gluco starch lipid synthesis

Overheads for Section 3 A brief interlude on digestion Overview of digestion More digestion facts Overview of biochemical pathways Chapter 14 Glycolysis The glycolytic pathway Another v

Overheads for Section 3

A brief interlude on digestion

Overview of digestion

More digestion facts

Overview of biochemical pathways

Chapter 14

Glycolysis

The glycolytic pathway

Another view of the glycolytic pathway

The test version

Details of one individual reaction step

Enzyme compexes facilitate channeling

The energy landscape of glycolysis

The "metabolic" regulation of glycolysis

Two other bypasses

Gluconeogenesis and mitochondria

The Pentose pathway

Alternative views of the Pentose pathway

Chapter 15

The role of glycogen phosphorylase

The mechanism of GP

The breakdown of glycogen

Transporting glucose to the blood

Activating glucose for synthesis

The synthesis of glycogen

Regulation of GP

The alloseric regulation of PFK

Coordinate regulation of PFK and FBP

The role of F2,6BP

Pyruvate Kinase is regulated

Coordinate regulation of glycolysis/gluconeogenesis Hormonal influence on glucose metabolism

Glycogen synthase is regulated by hormones

Synthesis and hydrolysis of F2,6BP

More on PFK2 and FBPase2

Summary of hormone regulation in the liver

Chapter 16

The TCA cycle in metabolism

Some headlines in C-C chemistry

C C bond reactions in biochemistry

Enolate stabilization in carbon-carbon bonds

TPP modifies α-keto acids for decarboxylation

Steps of the TCA cycle

The test version

Mech of citrate synthase, more C-C chem The energy profile of TCA

Regulation of the TCA cycle

Depletion of TCA intermediates

The anaplerotic reactions

Chemistry of pryuvate carboxylase

The aerobic metabolism of glucose

The glyoxylate cycle

The glyoxylate shunt

Linking TCA and glyoxylate shunt

Lipids released from adipocytes

Post lipase chemistry

Carnitine mediated transport

Beta-oxidation: the big picture

Beta-oxidation:detailed chemistry

Energy production from ox of palmitoyl CoA β-ox of oleic acid

β-ox of poly unsaturates

β-ox of odd numbered fatty acids

Peroxisomes in eucaryotes

Branched lipids can undergo α Oxidation Synthesis of ketone bodies

Use of ketone bodies

Ketone bodies in metabolism

The Redox Table

Redox example from complex 1

Proton Motive Force

The Chemiosmotic theory

Some experimental support

Motive force of NADH in the ETS

The energetics of ATP synthesis

The mechanism of ATP synthase

ATP synthase in action

A movie of the synthase from the side

A movie of the synthase from the top

A movie of the whole synthesis model

Nucleotide translocation

The glycerol phosphate shuttle for cytoplasmic NADH

The malate-aspartate shuttle

Thermogenin and heat

Photosynthesis

Our Friend, Mr Sun

Photo pigments

Harvesting the light spectrum

Light harvesting machinery

Exciton capture

Bacterial photosystems are simple

Structure of a bacterial photosystem

The "Z" scheme of higher plants

Membrane organization of PS

Creating a proton gradient

The Mn water splitter

The energetics of photosynthesis

Comparison of mitochondrion and chloroplasts

The simplest light pump

Photosynthesis - Dark Reacton Headlines

Rubisco fixes CO2

The Calvin Cycle

Giant Catabolic Roundup

catabolic roundup

The Cori Cycle

Animals can synthesize glucose 6-phosphate via gluconeogenesis just like all other species However, unlike most species, animals can convert glucose 6-phosphate to glucose, which is secreted into the circulatory system Mammals, in particular, have a sophisticated cycle of secretion and uptake of

glucose It's called the Cori cycle after the Nobel Laureates: Carl Ferdinand Cori and Gerty Theresa Cori

The glucose 6-phosphate molecules synthesized in the liver can either be converted to glycogen

are taken up by muscle cells where they can be stored as glucogen During strenuous exercise the

glycogen is broken down to glucose 6-phosphate [Glycogen Degradation] and oxdized via the glycolysis

pathway This pathway yields ATP that is used in muscle contraction.

If oxygen is limiting, the end product of glucose breakdown isn't CO2 but lactate Lactate is secreted into the blood stream where it is taken up by the liver and converted to pyruvate by the enzyme lactate dehydrogenase Pyruvate is the substrate for gluconeogenesis The synthesis of glucose in the liver requires energy in the form of ATP and this energy is supplied by a variety of sources The breakdown

of fatty acids is the source shown in the figure

The Cori cycle preserves carbon atoms The six carbon molecule, glucose, is split into two 3-carbon molecules (lactate) that are then converted to another 3-carbon molecule (pyruvate) Two pyruvates are joined to make glucose

Production of biocellulose (bacterial cellulose)

1 Biocellulose

Cellulose is the main component of plant cell wall Some bacteria produce cellulose (celled biocellulose

or bacterial cellulose) Plant cellulose and bacterial cellulose have the same chemical structure, but different physical and chemical properties Figure 1 shows an electron microscopic image of

biocellulose and plant cellulose Bacterial cellulose is produced by an acetic acid-producing bacterium,

Acetobacter xylinum The diameter of biocellulose is about 1/100 of that of plant cellulose and Young's

modulus of biocellulose is almost equivalent to that of aluminum Therefore, biocellulose is expected to

be a new biodegradable biopolymer

Fig 1 Bacterial cellulose and plant cellulose

2 Production of biocellulose in an airlift reactor

In the mass production of biocellulose, conventionally an agitated reactor is used In our laboratory, we applied an airlift reactor to produce bacterial cellulose because this reactor is simple in structure, its energy requirement is low, its shear stress to cells is small, and the possibility of contamination is low Figure 2 shows a 50-liter airlift reactor In the airlift reactor, the productivity of bacterial cellulose was equivalent to that in conventional agitated reactors and its energy requirement was one-tenth of that in agitated reactors The bacterial cellulose produced in an airlift reactor formed a unique pellet-type cellulose

Fig 2 50 liter airlift reactor.

3 Analysis of genes for biocellulose synthesis

All genes responsible for biocellulose synthesis have been cloned and their characterization is under way Figure 3 shows the predicted steps of bacterial cellulose synthesis when glucose is used as the carbon source The analysis of genes will lead to higher productivity of bacterial cellulose and to new biocellulose with different properties

Fig 3 The predicted pathway of cellulose synthesis and secretion when glucose is

taken into Gluconacetobactor xylinum from the outside of the cell.

4 Future aspects

Preservation of forest resources is essential to prevent global warming because the increase in CO2

concentration can be stopped only by the absorption of CO2 by plants and trees However, the use of trees for the production of paper and construction materials has continuously depleated forest resources Bacterial cellulose is the only alternative for plant cellulose because bacteria produce bacterial cellulose

in a few days, while trees need more than 30 years to realize full growth In this respect, bacterial

cellulose is the key material for preventing global warming and preservation of the nature

Metabolism of Major Non-Glucose Sugars

Fructose Metabolism

Diets containing large amounts of sucrose (a disaccharide of glucose and fructose) can utilize the fructose as a major source of energy The pathway to utilization of fructose differs in

muscle and liver

Muscle which contains only hexokinase can phosphorylate fructose to F6P which is a direct

glycolytic intermediate

In the liver which contains mostly glucokinase, which is specific for glucose as its substrate,

requires the function of additional enzymes to utilize fructose in glycolysis Hepatic fructose is

phosphorylated on C-1 by fructokinase yielding fructose-1-phosphate (F1P) In liver the form

of aldolase that predominates (aldolase B) can utilize both F-1,6-BP and F1P as substrates Therefore, when presented with F1P the enzyme generates DHAP and glyceraldehyde The

DHAP is converted, by triose phosphate isomerase, to G3P and enters glycolysis The

glyceraldehyde can be phosphorylated to G3P by glyceraldehyde kinase or converted to DHAP through the concerted actions of alcohol dehydrogenase, glycerol kinase and

glycerol phosphate dehydrogenase.

