inhibited hy fructose 2.6-bisphosphatc. A bifunctional regula-lory protein comprises both the synthetic activity of 6-phosphofructo-2-kinase (EC2.7.1.105) and the opposite activity of fructose-2,6-bisphosphate 2-phosphatase (EC3.1.3.46). At least four different genes code for isoenzymes in liver, heart, brain, and testis. Phosphorylation brings out the (i-phosphofructo-2-kinase activity and abolishes fructose 2,6-bisphosphate 2-phosphatase acliv itv. I ^phosphorylation switches those actix ities again. The glucose 6-phosphatase (EC3.1.3.9, zinc-containing) then completes Glc synthesis.

Glc synthesis from glycerol, which is of particular importance in tasting and starvation, starts with the rate-limiting step of activation by glycerol kinase (EC2.7.1.30). Three genes encode distinct isoenzymes, and alternative splicing generates additional tissue-specific isoforms. The resulting glycerol 3-phosphatc can then be convened into di hydroxy ace tone phosphate by NAD-dependent glycerol 3-phosphate dehydrogenase (LCI.1.1.8) m cytosol or by the FAD-containing glycerol 3-phosphate dehydrogenase (LCI.1.49.5) complex at the mitochondrial membrane, this latter mitochondrial complex transfers reducing equivalents via ubiquinone directly to the electron-transport chain for oxidative phosphorylation. The last five gluconeogenic enzymes described above can then complete Glc synthesis from d i hydroxy acetone phosphate.

Dietary sources

Bioavailable food sources arc monomerie Glc, oligo- and polysaccharides containing only Glc (starches, maltodextnn. maltose, isomaltose, and trehalose in planl foods, and glycogen in animal foods), and the mixed disaccharides lactose (n-D-galaetopy-ranosyH I >4) D-glucose) and sucrose (Glc o-( I >£¡2) fructose). About two-thirds of carbohydrate intake in developed countries is Glc. Glc is combined with other monosaccharides in sucrose and lactose. Amylosc, the t*-( I >4) Glc polymer with a molecular weight of around 60 kD, typically comprises about 20% of starch in plants and is thus consumed with many foods, Amy losc provides X 10% of the energy in a mixed diet in the US. Amylopeciin. a mixed «-(1 >4) and (about 1 25) «-( 1>6) Glc polymer, typically accounts for 80% of the starch in plant foods and provides nearly half of the food energy in the US. Glycogen, a mixture of Glc polymers with mainly <M I >4) and some a-( 1 >6) Glc linkages, is consumed with meats (typically less than 3 mg/g) and liver (about 30 mg g).

While trehalose (Glc «-(I-a) Glc) is ubiquitous in nature, the amounts consumed with common foods are small. A typical serving of mushrooms docs not contain more than 6 g (Arola et a/., 1999). Yeast and other single-cell foods arc other food sources containing more than minima] amounts. Trehalose is also used in some countries as a food additive.

Glc is constituent of many other plant oligo- and polysaccharides, such as cellulose, raffinose, stachyose, and vcrbascose, which are not at all or only partially hydrolyzed by humans, but which have their own distinct effects on the digestive tract, nutritional status and health. Fermentation of such dietary liber by intestinal bacteria can generate methane and hydrogen gas and cause abdominal discomfort and flatulence. In appropriate quantities, however, dietary iibercan reduce cancer and cardiovascular risk and promote normal bowel movements.

Digestion and absorption

Digestion: Alpha-amylase (EC3.2.I.1). both from salivary gland and pancreas, cleaves (I >4) Glc bonds in starch, glycogen and similar poly- and oligosaccharides. Amylase is not well digestible unless cooked, steeped, or thoroughly chewed and wetted. because otherwise the starch granules in foods remain inaccessible for digestion by alpha-amvlase: most cooked amylose is digested and absorbed. Alpha-amylase produces a mixture of maitotriose, maltose, glucose, and oligomers (isomaltose and alpha-limit dextrins) containing both 1,4- and t .6-alpha-D-glucosidic bonds. Maltase-glucoamyla.se (EC3.2.1.20/EC3.2.1.3) hydrolyzes terminal non-reducing 1,4-1 inked glucose residues. The brush border sucraseiisomaltase (EC3.2.1.4X, FC3,2,1.1(1) complex finally hydrolyzes the 1,6-alpha-D-glucosidic bonds of branched oligomers as well as the 1.6-alphii-D-giucosidic bonds in maltose and sucrose.

Lactose and cetlobiose are cleaved by the bmsh border enzyme lactase (EC3.2,1.108), a /3-glucosidase residing mainly on the microvillar tips of the proximal small intestine. Trehalose from mushrooms, yeast, and other single-cell food sources is cleaved by the a-glucosidase trehala.se (EC3.2.I.28). another intestinal brush border enzyme (Murray et at. 2000).

