Organic chemistry and Biological chemistry for Health Sciences
59-191
Lecture 23
When muscular work starts, the adrenal medulla secretes a hormone, epinephrine.
Epinephrine triggers the cascade of reactions of glycogenolysis. At its target cells,
epinephrine activates the enzyme adenylate cyclase that catalyzes conversion of some
ATP to cAMP. Cyclic AMP (cAMP) then activates another enzyme, and this activates
still another enzyme and so on in a cascade of events. The effect of each molecule of
epinephrine is multiplied by each step so that a single molecule of hormone can change
the activity of thousands of enzyme molecules to produce thousands of glucose
molecules. While the epinephrine cascade releases glucose from glycogen, the affected
tissue shuts down a team of enzymes called glycogen synthetase that are involved in the
synthesis of glycogen from glucose. An enzyme called protein kinase, in the epinephrine
cascade inhibits conversion of released glucose back to glycogen by inactivating an
enzyme called glycogen synthetase. Protein kinase catalyzes the phosphorylation of two
enzymes. One is inactive phosphorylase kinase and another one is active gylcogen
synthetase. Phosphorylation of inactive phosphorylase kinase continues the epinephrine
cascade to form glucose. phosphorylation of active gycogen synthetase stops the process
of reforming glycogen from glucose.
The end product of glycogenolysis is glucose-1-phosphate instead of glucose. Cell that
can perform glycogenolysis also has an enzyme called phosphoglucomutase that
converts glucose-1-phosphate to glucose-6-phosphate, an intermediate of glycolysis.
Glucagon, a peptide hormone, released from -cells of the pancreas helps maintain
normal blood sugar level. When blood sugar level drops -cells release glucagon. It
activates glycogenolysis in liver. Like epinephrine it triggers the activation a cascade of
reactions. Like epinephrine glucagon also activates adenylate cyclase to produce cAMP.
Unlike epinephrine glucagon inhibits glycolysis, which helps to maintain glucose supply
by not letting it be used for energy.
Liver cell can release glucose to circulation. In the liver glucose-6-phosphate, made by
glycogenolysis, is hydrolyzed to glucose and inorganic phosphate.
Glusose-6-phosphatase
Glucose-6-P + H2O
Glucose + Pi
Glucose leaves the liver to help increase the blood sugar level. During the period of
fasting, the liver is actually a major supplier of glucose for the blood. Because the brain
depends on glucose for energy the above reaction in the liver also help maintain this
supply.
The -cells of pancreas releases another polypeptide hormone called insulin that lowers
the blood sugar level. Its release is stimulated by an increase in the blood sugar level,
which normally occurs after a carbohydrate rich meal. Insulin binds to its receptors at the
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membrane of muscle and adipose tissue. Insulin receptor complex stimulates the uptake
of glucose by the cells to lower the blood sugar level.
Diabetes Mellitus is caused by a deficiency in the secretion or action of insulin. There are
two major clinical classes of the disease.
 Insulin dependent diabetes mellitus
 Non-insulin dependent diabetes mellitus
Insulin dependent diabetes mellitus:
-cells of the pancreas have been destroyed so they are unable to produce insulin. The
persons with this defect have to receive insulin intravenously to lower the blood sugar
level. If more insulin is put into circulation than needed, the blood sugar level falls too
low causing insulin shock.
Non-insulin dependent diabetes mellitus:
Insulin resistance develops in those tissues that normally use insulin. So these cells
cannot use insulin. Since those cells cannot take out glucose from circulation blood
glucose level rises, resulting in hyperglycemia. The causes for this insulin resistant are
complex but they are associated with obesity, hypertension and elevated blood lipid
levels.
The hypothalamus makes another hormone, somatostatin that participate in the
regulation of of the blood sugar level. When the -cells of the pancreas secrete insulin,
which helps to lower the blood sugar level, the alpha-cells should not at the same time
release glucagon as well, which helps to raise this level. Somatostatin acts at the pancreas
to inhibit the release of glucagon as well as to slow down the release of insulin. It thus
helps to prevent a wild swing in the blood sugar level that insulin alone might cause.
Diabetes is the major cause of hyperglycemia. Sustained hyperglycemia damages those
tissues that are freely permeable to glucose, such as retina, kidneys, and the nerves. Those
with persistent hyperglycemia face the increased risk of blindness, kidney failure and
disorders of the glucose.
Glucose is toxic in sustained high levels because it promotes unwanted increases in the
activities of certain enzymes. It also reacts with and damages some of the proteins of
smooth muscles, for example some of the blood vessels. Glucose also reacts with
hemoglobin, giving glycosylated hemoglobin (glucohemoglobin). For hyperglycemic
individuals, measurements of one’s glycosylated hemoglobin level has become the best
way to determine the average blood sugar level.
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GLUCOSE TOLERANCE:
Glucose tolerance is the ability of the body to manage its blood sugar level within the
normal range. Many factors contribute to it.
Glucose tolerance test:
In the glucose tolerance test the individual is given a drink that contains glucose,
generally 75g for an adult and 1.75g per kilogram body weight for children, and then the
blood sugar level is checked at regular intervals.
After glucose intake blood glucose level increases both in healthy individuals and in
diabetic patients. But in the healthy individual it quickly comes back to normal with the
help of insulin and somatostatin. In the diabetic, the level of glucose declines slowly and
remains mostly in the hyperglycemic range throughout.
The persons with diabetes have impaired glucose tolerance. Their blood glucose is
persistently high. A person with untreated diabetes has glucosuria.
GLYCOLYSIS:
Glycolysis is a series of reactions that change glucose to pyruvate (or lactate), while
making a small amount of ATP.