Three inherited abnormalities in fructose metabolism have been identified Essential

fructosuria is a benign metabolic disorder caused by the lack of fructokinase which is

normally present in the liver, pancreatic islets and kidney cortex The fructosuria of this disease depends on the time and amount of fructose and sucrose intake Since the disorder is

asymptomatic and harmless it may go undiagnosed

Hereditary fructose intolerance is a potentially lethal disorder resulting from a lack of aldolase

B which is normally present in the liver, small intestine and kidney cortex The disorder is

characterized by severe hypoglycemia and vomiting following fructose intake Prolonged intake

of fructose by infants with this defect leads to vomiting, poor feeding, jaundice, hepatomegaly,

hemorrhage and eventually hepatic failure and death The hypoglycemia that result following fructose uptake is caused by fructose-1-phosphate inhibition of glycogenolysis, by interfering

with the phosphorylase reaction, and inhibition of gluconeogenesis at the deficient aldolase

step Patients remain symptom free on a diet devoid of fructose and sucrose

Hereditary fructose-1,6-bisphosphatase deficiency results in severely impaired hepatic

gluconeogenesis and leads to episodes of hypoglycemia, apnea, hyperventillation, ketosis and lactic acidosis These symptoms can take on a lethal course in neonates Later in life episodes are triggered by fasting and febrile infections

Clinical Significance of Fructose Metabolism

Galactose Metabolism

Galactose, which is metabolized from the milk sugar, lactose (a disaccharide of glucose and galactose), enters glycolysis by its conversion to glucose-1-phosphate (G1P)

This occurs through a series of steps First the galactose is phosphorylated by galactokinase

to yield galactose-1-phosphate Epimerization of galactose-1-phosphate to G1P requires the transfer of UDP from uridine diphosphoglucose (UDP-glucose) catalyzed by galactose-1- phosphate uridyl transferase (official name: UDP-glucose hexose-1-phosphate

uridylyltransferase) This generates UDP-galactose and G1P The UDP-galactose is

epimerized to UDP-glucose by UDP-galactose-4 epimerase (see reaction mechanism) The UDP portion is exchanged for phosphate generating glucose-1-phosphate which then is

converted to G6P by phosphoglucose mutase.

Galactose on the Web:

Metabolic Pathways of Biochemistry: Galactose PathwayClinical Significance of Galactose Metabolism

Three inherited disorders of galactose metabolism have been delineated Classic galactosemia

is a major symptom of two enzyme defects.One results from loss of the enzyme phosphate uridyl transferase.The second form of galactosemia results from a loss of

galactose-1-galactokinase These two defects are manifest by a failure of neonates to thrive Vomiting and diarrhea occur following ingestion of milk, hence individuals are termed lactose intolerant Clinical findings of these disorders include impaired liver function (which if left untreated leads

to severe cirrhosis), elevated blood galactose, hypergalactosemia, hyperchloremic metabolic acidosis, urinary galactitol excretion and hyperaminoaciduria Unless controlled by exclusion of galactose from the diet, these galactosemias can go on to produce blindness and fatal liver damage Even on a galactose-restricted diet, transferase-deficient individuals exhibit urinary galacitol excretion and persistently elevated erythrocyte galactose-1-phosphate levels

Blindness is due to the conversion of circulating galactose to the sugar alcohol galacitol, by an

NADPH-dependent galactose reductase that is present in neural tissue and in the lens of the

eye At normal circulating levels of galactose this enzyme activity causes no pathological

effects However, a high concentration of galacitol in the lens causes osmotic swelling, with the resultant formation of cataracts and other symptoms The principal treatment of these

disorders is to eliminate lactose from the diet

The third disorder of galactose metabolism result from a deficiency of epimerase Two different forms of this deficiency have been found One is benign affecting only red and white blood cells The other affects multiple tissues and manifests symptoms similar to the transferase deficiency Treatment involves restriction of dietary galactose.

UDP-galactose-4-Mannose Metabolism

The digestion of many polysaccharides and glycoproteins yields mannose which is

phosphorylated by hexokinase to generate mannose-6-phosphate Mannose-6-phosphate is converted to fructose-6-phosphate, by the enzyme phosphomannose isomerase, and then

enters the glycolytic pathway or is converted to glucose-6-phosphate by the gluconeogenic pathway of hepatocytes

In eukaryotes,mannose is constituent of N- and O-linked glycans as well as GPI anchors

GDP-mannose is the donor form of mannose

more likely fate of glycerol is to enter the gluconeogenesis pathway in order for the liver to produce glucose for use by the rest of the body

Glucuronate Metabolism

Glucuronate is a highly polar molecule which is incorporated into proteoglycans as well as combining with bilirubin and steroid hormones; it can also be combined with certain drugs to increase their solubility Glucuronate is derived from glucose in the uronic acid pathway

The uronic acid pathway is utilized to synthesize UDP-glucuronate, glucuronate and

L-ascorbate The pathway involves the oxidation of glucosae-6-phosphate to UDP-glucuronate The oxidation is uncoupled from energy production UDP-glucuronate is used in the synthesis

of glycosaminoglycan and proteoglycans as well as forming complexes with bilirubin, steroids

and certain drugs The glucuronate complexes form to solubilize compounds for excretion The synthesis of ascorbate (vitamin C) does not occur in primates.

The uronic acid pathway is an alternative pathway for the oxidation of glucose that does not provide a means of producing ATP, but is utilized for the generation of the activated form of glucuronate, UDP-glucuronate The uronic acid pathway of glucose conversion to glucuronate begins by conversion of glucose-6-phosphate is to glucose-1-phosphate by

phosphoglucomutase, and then activated to UDP-glucose by UDP-glucose

pyrophosphorylase UDP-glucose is oxidized to UDP-glucuronate by the NAD+-requiring

enzyme, UDP-glucose dehydrogenase UDP-glucuronate then serves as a precursor for the

synthesis of iduronic acid and UDP-xylose and is incorporated into proteoglycans and

glycoproteins or forms conjugates with bilirubin, steroids, xenobiotics, drugs and many

compounds containing hydroxyl (-OH) groups

Clinical Significance of Glucuronate

In the adult human, a significant number of erythrocytes die each day This turnover releases significant amounts of the iron-free portion of heme, porphyrin, which is subsequently

degraded The primary sites of porphyrin degradation are found in the reticuloendothelial cells

of the liver, spleen and bone marrow The breakdown of porphyrin yields bilirubin, a product that is non-polar and therefore, insoluble In the liver, to which is transported in the plasma bound to albumin, bilirubin is solubilized by conjugation to glucuronate The soluble conjugated

bilirubin diglucuronide is then secreted into the bile An inability to conjugate bilirubin, for

instance in hepatic disease or when the level of bilirubin production exceeds the capacity of the liver, is a contributory cause of jaundice