Epidermal growth factor (EOF), which binds to a specilic membrane receptor, exerts control over the expression of the intestinal brush border enzymes, promoting lactase expression upon feeding alter birth. Expression of the other two enzymes is low during infancy, and all three enzymes are repressed in epithelial cells of the distal small intestine and colon (reference values for mucosal dtsaccharidase activi-ties in children can be found in Gupta el til.. I999|. About I in 500 North Americans does not express sue rase. Trehalose deficiency is not common except in Greenland Inuit. 10 15% of whom do not express this enzyme. Nonetheless, some Caucasians suffer mild abdominal discomfort when eating trehalose-rich mushrooms (Arola el ul.. 1999). Intestinal lactase activity usually declines within a few years to a small percentage of infancy values. Persistently high lactase expression is found in people of North European descent and some North African. Arabian, and Asian populations (Harvey et ul.. I99,S). It may be worth mentioning that smoking appears to decrease the adi\ itics of both lactase and trehalase (Kaura et ul„ 2001). The main biological significance of intestinal trehalase may be the inactivation of trehalose-containing compounds of pathogens (e.g., trehaIose-6,ö'-dirnycoEate in Mycoplasma tuberculosis). The energy yield of glucose from digested trehalose may be much less important in comparison.

Capillary lumen

Figure 7.3 Intestinal absorption of glucose

Unabsorbed oligosaccharides in legumes and other vegetables o I ten cause llatulence due to metabolism to methane by intestinal bacteria. Food-grade preparations of alpha-galactosidasc are now commercially available. This enzyme cleaves galactose From raffinose. stachyose, and verbascose and the residual sucrose can then be digested by brush border sucrase.

Absorption: Glc is actively taken up into enterocytes along with two sodium ions and 210 water molecules by the sodium/glucose cotransportcr [SGI.T I, SLC5A11. Uptake of I00g glucose and/or galactose via this transporter thus transfers 25 g sodium ions and 2.1 I water from the lumen into and across the intestinal mucosa. A regulatory protein. RSCIA1, inhibits SGLT1 activity. The facilitate glucose transporter 2 (OI 1 F2. SLC5A2) provides an additional, though minor, entry route (Heltiwcll et <tl., 2000). Most Glc leaves enterocytes again rapidly and is transferred into portal blood via the iacilitative glucose transporter 2 (GLUT2, SLC5A2. Levin. 1994). GLÜT1 ISLC2AI) is also present on the basolateral side of intestinal cells and transports Glc, though the extent of its contribution is uncertain (Pascoe et <;/.. 1996).

Enterocytes use some of the ingested Glc to meet their own energy and growth needs. When the intestinal lumen is empty and intracellular Glc concentration declines, the direction of the llux across the basolateral membrane reverses and Glc moves from capillary blood into the cells.

Transport and cellular uptake

Blood circulation: Glc is dissolved in plasma in its free form. Typical blood concentrations are around 1 g/l and vary normally by 50% or more. Current blood Glc concentration depends on composition of recent meals, time lapsed since recent intakes, and the action of insulin and other hormones.

sucrose, (tmil ttenlrins.

ma II oses lactose, trehalose glucose

StSC

sucrasafisomiiltase 1 mallasegkicoamyl.ise lactase irehalase glucose

Intestinal lumen

StSC

glucose glucose

Intestinal lumen sucrasafisomiiltase 1 mallasegkicoamyl.ise lactase irehalase

Brush border membrane

Enteroeyle

Brush border membrane

Basolateral membrane

Capillai endothel

Several facilitative glucose transporters have been identified that mediate Glc uptake into cells (Shepherd and Kahn. 1999), in some instances also in the reverse direction GLL'TI is the constitutive conduit forGlc entry into most cells. Both GLUT I (SLC2A1) and GLUT41SLC2A4) are present in muscle and adipose tissue. In these tissues GLUT 1 provides lor a constant low influx of Glc. while GLUT4 can accommodate much higher transport rates upon stimulation by insulin. Liver imports Glc via GLUT1, but uses GLUT2 for export in arterial blood (Nordlie etui., 1999).

tile uptake by erythrocytes is mediated at least in part by a chloride/bicarbonate anion exchanger (band 3 of red cell membrane, SLC4A1).

Glucose transporters with more limited tissue distribution include the brain and neuron-specificGLUT3,GLUT6(in brain, leukocytes, adipose tissue). GLUTS (mainly in testicular cells, less in skeletal muscle, heart, small intestine, and brain), GLLIT10 in human heart, lung, brain, liver, skeletal muscle, pancreas, placenta, and kidney (Dawson eta!., 2(H) I). and GLUT 11 in skeletal and heart muscle (Sasaki etal., 2001).

