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Glucose is the major carbohydrate fuel for many cells.

Galactose & Fructose are metabolized by conversion to a Glycolysis intermediate.

One main purpose is to produce energy in the form of ATP.

Carbohydrates act as the chemical intermediates by which solar energy is stored and used to support life.

When ATP AMP + PPi

PPi is P2O74- and is called pyrophosphate

The pyrophosphate anion is unstable in aqueous solution and

hydrolyzes into inorganic phosphate: P2O74− + H2O → 2 HPO4

2−

or in biologists' shorthand notation: PPi + H2O → 2 Pi

Glucose is the body’s primary energy source for short term needs.

Metabolic reactions that extract energy from food involve Redox reactions.

During OX H atoms are removed from a substrate as hydrogen ions and electrons 2 H 2 H+ + 2 e-

During RED H ions and e-s are picked up by a substrate 2 H+ + 2 e- 2 H

X + 2 H+ + 2 e- XH2It is common to represent this H transfer as:

Reduction = gain of hydrogen

Oxidation involves the loss of electrons from a substrate, and the electrons are transferred to an electron acceptor, which thereby becomes reduced.

gains HRED

NAD+ produces C=OBy removing H’sIt is a reducing agent, it allows oxidation to take place.

Example: oxidation of ethanol ethanol is the reducing agentby reduction of NAD+ NAD+ is the oxidizing agent

Nicotinamide Adenine dinucleotide – NAD+ is a coenzyme.

NAD+ + H+ + 2 e- NADH

NAD+ is a coenzyme able to act as an oxidizing agent.

Gains HRED

Flavin Adenine dinucleotide – FAD

FAD is a coenzyme able to act as an oxidizing agent.

FAD produces C=CBy removing H’sIt is a reducing agent, it allows oxidation to take place.

Example: oxidation of succinate reducing agentby reduction of FAD oxidizing agent

glucose pyruvate

Glycolysis turns glucose into pyruvate.It is an oxidation reaction.

aldehyde Carboxylic acid Carboxylate anion

1˚ alcohol aldehyde Carboxylic acid Carboxylate anion[O][O] pH

[O] pH

2˚ alcohol ketone

2˚ alcohol ketone

[O]

[O]

Gains O or loses H = OX

Oxidation requires reduction.

NAD+ is reduced to NADH

The conversion of glucose to pyruvate oxidizes the carbons of glucose,

but also involves the reduction of two equivalents of NAD+ to NADH.

C6H12O6 + 2 NAD+ + 2 ADP + 2 Pi 2 pyruvate + 2 ATP + 2 NADH + 4 H+ +

2 H2O

The overall reaction of glycolysis which occurs in the cytoplasm is represented simply as:

The conversion of glucose to pyruvate oxidizes the

carbons of glucose, and reduces two equivalents of NAD+ to NADH.

Glucose is activated by phosphorylation producing fructose-1,6-bisphosphate, which undergoes cleavage to 2 triose phosphate: glyceraldehyde-3-phosphate and dihydroxyacetone phosphate.

Triose phosphates undergo further activation to give 1,3-bisphosphoglycerate and phosphoenolpyruvate.These phosphorylate ADP to give ATP.The process is called substrate-level phosphorylation- the direct transfer of a phosphoryl group from a donor compound to ADP. This takes place in reactions 7 and 10.

5 reactions to break glucose in half:

C6 2 C3

5 reactions to produce ATP:4 ADP 4 ATP

Substrate-levelPhosphorylation#7#10

4 C-O bonds

5 C-O bonds

4 C-O bonds

5 C-O bonds

Other monosaccharides can enter the pathway after they are converted to intermediates of the pathway.

Galactose is principally derived from hydrolysis of lactose.

Fructose is present as the free sugar in many fruits, and is also derived from the hydrolysis of sucrose.

Fructose is metabolized almost completely in the liver in humans, and is directed toward replenishment of liver glycogen and triglyceride synthesis.

Extent of glycolysis is regulated by the cell’s need of ATP.3 enzymes control ATP production:Hexokinase (rxn 1)

If G-6-P It inhibits hexokinase via feedback control

Phosphofructokinase (rxn 3)an allosteric enzyme

inhibited by ATP activated by ADP , AMP

Pyruvate kinase (rxn 10)An allosteric enzyme

If ATP or acetyl-CoA

Inhibit pyruvate kinase

Once formed, pyruvate can react further and give rise to 3 different products depending on the existing conditions and the organism.