The conjugation of glucuronate to certain non-polar drugs is important for their solubilization in the liver Glucuronate conjugated drugs are more easily cleared from the blood by the kidneys for excretion in the urine The glucuronate-drug conjugation system can, however, lead to drug resistance; chronic exposure to certain drugs, such as barbiturates and AZT, leads to an

increase in the synthesis of the UDP-glucuronyltransferases in the liver that are involved in

glucuronate-drug conjugation The increased levels of these hepatic enzymes result in a higher rate of drug clearance leading to a reduction in the effective dose of glucuronate cleared drugs

PHOTOSYNTHESIS - - an understandable (not necessarily easy) approach

Pinus palustris -Pearson Creek

Everything should be made as simple as possible, but not simpler - Albert Einstein

(it will take some time to understand this; read deliberately and understand what you have read before going on to the next paragraphs)

Photosynthesis is defined as the formation of carbohydrates in living plants from water and carbon dioxide (CO2) It is the most important chemical pathway (series of chemical reactions) on our planet Almost all of the biomass on Earth was initially created by photosynthesis

Each year 100 quadrillion (or 10 to the 17th) Kilocalories (K.cal.) of useful energy are produced by photosynthesis (about 100 times more energy than is consumed by burning of fossil fuels) At least half

of the photosynthesis in the world takes place in oceans, lakes and rivers, brought about by many

different microorganisms that constitute the phytoplankton

All organisms on Earth can be classified on the basis of two fundamental physiologic requirements:

(A) Energy source:

(1) use sunlight for energy: Phototrophs

(2)use chemical compounds for energy : Chemotrophs

(B) Carbon source:

(1)source is CO2: Autotrophs

(2) source is chemical compounds: Heterotrophs

Chemoautotrophs (use chemical compounds for energy and CO2 for carbon) -bacteria (some)

Chemoheterotrophs (use chemical compounds for both energy and carbon) -animals

Photoaututrophs (use sunlight for energy and CO2 for carbon) -plants and photosynthetic bacteria

Photoaututrophs utilize sunlight for energy and CO2 for their carbon source by this process of

PHOTOSYNTHESIS whereby sunlight is absorbed by a complex compound known as chlorophyll and converted to energy which drives a series of chemical reactions that ultimately removes hydrogen from water or other compounds and then combines the hydrogen with carbon dioxide in a way that produces sugars

Photosynthetic organisms can be divided into two classes: those which produce oxygen and those which

do not Photosynthetic bacteria do not produce oxygen (in fact some of them called anaerobes cannot tolerate oxygen) and this is considered a more primitive type of photosynthesis (in which the hydrogen donor is hydrogen sulfide, lactate or other compounds, but not water) Plants and one type of bacteria (cyanobacteria) do produce oxygen, an evolutionarily more advanced type of photosynthesis (in which the hydrogen donor is water)

In a broad chemical sense, the opposite of photosynthesis is respiration Most of life on this planet (all except in the deep sea vents) depends on the reciprocal photosynthesis-driven production of carbon containing compounds by a series of reducing (adding electrons) chemical reactions carried out by plants and then the opposite process of oxidative (removing electrons) chemical reactions by animals (and plants, which are capable of both photosynthesis and respiration) in which these carbon compounds are broken down to carbon dioxide and water

The oxidative chemical reactions of respiration release energy, some of which is heat and some of it is captured in the form of high energy compunds such as Adenosine triphosphate (ATP) and Nicotinamide adenide dinucleotide phosphate (NADPH) These compounds have a high energy (unstable) terminal phosphate bond and that terminal phosphate is easily detached with the transfer of the energy to drive chemical reactions in the synthesis of other biomolecules In this case, the ATP loses one phosphate to become the energy-depleted ADP (Adenosine diphosphate) and the NADPH loses one electron to become energy-depleted NADP+

Photosynthesis converts these energy- depleted compounds (ADP and NADP+) back to the high energy forms (ATP and NADPH) and the energy thus produced in this chemical form is utilized to drive the chemical reactions necessary for synthesis of sugars and other carbon containing compounds (e.g., proteins, fats) The production of high energy ATP and NADPH in plants occurs in what is known as Light Phase Reactions (Z Scheme) (requires sunlight) The energy releasing reactions which converts them back to energy-depleted ADP and NADP is known as Dark Phase Reactions (Calvin Cycle) (does not require light) in which the synthesis of glucose and other carbohydrates occurs.

So we can summarize by saying that the photosynthetic plants trap solar energy to form ATP and NADPH (Light Phase) and then use these as the energy source to make carbohydrates and other

biomolecules from carbon dioxide and water (Dark Phase), simultaneously releasing oxygen in to the

atmosphere The chemoheterotrophic animals reverse this process by using the oxygen to degrade the energy-rich organic products of photosynthesis to CO2 and water in order to generate ATP for their own synthesis of biomolecules.

Plant photosynthesis, both the Light Phase and Dark phase reactions, takes place in chloroplasts, which may be regarded as the "power plants" of the green leaf cells At night, when there is no sunlight energy, ATP continues to be generated for the plant's needs by respiration, i.e., oxidation of (photosynthetically produced) carbohydrate in mitochondria (similar to animals)

Chloroplasts have many shapes in different species but are generally fusiform shaped (and much larger than mitochondria) and have many flattened membrane-surrounded vesicles called thylakoids which are arranged in stacks called grana These thylakoid membranes contain all of the photosynthetic pigments

of the chloroplast and all of the enzymes required for Light Phase reactions The fluid in the stroma surrounding the thylakoid vesicles contains most of the enzymes for Dark phase reactions

There are several light-absorbing pigments in the thylakoid membranes The most important are the green chlorophylls which are complex protoporphyrin (resembles hemoglobin) molecules which have a magnesiun ion in the center There are two types of chlorophyll: chlorophyll a, which is always present

in all green plants, and a second, chlorophyll b which is also present (about half as much as chlorophyll a) in some plants The chlorophylls are the major light receptors, absorbing light mostly in the 400 to

500 and 600 to 700 nanometer (nm.)wavelength ranges The absorption spectra for chlorphylls a and b are shown below Other pigmented compounds present in the thylakoid membranes include carotenoids (are red, yellow or purple), the most important of which is beta-carotene, the precursor of vitamin A in animals The carotenoid pigments absorb sunlight at wavelengths other than those absorbed by the chlorophylls and thus are supplementary light receptors

The thylakoid membranes of plant chloroplasts have two different sets of light harvesting chlorophyll

and carotenoid molecules combined with a special protein There are two of these Photochemical

Reaction Centers:

Photosystem I: has a high ratio of chlorophyll a to chlorophyll b

PhotosystemII: has relatively more chlorophyll b and may also contain a chlorophyll c

The plants and cyanobacteria (which use water as a hydrogen donor and produce oxygen) have

Photosystems I and II, whereas the less highly evolved other photosynthetic bacteria(which do not use water as their hydgrogen donor and do not produce oxygen) have only Photosystem I

How does the absorption of light by the chlorophyll pigments in the thylakoid membrane cause the conversion of light energy to chemical (ATP & NADHP) energy?