GLUT? is the transporter for glucose out of the endoplasmic reticulum after its dephosphorylation by ghtcose-6-phosphatasc (l.t'3.1.3.9).

Blood brain barrier: GLUT I is the main Glc transporter on both sides of brain capillary barrier epithelial cells. I lowever. the absence of GLUT 1 is not fatal (Boles etal.. 1999), and some Glc may reach the brain through other carriers or channels. The capillary endothelial celts in a limited area of the ventromedial hypothalamus contain GLUT4 in addition to GLUT1. This transporter is thought to link the bloodstream to glucose-sensing neurons (Ngarmukos et al.. 2001), but is not a quantitatively important mechanism of Glc transfer into brain,

Materno-fetal transfer: GLUT1 is the main Glc carrier on both sides of the syntro-phoblast (lllsley. 2000). GLUT3 and additional transporters arc present in placenta, but may be more important for nutriturc of the placenta itself than lor transport to the fetus. Expression of GLUT1 in placenta is limited for the remainder of the pregnancy when maternal blood Glc concentrations are high in the first trimester (Jansson et al.. 2001).

Metabolism

I here are two major metabolic pathways for the utilization ofGlc. The main route is the glycolytic pathway, which proceeds via pyruvate and acetvl-CoA to the Krebs cycle or feeds various synthetic pathways through its intermediate metabolites. Complete oxidation of Glc through this route yields ten NADU, two reduced ubiquinones, and four ATP GTP, If there is not enough oxygen (anaerobic conditions) for NADU utilization, Glc metabolism can be terminated at the level of lactate without a net production of NADH. Glc breakdow n via glycolysis and the Krcbs cycle is the staple of muscles and most other cells. The pentose phosphate cycle (hexosc monophosphate shunt) removes one carbon from Glc with each cycle. This pathway is particularly important for rapidly growing cells, because it generates two NADPII (used for many synthetic pathways) with each cycle and provides ribose for DNA and RNA synthesis. Red blood cells also depend largely on the pentose-phosphate cycle for their fuel metabolism. Glycolysis: The initial phosphorylation of glucose is catalyzed by hexokinase (UK.: EC2.7.1 I) on the outer mitochondrial membrane. Four genes encode I IK which are present at different levels in most tissues. Alternative splicing of 1 IK 4 (glucokinase) produces two liver-specific isoforms and a pancreas-specific one. Alternative promoters respond selectively to insulin (liver iso forms) or glucose (pancreas isoform). The large number of genes and iso forms and their different characteristics is commensurate to the diverse needs in different tissues that can be met by a finely tuned mixture. The product, glucose 6-phosphate, allosterically inhibits all of these forms. An alternative for Glc phosphorylation in the liver is a non-classical function of the zinc-enzyme glucose 6-phosphatase (1X3,1.3.9). 1 his is actually a multicumponcnt complex embedded in the endoplasmic reticulum membrane, which comprises both complex catalytic activities and at least four distinct substrate transport properties. (ilucose 6-phosphatase can use both carbamyl-phospliate and pyrophosphate as phosphate donors (Nordlie et at.. 1090).

The next steps depend on glucose 6-phosphate isomerase (ECS.3.1.9) and phos-phofructokinase-l (EC2.7.1.11). Phosphofruetokinase is activated by the regulatory metabolite fructose 2,6-bisphosphate described above. The resulting fructose 1.6-bisphosphate is eieaved into three-carbon molecules by fructose-bisphosphate aldolase (aldolase: EC4.I.2.13). a key regulatory enzyme for glycolysis that is activated by AMP. A DP. and fructose bisphosphate, and inhibited by the downstream products citrate and A'l P. Three different genes code for the main forms of the latter in muscle (aldolase A), liver (aldolase B), and brain (aldolase C). and additional iso-fonns are generated by alternative splicing.

Triose isomerase (EC5.3.1.1) converts dihydroxyaeetonc phosphate into glycer-aldchyde 3-phosphate in a near-equilibrium reaction. Glyceraldehyde 3-phosphate dehydrogenase/phosphorylating (GAPDH; EC!.2.1.12) for the following, oxidizing reaction exists as muscle and liver forms encoded by different genes. Metabolism to pyruvate continues with phosphoglyccrate kinase (EC2.7.2.3, ubiquitous and testis specific forms), phosphoglyccrate mutase (EC5.4.2.1, three different isoenzymes for muscle, erythrocytes, and other tissues), phosphopyruvatc hydratase (enolase; EC4.2.1.11, magnesium-dependent, multiple isoenzymes encoded by at least four genes), and pyruvate kinase (IC2.7,1.40, multiple isoenzymes due to three genes and alternative splicing).