1. Acetyl CoA, is formed under aerobic conditions.2. Lactate, is formed under anaerobic conditions.3. Ethanol, is formed in fermentation.

Anaerobic conditionReduction of pyruvate to lactate

Oxygen is needed to oxidize the NADH formed in step [6] of glycolysis back to NAD+. If there is not enough O2 to re-oxidize NADH, cells must get NAD+ in a different way. The conversion of pyruvate to lactate provides the solution.

Cells need a constant supply of NAD+ since it is needed in step 6 of glycolysis where NAD+ is reduced to NADH. Since the cell has a limited amount of NAD+, NADH needs to be reconverted to NAD+ for glycolysis to continue.

+ NADH + H+ + NAD+

Reduction of pyruvate with NADH forms lactate and NAD+, which can now re-enter glycolysis and oxidize glyceraldehyde 3-phosphate at step [6] and continue producing ATP.

Anaerobic conditionReduction of pyruvate to ethanol

Anaerobic microorganisms such as yeast convert pyruvate to ethanol in what is called alcoholic fermentation.

Anaerobic metabolism leads to an increase in lactate levels in muscles, which in turn is associated with soreness and cramping. During these periods an “oxygen debt” is created. When vigorous activity ceases, an individual inhales deep breaths of air to repay the oxygen debt caused by heavy exercise. Lactate is then gradually re-oxidized to pyruvate, which can once again be converted to acetyl CoA, and muscle soreness, fatigue, and shortness of breath resolve.

In any tissue deprived of oxygen, pyruvate is converted to lactate rather than acetyl CoA. The pain produced during a heart attack, for example, is caused by an increase in lactate concentration that results when the blood supply to part of the heart muscle is blocked. The lack of oxygen delivery to heart tissue results in the anaerobic metabolism of glucose to lactate rather than acetyl CoA.

Aerobic conditionOxidation of pyruvate to acetyl-CoA

When oxygen is plentiful, oxidation of pyruvate by NAD+ in the presence of coenzyme A and a dehydrogenase enzyme forms acetyl CoA and carbon dioxide. For this process to occur, pyruvate must diffuse across the outer membrane of a mitochondrion, and then be transported across the inner mitochondrial membrane into the matrix.

Excess G/high blood G levelsExcess glucose is used to replenish E reserves by synthesizing glycogen that is stored in limited quantities in skeletal muscle & liver.

Glycogenesis

Glucose

When glycogen stores are full, any remaining glucose is converted to TAGs & stored as body fat.

Glycogen storage is limited, in humans it is exhausted after ~24 hrs. of starvation. The liver provides glucose to the blood for utilization by other tissues, especially the brain.Shortage of G/low blood G levels

When diet does not supply sufficient glucose or blood glucose has been utilized, we degrade the stored glycogen & release glucose.

Glycogenolysis

Glucose

Glucose Balance

Glycogenesis = glycogen biosynthesis

Glucose Glycogen A polymer of (14)-linked D-glucosewith (16) linked branches every 8-14 residues

Starts with G-6-PIsomerizes to G-1-P

G-1-P is activated by UTP (uridine triphosphate) to form UDP-G, Uridine diphosphate glucose.

mostly in skeletal muscles and the liver

Glycogen synthase is a glycosyltransferase, transfers an activated sugar unit to a nonreducing sugar hydroxyl group.

UDP-G + Glycogen UDP + glycogen ∆G= -13.4 n residues n+1 residues

Generates (14)-linkages to yield -amyloseBranching to form glycogen is accomplished by a separate enzymeAmylo-(1,41,6)-transglycosylate (branching enzyme)

Glycogenolysis = glycogen break-

down Glycogen GlucoseGlycogen occurs as intracellular granules, each containing up to 120,000 glucose units.

phosphoglucomutase

Muscle cells ( up to 1-2% glycogen by weight)Liver cells ( up to 10% glycogen by weight)

Glycogen Granule

Cleavage of (14) bonds

Glycogen debranching enzyme

Removes glycogen’s branches :. Making glucose residues accessible to glycogen phosphorylase.