The quick answer is that an electron is stripped from water and transferred to NADP+ to form NADPH which is an endergonic (requires energy imput) reaction.That energy is supplied by the sunlight

absorbed in the chloroplasts And in the process, a phosphorus is added to ADP to produce ATP

When the chlorophyll molecule is excited by light, the energy level of an electron in its structure is

"boosted to a higher energy level and this "excited" chlorophyll (now is called an exciton) moves rapidly

the the reaction center of the Photosystem I where it transfers its extra energy to an electron which is then expelled from the reaction center and is accepted by the first member of a chain of electron carriers and ultimately reaches NADP+, reducing it to NADPH The reaction center has lost an electron and this

"electron hole" is filled by by stripping electrons from water which leaves hydrogen ion (H+) and

molecular oxygen (O2) The pathway of electrons from water to NADP+ has "Z" shape when diagramed and is refered to as the Z Scheme

The Z Scheme diagram shows the pathway of an electron from water (lower right) to NADP+ (upper left) It also shows the energy relationships which are measured as voltage potential shown on the

scaleon the right To raise the energy of the electrons derived from water (+0.82 volts) to the level necessary to reduce NADP+ to NADPH (-0.32 volts), each electron must be boosted twice (vertical red arrows) by light energy absorbed in Photosystems I and II After each boosting , the energized electrons flow "downhill" (diagonal black lines) and in the process transfer some of their energy to a series of reactions which ultimately adds a phosporus to ADP to produce high energy ATP and reduces NADP+

to NADPH There is an alternative shunt whereby the electron flow turns back to cytochrome b563

(green line)and this is called cyclic electron flow and it occurs when there is no need for NADPH, so

only ATP is produced

How are the electrons lost from Photocenters replaced? The "electron hole" in Photosystem I is filled by the electron which was expelled by sunlight energy from Photosytem II and travels to Photosystem I via the chain of electron carriers (the right red vertical and right black diagonal lines) Then the resulting

"electron hole" in Photosystem II is in turn filled by the splitting of water (by an enzyme named water

dehydrogenase) into electrons and H+ ions and molecular oxygen The electrons go to Photosystem II

"electron holes" and the H+s go into the fluid medium and the oxygen is released into the air

For each electron flowing from water to NADP+ (a net change in 1.14 volts), two quanta of light are absorbed, one by each Photosystem Each molecule of oxygen released involves the flow of four

electrons from two water molecules to two NADP+s and requires four quanta of sunlight absorbed by each Photosystem to provide the energy to do this These are the "Light Phase Reactions" of

photosynthesis, which produce two high energy chemical products, namely NADPH and ATP

Now what are the "Dark Phase Reactions" (aka Calvin Cycle)? This is the cycle that converts CO2 into glucose Since it utilizes the chemical energy in the ATP and NADPH, it does not require sunlight (hence the name) It is a complex cycle of mostly phosphorylation (adding or removing phosphate) and oxidative (electron removal) chemical reactions whereby 6 molecules of CO2 are converted into one molecule of glucose It requires the energy-releasing cleavage of high energy bonds of 18 ATPs and 12 NADPHs The resulting 18 ADPs and 12 NADP+s are then restored by the Light Phase process to their high energy forms (ATP and NADPH)

Therefor these two (Light and Dark) phases are interlinked and complimentary And in the end, the plants have utilized the energy of sunlight to produce glucose (and ultimately other carbohydrates, proteins and fats) and oxygen from water and carbon dioxide

1) Monosaccharides (simple sugars)

These molecules consist of open-chain or ring forms of 3 to 8 carbon atoms The most common type of monosaccharide is the simple sugar "glucose"

Glucose is an important energy source in metabolically active cells

Another important monosaccharides are shown below

Fructose is a common sugar in fruit), and Galactose is the sugar found in milk

Sugars with 6 carbons are called "hexoses" Five carbon sugars are "pentoses" Whereas 7 carbon sugars are called "heptoses".

Two very important "pentoses" (5 carbons) are, Ribose found in Ribonucleic Acid, RNA, and Deoxyribose found in Deoxyribonucleic Acid, DNA

Disaccharides

When two monosaccharides are joined together they form a "disaccharide"

This linking of two sugars involves the removal of a molecule of H2O (water) and is therefore

called a "dehydration linkage" The reaction is called "dehydration synthesis".

e.g Glucose + Glucose = Maltose

This forms a bond between the #1 carbon of one glucose and the #4 carbon of the other, therefore it is called an 1-4 linkage, (or Glycosidic Linkage).

Other disaccharides are:

Glucose + Fructose = Sucrose

Glucose + Galactose = Lactose

Polysaccharides

These are long chains of monosaccharides linked together by dehydration linkages

The simplest polysaccharide is a long chain (polymer) of glucose, called "starch".

There are three types of starch:

(1) Amylose: a non-branching straight chain of glucose - used to store glucose in plants.(2) Amylopectin: a branched chain, also used to store glucose in plants

(3) Glycogen: another branched chain molecule used to store glucose in animals

Polysaccharides can also form very important structural components in plants and animals

Cellulose: is the principal constituent in plant cell walls.

This macromolecule is a long chain of glucose subunits held together by β(1-4) linkages (Not

α(1-4) as in starch!)

This different linkage makes cellulose insoluble (and very tough to digest!) therefore is a good structural component.

Chitin: is an important structural material in the outer coverings of insects, crabs, and lobsters

In chitin the basic subunit is not glucose (but N-acetyl-D-glucoseamine) in 1-4 linkages These polymers are made very hard when impregnated with calcium carbonate

Carbohydrate metabolism

Acrobat PDF file can be downloaded here.

Blood sugar (glucose) is the main energy source for the brain, red blood cells and many of our muscles Yet, blood glucose levels are more or less constant in spite of the very rapid and large turnover This constancy is essential for normal body function Stabile sugar levels are the result of precisely controlled chemical and hormonal feed-forward and feed-back information loops Let us look at the basic metabolism that underlies this system and try to answer some "simple" questions How does metabolism of sugars start? Are there differences in the metabolism of the various sugars found in the diet? How do we start up storage of glucose after a meal? How do we stabilize blood glucose levels between meals? Are the differences in metabolism of common sugars in various organs?

Transport of monosaccharides over tissue membranes.

The initial step in metabolism of sugars is their transport over the cell's outer membrane "Small" sugars (glucose, fructose and galactose) cannot cross cell membranes without "carriers" Sugar carriers are proteins embedded in the cell's outer membrane that provide transport systems for monosaccharides The glucose transport protein family (called GLUT) is discussed elsewhere in MedBio Click here for more information These carriers are bidirectional; they can transport glucose both into and out of cells and are driven by the concentration gradient This, in principal,

is true for all tissues However, export of glucose from tissues to the circulation is limited to organs that produce sugar (liver and kidney) or to organs that receive sugar from the outer milieu (the small intestine) The direction of movement is determined by the differing concentrations of glucose on either side of the plasma membrane This is illustrated in the following figure Drawing "1" shows the situation when the portal blood and the liver cell have equal concentrations of glucose; sugar moves in both directions simultaneously This may seem to be wasteful, but gears the system to react to small changes in glucose concentration

The second drawing shows what happens when blood glucose tends to fall Glucose production in the liver accelerates and the net flow of glucose is outward, stabilizing the blood sugar level This is extremely important The total amount of sugar present in the blood can support resting activity not more than about 40 minutes Just walking increases glucose use to a point where the entire blood content is used up in about 15 minutes Since mental activity is completely dependent upon stable blood glucose levels, there must be a way of smoothing out blood glucose levels This is one of the major duties of the liver which normally can produce around 200 mg of glucose per hour On a short-term basis, this is the only organ capable of replacing blood sugar used by other organs Click here for the details Gluconeogenesis in the kidneys becomes important only during prolonged fasting.