Anaerobic metabolism: The capacity for ATP production is more likely to be limited by the availability of oxygen for oxidative phosphorylation than by the availability of oxidizable substrate. This is typical for intense short-term exercise. Muscles can metabolize anaerobically, though with a much smaller energy yield than with aerobic metabolism. In this ease pyruvate is reduced to lactate by l.-laetate dehydrogenase (EC1.1.1.27) providing a renewed supply of oxidized NAD for continued glycolysis. Two molecules of ATP and two lactates can be produced anaerobically from one glucose molecule. The protons arising from the lactate production increase intracellular acidity and help to push out excess lactate via the proton monocarhoxylic acid col runs porter 1 (MCTl. SLCI6AI). Lactate is readily taken up by the liver, used for Glc synthesis, and returned into circulation and muscle again as needed. This shuttling of lactate and Glc between muscle and liver (the Con cycle) allows individual muscles to continue working without the burden of metabolic liabilities from previous bouts of exercise. Aerobic metabolism: Pyruvate is transported across the inner mitochondrial membrane by pyruvate translocase, where the enzymes for oxidative metabolism reside. If there is

H-COMjPO)

G»yeeialclehyde-3*P itetty^ogeriAse

D-Glyceraktehyde-3-pbosphale

Dihydioxyscetone phosphate ho 1 /-oh; poi Fructose 1.6-bisphoophale

H-COMjPO)

Dihydioxyscetone phosphate

G»yeeialclehyde-3*P itetty^ogeriAse

D-Glyceraktehyde-3-pbosphale

t mutait

COMfPO. (Pha&ptogtycftraio mutasoi ho 1 /-oh; poi Fructose 1.6-bisphoophale

PtKaenty- ADP ' p Iruero-

PhospfcOtrulA^ 2

IphosohnfytitHJI

Piweiti kifiaseA Y

Fructose 2.6-bi5pho3ptiat?

nctJvale>Ji[ViTP

nctJvale>Ji[ViTP

HO ' f-OH Fructose 6-nhosphate nu. EVI.

HO ' f-OH Fructose 6-nhosphate

0klCOM-fr(llH4ph«t»Se I OH

Glucose 6-phosphato

0klCOM-fr(llH4ph«t»Se I OH

Glucose 6-phosphato

1,3'8t5ptio5cfiogtycerate

Phc^hoglyErraie I birciai? If tmatmosiumi Ik Jtp

COOH 3 -Phosprioglyoo rate

H-COHjPO,

COOH ï-PtiospnoQlyteratu

Phasphopyrwiitft hydrate»

imigntikjmi h

minor painway in erythrocytes

BitDhoephogtyceraiu pntiKphgia&fl

TOftM

h-comjpoj h-cohjpo,

COOH 2.3-Bisphospho-gtycernle minor painway in erythrocytes

H-COH,PO,t COOH

Phosphoenolpy ruvale Pyiuvntc- yA0P

nn»onoslufn)k p

COOH Pyruvate

NADH NAD

Lactate dehydrogenase

COOH Lactate

Figure 7,4 Glycolysis encompasses this initial anaerobic steps of glucose metabolism an adequate supply of oxygen, pyruvate is metabolized by the pyruvate dehydrogenase (EC 1.2.4.11 complex to acetyl-CoA in an NADH-producing reaction. The multisub-unit enzyme complex requires thiamin pyrophosphate (bound to the El subunits), lipoate (bound to the E2 subunits, dihydrolipoamide S-acetyltransferase; EC2.3.I.12), and FAD (bound to the E3 subunits, dihydrolipoamide dehydrogenase; ECI.8.1.4). Phosphorylation of serines in the El subunit by [pyruvate dehydrogenase (lipoamide)] kinase (EC2.7.1.99) inactivates the enzyme complex. The dephosphorylalion by [pyruvate dehydrogenase (1 ipoamide)]-phosphatase (EC3.1.3.43) activates it again. Pentose phosphate pathway This alternative pathway for Glc metabolism is especially important for rapidlv dividing tissues, because it generates ribose 5-phosphate. which is the sugar precursor for DNA and KSA synthesis, and NADPH, which is used by many biosynthetic pathways. NADPH is essential for the reduction of oxidized glutathione in erythrocytes. Reduced NADPII availability (typical with glucose ft-phosphate dehydrogenase deficiency) increases erythrocyte vulnerability to oxidative stress and tendency lor hemolysis, flic ingestion of the pyrtmidine aglvcone divicine with Vicia lava beans (or exposure to their pollen) in individuals with glucose 6-phosphate

COOH

Pyruvate

Pynryale V 1 Pyruvate carboxylase I HAD -A ttplvl't*)flruis<i (biotml / llTWJFAOillpoiiie)

NADH

NAD Malals a

O*aio-acetate

Furniir-iUi

FAD-

Socctnnte

CaA-SH

NAOH

glutaraio ^

Acelyl-CoA

Acelyl-CoA

CoA-SH

Ciirate

CoA-SH

Ciirate isocitrale

Figui* 7.S The .1 urn bit part nfgtucoM* metabolism «arts wirli the Iran iff r of pyruvate into mitochondria dehydrogenase deficiency induces oxidative modification of hemoglobin and may precipitate an acute hemotoxic crisis in them (McMillan el at., 2O0I).