Except during exercise glycolysis is operated with sufficient oxygen (aerobic). The
overall reactions of glycolysis in the presence of oxygen are as follows:
Aerobic glycolysis thus makes 2ATP by substrate phosphorylation. The NADH
generated in glycolysis delivers the H:- to the respiratory chain which drives the
synthesis of more ATP by oxidative phosphorylation.
When a cell receives oxygen at a rate slower than needed, glycolysis can still operate, but
the end product is lactate instead of pyruvate. The following reaction is the anaerobic
sequence of glucose catabolism: (See figures attached!)
So two ATP can still be made by substrate level phosphorylation even though the cell is
anaerobic and not able to use respiratory chain. It is an important backup source of ATP.
How glycolysis works?
The breakdown of six-carbon glucose into two molecules of three carbon pyruvate occurs
in ten steps, the first five of which constitute the preparatory phase. In summary, glucose
is first phosphorylated at the hydroxyl group on C-6 (step 1). The D-glucose-6-phosphate
thus formed is converted to D-fructose-6-phosphate (step 2) which is again
phophorylated at C-1 to yield D-fructose-1,6-bisphosphate (step 3). For both
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phosphorylations ATP is the phosphate donor. Fructose-1,6-bisphosphate is next split to
yield two three carbon molecules, dihydroxyacetone phosphate and glyceraldehyde-3phosphate (step-4). The dihydroxyacetone phosphate is isomerized to a second molecule
of glyceraldehyde-3-phosphate.
This ends the preparatory phase of glycolysis. Two molecules of ATP must be invested to
activate or prime the glucose molecule for its cleavage into two three carbon pieces; later
there will be a good return on this investment.
The energy gain comes in the payoff phase of glycolysis. Each molecule of
glyceraldehyde-3-phosphate is oxidized and phosphorylated by inorganic phosphate to
form 1,3-bisphosphoglycerate. Energy is released as the two molecules of 1,3bisphosphoglycerate are converted into two molecules of pyruvate (step 7 to 10). Much
of this energy is conserved by the coupled phosphorylation of four molecules of ADP to
ATP. The net yield is two molecules of ATP per molecule of glucose used, because two
molecules of ATP were invested in the preparatory phase of glycolysis. Energy is also
conversed in the payoff phase in the formation of two molecules of NADH per molecule
of glucose.
The ten steps of glycolysis are as follows:
1.
Glucose is phosphorylated by ATP under catalysis by hexokinase to give glucose6-phosphate.
2.
Glucose-6-phosphate changes to its isomer, fructose-6-phosphate. The enzyme is
phophoglucose isomerse.
3.
ATP phosphorylates fructose-6-phophate to make fructose-1,6-bisphosphate. The
enzyme is phophofructokinase. This reaction is essentially irreversible.
4.
Fructose-1,6-bisphosphate breaks apart into two triose monophosphate,
glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Aldolase is the
enzyme involved.
5.
Dihydroxyacetone phosphate, in the presence of triose phophate isomerase,
changes to its isomer, glyceraldehyde-3-phosphate because only glyceraldehyde-3phosphate can be directly degraded in the subsequent reaction steps of glycolysis.
So all dihydroxyacetone shuttles through glyceraldehyde-3-phosphate.
This reaction completes the preparatory phase of glycolysis, in which the hexose
molecule has been phophorylated at C-1 and C-6 and then cleaved to form two
molecules of glyceraldehyde-3-phosphate.
6.
Glyceraldehyde-3-phosphate is simultaneously phosphorylated and oxidized, to
give 1,3-bisphosphoglycerate. This reaction is catalyzed by gyceraldehyde-3phosphate dehydrogenase. This enzyme has NAD+ as a cofactor that is converted to
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NADH after the reaction. Inorganic phosphate is the source of the new phosphate
group.
7.
The enzyme phosphoglycerate kinase transfers the high energy phosphate group
from the carboxyl group (1,3-bisphosphoglycerate has higher phosphate group
transfer potential than ATP) of 1,3-bisphosphoglycerate to ADP, forming ATP and
3-phophoglycerate.
8.
The enzyme phosphoglycerate mutase catalyzes a reversible shift of the phosphate
group between C-2 and C-3 of glycerate.
9.
The dehydration of 2-phophoglycerate to phosphoenolpyruvate is catalyzed by
enolase. In this step, dehydration of an alcohol, converts a low energy phosphate
into the highest energy phosphate in all of metabolism.
10.
The last step in glycolysis is the transfer of the phosphate group from phosphoenol
pyruvate to ADP, catalyzed by pyruvate kinase.
In step 6, coenzyme NAD+ has been reduced to NADH. Enzyme cannot function again if
the coenzyme is not converted back to NAD+, so glycolysis cannot happen again. In the
presence of oxygen H:- is transferred to the respiratory chain and NAD+ is regenerated for
another run of glycolysis series.
When the cell is deficient in oxygen, NADH is changed back to NAD+ by transferring its
H:- to keto group of pyruvate, making it the 20 alcohol group in lactate. Lactate serves to
store H:- made at step 6 until the cell again becomes aerobic.
Anaerobic glycolysis generates acid (lactic acid), so excessive exercise that forces tissues
to operate anaerobically can overtax the blood buffer. A form of metabolic acidosis called
lactic acidosis results. The muscle become tired and sore. The lung responds by
hyperventilation, which blows out carbon dioxide and thus helps to remove acid from the
body. During a cool down period, the body reestablishes the acid-base balance of the
blood, and excess lactate is shuttled into the cori cycle.
Gluconeogenesis:
Gluconeogenesis is a series of reactions by which glucose is made from smaller
molecules. Excess lactate and breakdown product of several amino acids can be used as
starting material. The ability of the body to make glucose from non-carbohydrate sources,
even amino acids from the body’s own proteins is an important backup during times
when glucose either is not in the diet or is not effectively used.
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