The portal blood sugar level increases markedly following a meal This is shown in the third drawing where we see that the liver rapidly takes up glucose from the blood Once again, the liver stabilizes blood sugar As mentioned above, this two-way flow of glucose can forego in most tissues However, only the liver and kidneys are sugar

producers and export of glucose occurs only in these tissues Most of our organs are sugar-burners, taking up glucose

from the blood and using it for energy production Epithelial cells in the small intestine also transport sugars into the circulation, taking sugars from the intestinal lumen and moving these to the blood Uptake of glucose and galactose is coupled to sodium transport and Na + -K + ATPase In contrast to this, adsorption of fructose is passive or

"facilitated", being driven solely by the fructose concentration gradient over cell membranes

What determines this limit of glucose release from most of the body's tissues? Why cannot skeletal muscles release glucose from their large glycogen stores? The secret is that uptake of sugars to our organs involves immediate

phosphorylation at either carbon 1 or 6 The phosphorylated sugar derivatives cannot "leak" out of the cell There is

no mechanism for their cross-membrane transport Once sugars are

phosphorylated they stay put!

What is the key to production of glucose

in the liver and kidneys? These organs produce a specific enzyme, glucose-6- phosphatase, that cleaves the glucose- phosphate bond, releasing glucose and inorganic phosphate Regulation of the balance between phosphorylating and dephosphorylating enzymes is crucial and determines the net direction of transport of glucose in these organs

The second step in sugar metabolism;

phosphorylation.

Entry of sugar molecules into cells initiates sugar phosphorylation That is, kinases specific for each sugar quickly catalyze interaction between the monosaccharide and ATP and yield phosphorylated derivatives The small

structural differences we noted between the three monosaccharides found in our food determine which kinase initiate their metabolism The products resulting from the kinase catalyzed reactions differ Let's look at phosphorylation of the three sugars which we can use as energy sources.

Tissue distribution of monosaccharide kinases.

Most organs exhibit hexokinase activity As the name implies, this enzyme is relatively nonspecific and can react with most 6-carbon sugars However, its affinity for these sugars varies greatly dependent upon their structures

Hexokinase reacts strongly with glucose at levels long under those found in plasma and tissues While it in principle can catalyze phosphorylation of fructose and galactose, its affinity for these is relatively low Furthermore, glucose is

a potent competitive inhibitor of the binding of galactose and fructose to hexokinase This excludes active handling of fructose and galactose by hexokinase at the concentrations found in our bodies Hexokinase is product-inhibited That is, if the glucose-6-phosphate formed by the enzyme is not rapidly removed, hexokinase activity promptly falls Hexokinase is, therefore, well-adapted as the initiator of glucose metabolism in tissues utilizing glucose as an energy source, but not as the initiator of energy storage in the liver Here we need an enzyme that is active in spite of high glucose and G-6-P levels Glucokinase fills this role in hepatic glucose metabolism Other specialized hepatic kinases handle fructose and galactose The following table summarizes the distribution and substrate specificity of the kinases involved in the initiation of sugar metabolism Note that glucokinase is also found in tissues that require a

"glucose sensing system" Regulation of both insulin secretion and of appetite are functions of glucokinase.

Note also that it is the liver that has fructokinase and galactokinase activity The liver is the only organ that actively metabolizes these sugars Aside from spermatozoa, no other organ has an active fructokinase The liver very

effectively removes absorbed fructose from the portal blood In fact, this is necessary for uptake of fructose in the gut Remember that transport there is passive, relying on a steep concentration gradient to drive fructose uptake The liver's very active fructokinase removes fructose from the circulation and permits intestinal uptake of this sugar

Glucose, the major dietary monosaccharide.

Starch is actually "poly-glucose" and its hydrolysis in the small intestine yields only glucose "Sugar", that is table sugar or sucrose, is 50 % glucose and 50 % fructose Lactose (milk sugar) and HFCS or high fructose corn syrup, also contain 50 % glucose Glucose is that monosaccharide upon which nature has based our metabolism

It serves several differing functions in our tissues It is the only substrate for anaerobic metabolism (fast, intense exercise), it is one of several substrates for aerobic metabolism (slow, maintained work), is used to build up carbohydrate reserves (as glycogen) and, finally, is a signal substance for control of hormone secretion and appetite control Glucose metabolism is initiated by either hexokinase or glucokinase The former is involved in energy metabolism in most tissues and is feed-back controlled That is, glucose transport into the cell and hexokinase activity rise and fall according to the use of its product, glucose-6-phosphate (G-6-P) Hexokinase has

a low K m for glucose; it can be active at all normal blood glucose concentrations In other words, the activity of hexokinase is coupled to the substrate requirement of the moment Additionally, in muscle tissue, hexokinase is linked to storage of glucose as glycogen for later use

in anaerobic and aerobic glycolysis

In contrast to hexokinase, glucokinase has a K m of about 5 mmolar This

is equivalent to normal blood glucose levels Glucokinase is found in just a few tissues, the liver, ß-cells in the pancreas and

in the hypothalamus Uptake of glucose after a meal can increase the concentration of glucose in portal blood from the normal fasting level of 4-5 mmolar to 20 mmolar or even higher This activates inward hepatic glucose transport and glucokinase activity Since glucokinase is not product-inhibited, the liver is able to take up and store large amounts of glucose

as glycogen after a meal This can then be released to the circulation later to stabilize blood glucose levels

Pancreatic ß-cells secrete insulin in response to very small increases in blood glucose concentration The glucose transport protein in these cells (GLUT2) and glucokinase both have K m values of about 5 mmolar This appears

to be also the case for glucokinase-containing cells in the hypothalamus The couple GLUT2-glucokinase in these cells acts as a glucose sensor, controlling both insulin secretion and appetite Glucokinase activity automatically rises and falls in tact with changes in glucose concentration in the ß-cell.

Most organs exhibit hexokinase activity As the name implies, this enzyme is relatively nonspecific and can react with most 6-carbon sugars However, because of its low affinity for fructose and galactose (K m = 1.5 mmolar) and the strong competitive inhibitory action of glucose at normal blood glucose concentrations, hexokinase reacts only with glucose in the body's tissues Glucokinase is specific for glucose and does not catalyze reactions with other sugars.

Galactose, the "other half" of lactose (milk sugar).

Galactose is transported from the intestinal lumen by the same Na + -dependent symport that is responsible for glucose transport It is then taken up by the liver and phosphorylated by a specific enzyme, galactokinase The enzymes required for galactose metabolism are found in many tissues including erythrocytes, leucocytes, the brain and retina However, the liver is the main organ where active metabolism of galactose normally occurs Galactose is absorbed in the small intestine and transported to the liver via the vena porta The very active hepatic galactose metabolizing system ((galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT) and uridine diphosphate galactose- 4-epimerase (GALE))) almost completely removes galactose from the circulation Galactose metabolism is, in

practice, normally limited to this organ

Hexokinase, which might be thought to convert galactose to gal-6-P has a high

K m for galactose This follows the positioning of the hydroxyl group on carbon four This is on the same side

of the ring as carbon-6 and hinders phosphorylation of the hydroxyl group

at this carbon Galactokinase has high affinity for galactose and catalyzes phosphorylation of the hydroxyl group

on carbon-1

Galactose-1-P is then converted to glucose-1-phosphate by phosphoglucomutase and enters the "normal" glycolytic path This process is rather complex It involves exchanging a glucose-1-phosphate group in uridine diphosphate glucose (UDP-glucose) with galactose-1-P The resulting uridine diphosphate galactose (UDP-galactose) is then converted by an isomerase back to UDP-glucose Galactose is a good substrate for synthesis of glucose and for anaerobic and aerobic glycolysis As is the case with glucose, anaerobic glycolysis with galactose as substrate yields two ATPs per sugar.