After phosphorylation of (He by hexokinase (EC2.7.1.11 as described above, the successive actions ofglucose (»-phosphate dehydrogenase (ECU.1.49), gluconolac-tonase (EC3.I.1.I7). and 6-phosphogluconate dehydrogenase (EC1.1.1,44) generate the pentose ribnlose 5-phosphate. The first and third reactions generate NADPH.

Transkctolase (EC2.2.1.1) with covalently bound thiamin-pyrophosphate catalyzes two rearrangement reactions. One of these converts two pentose phosphates (X5P and ribose 5-phosphate) into a set of compounds with seven (D-sedohcptulose 7-phosphate) and three (glyceraldehyde 3-phosphate. GAP) carbons. T he other one rearranges X5P plus crythrose 4-phosphate into glyceraldehyde 3-phosphate and fructose 6-phosphatc (FhP) A third possibility is the rearrangement of two X5P molecules into two GAP molecules and one erythrulose (Uykova el at., 2001). The same reactions are catalyzed by transkctolase 2 (Coy el at.. 1^96), with different isoforms in brain and heart generated by alternative splicing. Variants of the transkctolase 2 gene may be implicated tn the pathogenesis of Wernicke Korsakoff-syndrome. Transaldolasc (EC2.2.I.2) complements the transkeiolase-catalyzed rearranging reactions by converting the compounds with seven and three carbons into crythrose 4-phosphate (4 carbons) and F6P (fi carbons). Two additional sleps. catalyzed

ww*» naoph

Gfucoso- dflityUragcnmi« fî Phoiphû

ti-phosptiato qlucoooiactone

Gtucono-

0=C-« f> Phospritigiucontifo tVinyrtro(>iifir.3#r

Ritoutose 5-pbos

Rib u lose &-phoeph{i1ft 3~ef»meriiae t^OH^Oj

0=C-« f> Phospritigiucontifo tVinyrtro(>iifir.3#r

Ritoutose 5-pbos t^OH^Oj

phosphaNT-^

M-COttPO,

fipliospht,. ylucHinle phosphaNT-^

Glucose V D-eiycs'aWsiryde-tlprwifjhaio\ 3-nhospHmii isomerjlm

O'MdonaptuKK«

Eryttimse Traniketolasn

(tppi yv

Figure 7.6 The pentose-phosphate pathway is » major source of NADPH

Eryttimse Traniketolasn

(tppi yv

■ Glycols w Glueoneogongfis

Figure 7.6 The pentose-phosphate pathway is » major source of NADPH

by glucose-6-phosphate i some ruse (EC5.3.E9) and glucose 6-phosphatase (EC3.I.3.9), can then generate glucose. Alternatively, depending on feeding status. 6-phosphofiructokinase {phospbofructo kinase I: EC2.7.1.1I) can initiate utilization via glycolysis.

Storage

Glycogen, a large polymer with predominant <r-( 1 >4} links and a smaller number of a-( I >6) cross-1 inks, is the storage form of Glc. There are two types of glycogen with different metabolic properties. Proglycogen (PG) is characterized by relatively small size (around 400 kDaland is the predominant form in muscle (as much as 55 mg/g dry weight). Macroglycogen (MG) can be as big as 10000000 kDa, Muscle can contain as much as 55 mg PG g dry weight, and 22mg MG/g dry weight (Shearer el <//.. 2000). Liver contains about 80 g glycogen (Petersen et a I., 2001),

Glycogen synthesis from glucose 6-phosphate proceeds in a three-step process catalyzed by phosphoglucomutase (EC5.4.2.2, magnesium-dependent), UTP-glucose-1-phosphate uridylyltransferase (UDP-glucosc pyrophosphorylase; EC'2.7.7.9. two isoenzymes), glycogen synthase (GVS; EC2.4.I.11), and 1,4-tr-glucan branching enzyme (EC2.4,1.18). The isoenzyme GVS I is the main isoenzyme in muscle. GYS2 is mostly expressed in liver. Alpha 1-6 cross-links are added by 1,4-o-glucan branching enzyme (EC2.4.I.I8). Glycogen synthase can only act on an oligosaccharide (primer) with several o-(l>4) linked tile residues attached to glycogenin-l or glycogenin~2 (EC2.4.1.I86), scaffold-like proteins with the ability to catalyze the manganese-dependent transfer of UDP-linked glucosyl residues to itself (autocatalysis). Glycogen synthase and glycogenin constitute an enzyme complex. The glvcogenin concentration in muscle is proportional to the number of glycogen molecules (Shearer el til., 2000). Repletion of spent glycogen stores, for instance after a long-distance run. starts with new primers and newly synthesized glycogenin and may take several days.