Glycogen phosphorylase

Glycogen + Pi glycogen + G1Pn residues (n-1) residues

Phosphoglucomutase

Converts G1P to G6P G6P continue glycolysiscontinue pentose phosphate pathway

In the liverG6P is made available for use by other tissues.Since G6P can not pass through the cell membrane, it is hydrolyzed by glucose-6-phosphatase (G6Pase):G6P + H2O glucose + PiGlucose leaves the liver cell via a specific glucose transporter GLUT2 and is carried by the blood to other tissues.Muscle and other tissues lack G6Pase and :. Retain their G6P.

Regulation of Glycogen metabolismThe brain, skeletal muscle and red blood cells require large amounts of glucose everyday in order to function properly.

To protect the brain, 3 hormones with opposing actions control blood glucose levels :Glucagon Epinephrine (adrenaline) insulin

The different physiological situations in humans are:1. Excess food available after a good meal2. Mild fasting during sleep3. Prolonged fasting or starvation more than 1-2 days4. Emergency response fight or flight

If glucose , glucagon ( a hormone produced in the pancreas), is secreted into the blood stream. In the liver, glucagon accelerates the rate of glycogenolysis which raises blood glucose levels.At the same time glucagon inhibits the synthesis of glycogen.

When presented with a dangerous situation, epinephrine (a hormone produced by the adrenal glands at the top of the kidneys) convert glycogen phosphorylase from an inactive to an active form.

Net effect : glucose

Effects similar to glucagon. It mobilizes glucose from glycogen.In contrast, it also promotes glucose catabolism in muscle tissue (for production of ATP needed for activity). If glucose , insulin( a hormone produced in the pancreas) is secreted into the blood stream. High insulin signals the tissues that times are good and that food should be stored both as glycogen and fat. Insulin promotes uptake of glucose by the cell by accelerating glycogen synthesis & glycolysis. It also inhibits the synthesis of glucose.

Regulation of blood glucose levels prevents hypoglycemia and /or hyperglycemia.

Right after a meal elevated glucose stimulatethe pancreas to secrete insulin into the blood stream

Insulin promotes glucose intake by thecells, and glycogenesis.

Low levels of glucose stimulate the pancreas to secrete glucagon.In the liver it promotes glycogenolysis and inhibits glycogenesis.Raises blood glucose levels.

When a quick “burst of energy “ is needed such as “fight or flight”, epinephrine (adrenaline) released by the adrenal glands convert glycogen phosphorylase from the inactive to the active form. Promotes glycogenolysis and glycogen is broken down quickly.

The glucose requirements of the human brain are relativelyEnormous – 120g/day, out of about 160 g/day needed by the entire body.

The amount of glucose that can be generated from the glycogen reserves is ~ 190 g, and the total amount of glucose in body fluids is little more than 20 g. Thus the readily available glucose reserves amount to about one day’s supply. During periods of fasting for more than one day, glucose must be formed from other precursors.

Like glycolysis, gluconeogenesis occurs primarily in the cytosol.The primary gluconeogenic organ in animals is the liver, with the kidney cortex contributing in a significant way.

Gluconeogenesis

Gluconeogenesis uses specific enzymes to bypass three irreversible reactions of glycolysis.

Bypass 1 uses Pyruvate carboxylase followed by Phosphoenolpyruvate carboxykinase:

noncarbohydrate precursors including: PyruvateLactateCAC intermediatesC skeletons of most AAs

For simplicity, we consider gluconeogenesis to be the pathway by which pyruvate is converted to glucose.Most reactions of gluconeogenesis are the reverse of glycolysis.

Gluconeogenesis is an anabolic pathway rather than a catabolic pathway since it results in the synthesis of glucose from smaller molecules.

Cycling compounds from the muscle to the liver and back to the muscle is called the Cori cycle.

Besides pyruvate, the principal substrates for gluconeogenesis are lactate and amino acids.

Some of the lactate produced in muscle enters the liver and is reoxidized to pyruvate by liver LDH. This pyruvate can undergo gluconeogenesis to give glucose, which is returned to the blood stream and taken up by muscle to regenerate glycogen stores.

Pentose phosphate pathway

Converts glucose to various other sugars that can be used for energy.The most important products are: NADPH for reductive biosynthesis.Ribose-5-phosphate for nucleotide biosynthesis.