Galactosemia is a condition seen in around 1 of 40-50000 of newly born children These children possess intestinal lactase activity and can split lactose and take up the liberated galactose and glucose However, they lack effective hepatic galactose sequestering and metabolism This follows a genetically determined lack of either hepatic

galactosyl uridylyltransferase (classical galactosemia) or galactokinase (non-classical galactosemia.

These metabolic "errors" to reduction

in blood glucose levels given that half

of the sugar in the diet (half of the lactose in milk) is not metabolized Even more threatening is the trapping

of inorganic phosphate as Gal-1-P in classical galactosemia This depletes hepatic inorganic phosphate and results in a reduction of ATP synthesis An adequate supply of ATP

is essential for gluconeogenesis Thus,

in classical galactosemia, the supply of sugar from the diet is limited and hepatic synthesis of glucose is also reduced The resulting fall in blood glucose can quickly lead to permanent brain damage.

Impaired hepatic galactose metabolism (galactosemia) leads to high circulating levels of galactose These then serve as substrates for alternative pathways of galactose metabolism Aldose reductase, found in the eye, converts galactose to galactitol As is the case with sorbitol formed from glucose, this reduced sugar is not transported over cell membranes Galactitol and sorbitol therefore accumulate in the lens, leading to increased osmotic pressure, protein denaturation and cataract formation

For informative review articles concerning galactose metabolism click here ( Galactokinase: structure, function and role in type II galactosemia, H M Holden et al, Cell Mol: Life Sci 61 (2004) 2471-2484) or here ( Galactosemia: The Good, the Bad, and the Unknown, J L Fridovich-Keil, J Cell Physiol (2006) 701-705).

Fructose or fruit sugar.

Fructose is found in most fruits (~5-6 %), honey (30-40 %) and in "table sugar" or sucrose (50 %) Fructose differs from glucose in that the double-bonded oxygen is found on carbon-2 This results in formation of a 5-ring (furanose)

in aqueous solution at room temperature and the formation of a 6-ring (pyranose) at higher temperatures The 5-ring form is sweeter than common sugar while the 6-ring is not Fructose has a three-dimensional structure quite unlike glucose (Click here for the 3D drawings of the common monosaccharides) Hexokinase has a much lower affinity for fructose than glucose (Km ~1.5 mmolar) In practice, hexokinase does not catalyze metabolism of fructose since glucose is a strong competitive inhibitor and is found at higher concentrations than fructose Fructose metabolism occurs only in tissues with a specific and quite active enzyme, fructokinase This is found exclusively in the liver and spermatozoa Fructokinase promotes formation of fructose-1-P which is not a component of glycolysis

Furthermore, we do not possess an enzyme that can catalyze conversion of 1-P to 6-P We must therefore split 1-P into two 3-carbon fragments, dihydroxyacetone phosphate and glyceraldehyde The latter is then phosphorylated

F-at the expense of an ATP The resulting DAP and GAP then enter glycolysis and can, in theory, enter gluconeogenesis

or aerobic glycolysis For this reason fructose has often been suggested as a treatment for hypoglycemia There are several good reasons to discourage this Firstly, conversion of fructose to glucose uses 2 ATPs Normal hepatic activity alone utilizes all of the liver's ATP-synthesizing capacity There is no good reason to increase hepatic ATP utilization One can just give common sugar in the form of juice or soda pop instead of fructose Glucose (also called dextrose) can be given intravenously too

Fructose is not a direct energy source for muscles and the brain as many of its producers claim These tissues rely on the hexokinase catalyzed phosphorylation of glucose for energy metabolism They do not take up fructose from the

circulation since they lack both fructokinase and GLUT2 Fructose does increase hepatic fatty acid production and serum lipids and these can be utilized in muscle However, dyslipidemia is not a desirable situation Sorry, but you do not become stronger and smarter by eating fructose

Fructose intolerance The human liver has a very large capacity for

phosphorylation of fructose

In fact, the fructokinase activity is usually more than twice that of the combined hexokinase and glucokinase activities Therefore, formation of F-1-P often exceeds the capacity of aldolase B and F-1-P levels can increase after meals These are then reduced between meals While F-1-P can act as a trap for P i , this

is usually not a problem for healthy persons However, individuals with an aldolase

B deficiency exhibit so-called fructose intolerance That is, they build up large amounts of F-1-P following fructose intake and their capacity for hepatic ATP synthesis becomes compromised by the resulting low P i levels This resembles the situation in classical galactosemia described above

Fructose and normal physiology.

Now, the fact is that we do not usually eat pure fructose After all, fructose is usually just a part of the sweeteners we use to season our food The normal hormonal responses we experience from eating and fasting are actual also when

we take in a meal containing sugar or fructose Eating increases insulin secretion and reduces glucagon release; fasting reduces insulin release and stimulates glucagon secretion These two hormones are the major determinates of hepatic energy metabolism Look at the figure to the left This depicts the situation in the liver after a meal with a little fruit, that is, food with normal levels of glucose and fructose We know that the increased insulin/glucagon ratio that follows a meal increases glycogen synthesis as well as anaerobic and aerobic glycolysis If there is carbohydrate

in excess this will be converted to fatty acids and sent out of the liver in VLDL particles Note that the balance

between glycolysis and gluconeogenesis is shifted toward the former; we do not produce glucose while there is an

excess in the circulation It is only in untreated diabetes that

gluconeogenesis proceeds while blood glucose levels are high

One might think that fructose could be converted to glucose and stored as glycogen This has been suggested many times by health faddists

However, the balance of insulin and glucagon after a meal rules this out Gluconeogenesis is turned off, glycolysis races forward and fructose is converted to fatty acids This is the most likely explanation for the increased triglyceride levels found after in people who use "normal amounts" of sugar Sugar consumption has increased from about

8 kg/year to over 50 kg/year in many societies during the past 150 years Genetically, we are designed to consume far less! Today's "normal" sugar consumption is, genetically seen, far from a normal sugar intake.

Let us take a look at hepatic metabolism after a meal rich in sugar regardless of whether we take in sucrose or replace some of that with fructose For example a nice piece of pie and a Cola on the side Perhaps a candy bar just before? Once again, glycogen is synthesized until storage is maximized, gluconeogenesis is turned more or less off, and fatty acid formation is very active The only metabolic pathway open to fructose is that which ends up in fatty acid

production And remember, excessive fatty acid and triglyceride levels are convincingly tied to development of the metabolic syndrome, hypertension, glucose intolerance and type 2 diabetes

Can fructose be converted to glucose or "blood sugar"? Clearly the metabolic pathway from fructose to glucose supports this But does this occur normally?

We can look at fructose and glucose metabolism between meals to gain insight here The reduced

insulin/glucagon ratio

stimulates gluconeogenesis and inhibits glycolysis That is, glucagon dominates the picture, increasing fructose

bisphosphatase activity and leading to formation of glucose, mainly from amino acids, lactate and pyruvate We have no form for fructose reserve, hence fructose is not a usual substrate for gluconeogenesis However, if one was to drink a pure fructose test drink one would certainly find conversion of that fructose to glucose However, the more usual situation is consumption of fructose as sugar as a sweetener in a

"normal" meal In other words, we eat fructose together with starch or sugar This leads to increases

in blood sugar and insulin levels directly with a rapid cessation of gluconeogenesis

We do not usually consume pure fructose!