Glycogen phosphorvlase (EC2.4.1.1) cleaves Glc residues one at a time off the nonreducing end of glycogen molecules and releases them as glucose I-phosphate. There are at least three distinct glycogen phosphorylases (EC2.4.1.1 > v\ iih tissue-specific expression (liver, muscle, and brain types), all of which require lysine-bound PLP as a eofactor. AMP activates glycogen phosphorvlase. while ATP, ADP, and glucose 6-phosphate inhibit the enzyme.

Branched ends of glycogen arc nol substrates for glycogen phosphors lase and arc clea\ ed by dcbranching enzyme, instead. Two activities reside on the same polypeptide, Oligo-1.4-l,4-glucanotransferase (EC2.4.1.25) moves the 1,4 alpha-linked chain segment to another 4-position in the molecule, which then leaves the chain end with the 1,6-alpha-lmked glucose exposed. The amylo-1,6-glucosidase (EC3.2.1.33) activity can then cleave off the 1.6-alpha-linked Glc. Alternative splicing of the same gene produces several tissue-specific isoforms. The ATP-yield from glycogen oxidation is slightly higher than from free Glc. because the main glycogen cleavage product does not require ATP-dependent phosphorylation.

A cascade of phosphorylating and dephosphorylating enzymes under cAMPmediated hormonal control modulates the activities of glycogen storing and mobilizing enzymes. By convention, the lower-case letter a may be attached to the name of the active forms of these enzymes, and the letter b to the name of the inactivated forms. Thus, the active form is glycogen synthase a. the inactive form glycogen synthase b.

Signaling through this system slows glycogen deposition and accelerates glucose release from glycogen. The binding of hormones to G-protein-linkcd receptors raises the intracellular concentration of eAMP. which in turn activates protein kinase

A (EC2.7.1.37). This enzyme near the top of the signaling cascade contains two regulatory chains and two catalytic chains, which respond to calcium ions and other effectors. Phosphorylation by protein kinase A activates glycogen synthase a kinase (EC2.7.1.37), which in turn inactivates glycogen synthase by phosphorylation. Protein kinase A also activates phosphorylase b kinase kinase (£('2.7.1.37). which in turn activates glycogen phosphorylase. Phosphorylase b kinase kinase is a multi-subunit complex that includes the calcium-binding protein calmodulin and is exquisitely sensitive to the intracellular calcium ion concentration.

The cAMP-induced actions are constantly opposed by corresponding dephospho-rylating enzyme activities. Protein phosphatase 1 (PPI; EC3.U.16) reverses the activation of glycogen synthase, phosphorylase kinase, and glycogen phosphorylase. Inhibitor 2 and glycogen synthetase kinase 3 fold the newly synthesized catalytic subunit of protein phosphatase I and attach it in a targeting subunit. If ii is attached to G(L). the hepatic glycogen-targeting subunit (expressed in both liver and muscle, despite its name), the complex binds to glycogen and modulates the level of active enzymes involved in glycogen metabolism (Munro et (//,. 2002). Glycogen phosphorylase phosphatase (EC3.1.3.17) inactivates the phosphorylase hy removing the four phosphates that link two dimers in the active tctrameric form. Glycpgen-svnthase-D-phosphatase (EC3.1.3.42), on the other hand, removes an inactivating phosphate from glycogen synthase and gets it started.

Excretion

Glc passes into renal primary filtrate owing to its small molecular size and complete water solubility. SGLTI actively transports Glc into tubular epithelium from where it is exported into blood mainly via the high-capacity transporter GLUT2, less via GLUT). As long as the transport capacity of the sodium glucose cotransporter is not exceeded little glucose is lost into urine (in voting healthy individuals losses occur only at bUwid glucose concentrations above 1800tng !: this threshold decreases with age and with renal insufficiency).

Regulation

Glc concentrations in tissues and body lluids are stabilized by many diverse mechanisms, many of which involve the action of specific hormones. Overall homeostasis is maintained through directing the flux of Glc to or from glycogen stores, balancing glycolysis versus glueoneogencsis, and promoting protein caiabolism in times of need. Hormonal regulation' Among the many hormones with some effect on particular tissues Or metabolic sequences a few stand out because of their dominant and overriding actions on Glc disposition. Insulin promotes uptake and oxidation of Glc by tissues and favors storage, particularly in the postprandial phase. Glucagon in response to tow blood Glc concentration increases Glc release from storage and synthesis from precursors. Adrenaline (epinephrine i mobilizes stores and accelerates utilization.

Insulin is produced in the beta cells of pancreatic islet cells and released in a zinc-dependent process together with its companion amylin. The rate of production and release into circulation is related to (ilc-sensing mechanisms in the beta cell, ATP

generation From Glc and eytosolic calcium concentration arc thought to be critical for Glc sensing. A zinc-containing enzyme, insulvsin (EC'3.4.24.56). inactivates insulin irreversibly in many tissues (Ding et ul.. 1992). Insulvsin activity is inhibited by high concentrations of both amy!in and insulin (Mukherjee et ul.. 2000). Insulin binds to specific insulin receptors in muscles, adipocytes, and some other insulin-sensitive tissues and triggers with the receptor kinase activity a signaling cascade. The chromium-containing peptide chromodulin binds to the insulin-activated insulin receptor and optimizes us receptor kinase activity (Vincent. 2000). In response to the insulin-initiated signaling cascade, GLUT4 (SLC2A4) moves to the plasma membrane and increases Glc uptake into insulin-stimulated cells several-fold. Another important insulin effect is increased transcription of hepatic hexokinase 4 (glucokinase), which increases the availability of glucose 6-phosphite, the precursor for glycolysis and glycogen synthesis. Glycolysis is further promoted by increased concentrations of the regulatory metabolite fructose 2,6-bisphosphate (due to induction of6-phosphofructo-2-kinase, EC2.7.1.105, and lower expression of truetose-2.(i-bisphosphatc-2-phosphatase. EC3,1,3.46). At the same time, gtuconeogcnesis is blocked by the inhibiting effect of insulin on phosphoenolpyruvate carboxykinase (EC4.1.1.32) and of fructose 2,6-bisphosphate on fructose 1,6-bisphosphatase (EC3.1.3.11). Insulin promotes glycogenesis through increasing the availability of the glucose 6-phosphalc precursor and decreasing the phosphorylation of enzymes of glycogen metabolism.

The metabolic functions of the insulin companion amylin. which tend to be in opposition to insulin action, are only beginning to be understood. They include promotion of glycogen breakdown and inhibition of glycogen synthesis. Years of excessive amylin secretion may he responsible for the beta cell decline in obesity and insulin resistance. Amylin may promote the deposition of amyloid plaques (Hayden and Tyagi. 2001) and induce beta cell apoptosis (Saali et ul.. 2001).

< tlucagon is produced and secreted by the alpha cells of the pancreas in response to low Glc concentration. Glucagon promotes the release of glucose I-phosphate from glycogen. Adrenaline and the less potently acting noradrenaline stimulate the breakdown of glycogen. These catecholamines also counteract the inhibitory effects of non-glucose fuels on glycolysis.

Appetite and satiety: Low blood Glc concentration induces the feeling of hunger. According to the long-held glucostatic theory, the brain, specific areas such as paraventricular and supraoptic portions of die hypothalamus, integrate input from peripheral and central Glc-responsive sensors and generate appetite sensation (Briski. 2(H)(1).

Amylin. on the other hand, is secreted in response to feeding and increased blood Glc concentration and acts on histamine 111 receptors with a significant satiety-inducing and anorectic effect (Mullet et ul., 2001). A satiety-inducing effect of insulin has also been reported but may be weak or mediated through other effectors (such as amylin). Postprandial metabolism: The inllux of new ly absorbed Glc and other nutrients alters the balance of hormonal and metabolic activ ¡ties. As outlined abo\e. the rate of insulin (and amylin) secretion increases and the rate of glucagon decreases in response to the higher blood Glc concentration. Gluconeogenesis is effectively turned olfand glycolysis is turned on. Glc utilization occurs in preference to fat oxidation. When high carbohydrate intake is coupled with excessive total energy intake, fat (both from diet and from adipose tissue turnover) is preferentially deposited and the carbohydrate is used as the near-exclusive energy fueL In fact, the release of fat from adipose tissue is slowed by the increased action of insulin. This is a reminder that both timing and quantity of carbohydrate ingestion matter.

The deposition of glycogen in liver and muscles increases, though with a considerable time lag. Reconstitution of depleted glycogen stores ¡s likely to take 1 2 days (Shearer et ul., 2000). Carbohydrate loading for one or more days can increase glycogen stores by a third or more (Taruopolsky etal.. 2001). Kepleting glycogen stores by carbohydrate feeding on the evening before elective surgery instead of fasting appears to improve outcome and reduce hospital stays (Nygrcti et ul., 2001).