Fructose does not stimulate insulin

of hunger Is this why we can drink so much soda pop without losing our appetite?

Hepatic glucose release and glucokinase.

While glucokinase has a high K m (low affinity) for its substrate, it reacts strongly with glucose at the concentrations found in portal blood after a carbohydrate meal The K m of the liver enzyme, around 5-6 mmolar, lies above fasting blood glucose levels This means that glucokinase activity is "turned on " by the glucose in portal blood following a meal (10-30 mmolar), and it must be "turned off" after glucose from the meal is absorbed Remember, a major function of the liver is to release glucose when blood sugar levels begin to fall Liver has an enzyme (glucose-6-

phosphatase) that cleaves phosphate from glucose-6-phosphate, yielding free glucose This leads to an increased concentration of glucose in the liver, and transport via GLUT2 out of the tissue and to the circulation

It is essential that glucokinase does not become activated and transform glucose to G-6-P during this export process The balance between glucokinase and glucose-6-phosphatase slides back and forth, increasing uptake to the liver and

phosphorylation when the level

of blood glucose is high, and releasing glucose from G-6-P when blood glucose falls This

is depicted in the next figure

Control of phosphatase activity appears to

glucose-6-be largely a function of enzyme concentration, that is,

regulation of the genes responsible for synthesis of the enzyme The minute to minute control of the system is thought

to lie in regulation of glucokinase activity As in several other metabolic systems, this concurrent activity of two opposing enzymes leads to "futile cycling" While this "wastes energy", it results in precise control over the system Well, we need to keep warm and energy "spills" do contribute to this Just how is

glucokinase regulated? It does not possess the "feedback" regulation we have noted for hexokinase

Earlier, it was thought that glucokinase was rapidly destroyed at low glucose levels and that it was rapidly

resynthesised when glucose levels increased We now know that a much more refined mechanism controls

glucokinase activity

Translocation of glucokinase between cytosol and nucleus.

One of the best ways to "turn off" an enzyme is to put it away Just move the protein to a compartment where it is not needed and inactivate it by binding to a parking place! This is the basis for insulin's control of GLUT4 and glucose transport in skeletal muscle and adipose tissue

Several publications during the past few years have shown that glucokinase

is translocated to the liver cell's

nucleus when plasma glucose concentrations approach fasting levels (around 5mmoles/l) It is bound there to a glucokinase regulatory protein called GKRP Release and translocation back to the cytosol is stimulated by increases in plasma glucose, trace amounts of fructose, and insulin This

translocation system is important in directing glucose flow in and out of the hepatocyte The following figure is taken from

"Regulation of Hepatic Glucose Metabolism by Translocation of Glucokinase between the Nucleus and the Cytoplasm in Hepatocytes",

Y Toyoda et al., Horm

Metab Res 33, 329-336

(2001) The bright areas in

the pictures are immunofluoresent areas in hepatocytes in culture The fluorescence comes from a material that binds specifically to glucokinase Clearly, the enzyme moves from the nuclei to the cytosol when glucose levels in the surrounding medium

is increased from 5 to 25 mmol/liter Surprisingly, small but naturely occurring amounts of fructose greatly promote this transfer Is this the reason for the genetic selection of high hepatic fructokinase acticvity?

While the total GK activity (cytoplasmic plus nuclear activity) was not altered after incubation with glucose, the enzyme migrated from the nuclei to the cytosol in these cells Inclusion of fructose at very low levels led to increased cytoplasmic glucokinase at 5 mM, and appeared to give a total transfer to the cytosol in the presence of 25 mM glucose The GK-GKRP complex was previously shown to disassociate in the presence of fructose-1-phosphate I believe that these are the first pictures showing a simultaneous translocation from nuclei to the cytosol

The following cartoon gives a simple expression of this "parking" control mechanism.

The time course of this migration has been recently

investigated by Chu et al Look

up "Rapid Translocation of Hepatic Glucokinase in Response to Intraduodenal Glucose infusion and Changes

in Plasma Glucose and Insulin

in Conscious Rats, Am J Physiology (in press 01.04) for details The next figure, taken from that work with

permission from Dr Shiota, clearly shows that migration from the liver cell's nucleus occurs rapidly and within the time interval required to participate in the observed increases in hepatic glucokinase seen after a meal While GKRP remained in the nucleus, the GK moved to the cytoplasm following perfusion

of fasted rats with glucose Significant increases were noted after only 10 minutes This corresponds well with the time course of glucokinase activation in these animals.

In summary, glucose , insulin and fructose control the activity of glucokinase through translocation in liver cells Storage of active enzymes and carriers as a method of metabolic control has been well-documented previously with respect to the insulin-sensitive glucose carrier GLUT4.

Fructose Metabolism and dyslipidemia.

Why is fructose such a strong signal for release of glucokinase Remember, glucokinase is "not interested" in reacting with fructose It is specific for glucose Starch, which yields glucose during digestion, has been a main energy source for mankind since the agricultural revolution 8000-10000 years ago Fructose is found in small quantities in many fruits and honey The amount of fructose in our former diets was far lower than starch-derived glucose found in the food we have eaten for thousands of years Combine an apple (5-7% fructose) and some wheat, potatoes or corn, and you get translocation of glucokinase and an active glucose metabolizing system (with a little fructose taken along for the ride) Fructose seems to have acted as a signal substance, used to activate glucose metabolism The enzyme

required to initiate fructose metabolism, fructokinase, is only found in quantity in the liver (and sperm cells)

Furthermore, it is not under metabolic control If fructose comes to the liver, it will be taken up and very quickly metabolized!

The rapid metabolism of sugar at today’s very large levels appears to be responsible for excessive fatty acid synthesis

in the liver Because fructose metabolism "fills" glycolysis with substrate at a very high rate, frequent use of sucrose (remember sucrose is a dimer of fructose and glucose) or fructose promotes fat production Measurement of plasma triglyceride levels has shown these to be increased by the chronic ingestion of sugar There is a reliable correlation between sugar consumption, dyslipidemia and metabolic syndrome.

Fructose in our diet.

Commercial production of fructose began in Finland in

1969 Since then it has become

"modern" to exchange fructose for sugar to cut down on the caloric content of sweetened food Fructose is sweeter than sucrose But, it is the 5-ring form

of fructose that is sweet, the ring form tastes about the same

6-as usual table sugar

Unfortunately, warming fructose leads to formation of the 6-ring form Sweetening coffee and tea and baking cakes with fructose requires just about as much of this sugar as sucrose to get the same taste Baking is also difficult as one needs to use about the same amount of fructose as table sugar and it burns

at lower temperatures

By the way, shifting out sucrose with less fructose may reduce total calorie intake, but it increases fructose

consumption Statistics from the USA suggest that people do not cut back sugar use when they use fructose They seem to choose sweeter food! Remember, half of table sugar is fructose, all of fructose is fructose! That excess

fructose will be largely converted to fat!