Exercise: A burst of exertion, as in a short sprint, taxes the capacity of muscle to generate ATP for contraction. Glycolytic breakdown ofGle to lactate is an inefficient mode of fuel utilization, because it generates only two ATP per glucose molecule. The advantages are that glycolysis is fast, because only 11 reactions are needed and that it operates anaerobically (i.e. does not require oxygen) The resulting lactate moves from the muscle ccll into circulation via the monocarboxylate transporter I (MCT1, SLC16A11. Due to the cotransport of protons, increasing acidification of the muscle cells will promote lactate export. Lactate is used in the liver for gluconeogenesis and the resulting Glc returned fo muscle for another potential round through this lactatc-glucose (Cori) cycle.

Another of the many adaptations to muscle exertion is the increased activity of GLl'T-i. which promotes Glc influx from circulation.

Fasting and starvation: When tissue levels of Glc decline and new supplies from food are not forthcoming, the liver and kidneys begin to release Glc into circulation. This Glc comes initially from glycogen stores and from the use of Glc metabolites < lactate, pyruvate, and others) for gluconeogenesis. later from tissue protein.

Function

Fuel energy: Glc. from both dietary and endogenous sources, is the predominant energy source of most tissues. Brain, which normally uses Glc to the near exclusion of other fuels for its energy metabolism (Wahren et at.. 1999), can take up nearly a hundred grams per day, and more upon intense stimulation and use (Dicncl and Hertz. 20011. Muscles rely almost as much on Glc as an energy fuel. Even alter one hour of running and considerable depletion of glycogen reserves more than 70% of the energy is derived from glucose (Arkinstall et til., 20011, Complete oxidation of file requires adequate supplies of thiamin, ribollavin. niacin, pantothenate, ubiquinone, iron, and magnesium, and yields about 4 keal g.

Reducing equivalents: The metabolism v ia glycolysis and Krebs cycle generates 10 reduced NADU per completely oxidized Glc (and 2 reduced ubiquinones directly for oxidative phosphorylation). Metabolism through the pentose phosphate cycle generates 12 reduced N ADPI1. These reducing equivalents are important prerequisites for the synthesis of many compounds and are essential for maintaining the appropriate redox state of ascorbatc, glutathione, and other components of cellular antioxidant defenses. Fructose precursor; Glc can provide for the synthesis of fructose when intakes become low. Fructose ii the precursor for the synthesis of hexosamines. w hich participate in nutrient sensing by modifying signaling proteins (Hanover, 2001 (and arc constituents of glycans (chondroitins. keratans, dermatans, hvaluronan. heparans, and heparin)

in the extracellular matrix of all tissues. Fructose is the predominant energy fuel of spermatozoa.

NADP-dependent aldehyde reductase (aldose reductase: EC1.1.1.21) reduces Glc to sorbitol, which is then converted into fructose by zinc-requiring l-iditol 2-dehydrogenase (EC 1.1.1.14),

UDP-Galactose precursor: Synthesis of cerebrosides, gangliosides, glucosammoglycans (chondroitin sulfate, dennatan sulfates, ketatan sulfates), and numerous glycoproteins as well as lactose for milk production starts with UDP-galactose. UTP-glucose-l-phosphate undylyltransferase (EC2.7.7.9) can link Glc to UDP and UDP-glucose-4'-epimerase (GALE; EC5.1.3.2) then generates I DP-galactose in the next and tinal step. Carbon source: Numerous cudogenously synthesized compounds originate from intermediates of Glc metabolism, in particular dihydroxyacetone phosphate (glycerol in triglycerides, phospholipids, cerebrosides and gangliosides), 3-phosphoglycerate (serine, glycine), pyruvate (alanine), acetyl-CoA (Cholesterol, bile acids, steroid hormones), a-ketoglutarate (glutamate, glutamine. proline, arginine), suceinyl-CoA (heme), and oxaloacetate (aspartate, asparagine).

Hexosamines: Glc is a precursor for glucosamine phosphate synthesis by gluta-mine:lructose-6-phosphate transaminase/isomenzing (GFAT: EC2.6.1.16. contains covalently bound pyridoxal 5'-phosphate). N-acetyl glucosamine and other hexo-samines are formed after the initial rate-limiting GFAT reaction. The addition of O-linked N-acetylglucosamine to proteins can modify their signaling function and give them roles in nutrient sensing (Hanover, 20011. Glc-derived hexosamines are critical constituents of glycans (chondroitins, keratans. dermatans. hyaluronan, heparans, and heparin) in the extracellular matrix of all tissues.

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