The new sweetener, high fructose corn syrup (HFCS)

While consumption of sucrose has actually fallen in the USA, the use of high-fructose corn syrup (HFCS) has

increased markedly during the past 30 years, such that total sugar consumption has markedly increased

Conservative estimates suggest that 16 % of the energy intake of average Americans comes from fructose HFCS contains either 42 % or 55 % fructose It is produced from corn through hydrolysis of starch and isomerization to fructose This is then combined with glucose to give an approximately 50:50 blend The final mixture is less

expensive than sucrose High fructose corn syrup is widely used today in commercial production of soft drinks, breakfast cereals, baked goods and condiments in the USA

As we can see from the following figure from Elliott et.al., total sugar consumption has increased in the USA during the past 30 years despite a real fall in sucrose consumption The decreased use of sucrose is more than balanced by substituting fructose for sugar in commercial food production The global distribution of soft drinks, breakfast cereals and fast food is leading to similar increases in sugar consumption in many areas

Fructose does not cause insulin release from beta cells, as these lack fructokinase One of the results of this is that fructose consumption does not dampen appetite This may lead to increased caloric intake with obesity and the metabolic syndrome as a result

The rapid and poorly controlled metabolism of fructose in the liver leads to increased hepatic lipogenesis,

dyslipidemia and increased storage of fat in the liver Increased lipid levels are associated with insulin insensitivity and, therefore, development of metabolic syndrome and type two diabetes Clearly, today's sucrose and fructose enriched diets are a threat to health.

You can read more about fructose, weight gain and insulin resistance in an excellent article by Elliott et al, Am J Clin

Nutr 76, 911-922 (2002) Just click here if you have access to a library.

Another article which takes up the fructose issue can be found here: ChREBP, a Transcriptional Regulator

of Glucose and Lipid Metabolism,

C.Postic et.al., Annu Rev Nutr., 2007

27:179-192 Click here if you have library connections.

Lactate; some cells make

it, others use it.

We usually think of pyruvic and lactic acids as normal end products of glycolysis Release of lactate follows increased energy utilization, especially

in skeletal muscles Anaerobic glycolysis is something that extra work brings forth What we often neglect is that some tissues serve as "lactate producers" with the intention of nourishing others.

Perhaps the easiest to understand here are erythrocytes After all, they do not have mitochondria and cannot oxidize glucose to CO 2 Furthermore, glycolysis in these cells is largely inefficient Erythrocytes produce (and require) 2-3 bisphosphoglycerate in amounts about equal to their hemoglobin content While this gives control over oxygen- binding to hemoglobin it precludes a net production of ATP Erythrocytes can take up and metabolize quantities of glucose without the inhibitory effects of high ATP levels What happens to all that lactate? It just so happens that our kidneys thrive on lactate and devour as much as the red cells produce Check the following diagram taken from the chapter about insulin Almost 10% of the carbohydrate content of a normal meal wings up as lactate which is used as an energy substrate in the kidneys About 2-3 g per hour are used here and most goes to aerobic metabolism and ATP production This is a rather simple case and is perhaps not so exciting Let's look at brain metabolism for some action!

Lactate metabolism in the brain

We have all learned that the the brain (and spinal cord and retina) require a steady supply of glucose These tissues have little or no glycogen; lack of glucose is just about as damaging as an oxygen cut in the CNS Even under

starvation, the brain must cover about 50% of its energy needs from blood sugar ß-OH butyrate and acetoacetate can supply only half of the substrate required Why?

The blood-brain-barrier protects the brain from most substances in plasma Even fatty acids are excluded here And,

in a way, glucose is among the excluded goodies That is, most of the glucose that crosses the blood-brain-barrier

never comes over the barrier (or glia cell) The next figure, taken from

a publication

by

Tsacopoulou and Magistretti ( click here if you are connected to a library) explains this phenomenon

The blood-brain-barrier is comprised of glia cells, primarily astrocytes A small fraction of the glucose released from capillaries wanders directly to nerves and synapses However, most is "trapped" in astrocytes and oxidized to lactate

by these cells Lactate goes further into the brain and nourishes the brain's neurons This seems to be especially important for glutamatergic neurons which comprise much of the brain The astrocytes also efficiently pick up released glutamate, convert this to glutamine, and send the product back to glutamatergic neurons where it continues

to cycle as a neurotransmitter The axons do not contain glycogen and are, therefore, completely dependent upon the lactate sent from astrocytes to maintain ATP levels Astrocytes and other glia cells appear to have some glycogen which can serve as a very short-term source of lactate

So the answer to the preceding question is that much of the brain is dependent upon lactate from glia cells to provide substrate for aerobic energy production; ketone bodies cannot cover their substrate requirements One can reduce glucose consumption and use ketone bodies during starvation However, some neurons must have lactate and the brain must continue to use blood sugar

Testicles too

We find the same sort of work division in the testicles Here, the sertoli cells enclose the seminiferous tubules,

effectively shielding them from the circulation and direct uptake of glucose This resembles the brain and the brain-barrier Substrates for energy metabolism in the tubules are delivered by the sertoli cells These take up glucose, convert it to lactate, and send this further to the tubules The lactate serves as the substrate of choice for spermatogenesis

blood-Glycogen Synthesis

All cells are capable of making glucose The pathways is called

gluconeogenesis and the end product is not actually glucose but a phosphorylated intermediate called

In times of plenty, G6P may not be needed in further biosynthesis reactions so cells have evolved a way

of storing, or banking, excess glucose The stored glucose molecules can then be retrieved when times get tough Think of bacteria growing in the ocean, for example There may be times when an abundant supply of CO2 combined with a surplus of inorganic energy sources (e.g., H2S) allows for synthesis of lots of G6P These cells can store the excess G6P by making glycogen—a polymer of glucose residues

Glycogen consists of long chains of glucose molecules joined end-to-end through their carbon atoms at the 1 and 4 positions The chains can have many branches Completed chains can have up to 6000 glucose residues making glycogen one of the largest molecules in living cells

The advantage of converting G6P to glycogen is that it avoids the concentration effects of having too many small molecules floating around inside the cell By compacting all these molecules into a single

large polymer the cell is able to form large granules of stored sugar (see photo above).

The first step in the synthesis of glycogen is the conversion of glucose-6-phosphate to

glucose-1-phosphate by the action of an enzyme called phosphoglucomutase (Mutases are enzymes that rearrange functional groups, in this case moving a phosphate from the 6 position of glucose to the 1 position.) The glycogen synthesis reaction requires adding new molecules that will be connected to the chain through their #1 carbon atoms so this preliminary reaction is required in order to "activate" the right end of the glucose residue

Glucose-1-phosphate is the "Cori ester"

this pathway [Nobel Laureates: Carl Cori and Gerty Cori]

The next step is the conversion of glucose-1-phosphate to the real activated sugar, UDP-glucose The enzyme is UDP-glucose pyrophosphorylase and the UDP-glucose product is similar to many other compound that are activated by attaching a nucleotide In some bacteria, the activated sugar is ADP-glucose but the enzyme is the same as that found in eukaryotes ADP-glucose is the activated sugar in plants, as well In plants the storage molecules are starch, not glycogen, but the difference is small (starch has fewer branches)

Glycogen synthesis is a polymerization reaction where glucose units in the form of UDP-glucose are added one at a time to a growing polysaccharide chain The reaction is catalyzed by glycogen synthase

[©Laurence A Moran Some of the text is from Principles of Biochemistry 4th ed ©Pearson/Prentice Hall]

FIGURE 3 The regulation of glucose metabolism in the liver.

From the following article:

Insulin signalling and the regulation of glucose and lipid metabolism

Alan R Saltiel and C Ronald Kahn

Nature 414, 799-806(13 December 2001)

doi:10.1038/414799a

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