Chapter 24

Integration of Metabolism:
Cellular Signaling
Connections between Metabolic Pathways
• All metabolism is ultimately linked to photosynthesis
and the energy from the sun

• The citric acid cycle plays a central role in

metabolism

• All metabolic pathways are related, and some

metabolites appear in several pathways

• Many reactions take place simultaneously

Connections between Metabolic Pathways
(Cont’d)
Biochemistry and Nutrition
• Macronutrients: carbohydrates, fats, and proteins
• Micronutrients: vitamins and minerals
• Macrominerals: Na, K, Cl, Mg, P, and Ca

• Microminerals: requirements well established for Fe,

Cu, Zn, I, and F

• Microminerals: requirements for some not clear and

no daily values yet established. For example, Cr for
glucose metabolism and Mn for bond formation
Recommended Daily Values
Vitamins
The Food Pyramid
• An approach to publicizing
healthful food selection was
the development of the
Food Guide Pyramid
The Food Pyramid (Cont’d)
The Food Pyramid (Cont’d)
Summary
• The sources of substrates for catabolism and for
anabolism are the nutrients derived from food stuffs
• In humans, the choice of diet becomes important in
the interest of obtaining enough of essential nutrients
while avoiding excesses of others, such as saturated
fats, where excess is known to play a role in the
development of health problems
• In 1992, a food guide pyramid was published to
explain nutrition basics to the public. The pyramid is
currently being replaced by a newer version that
recognizes the differences between various types of
fats and carbohydrates instead of just sending the
message that all fats are bad, and all carbohydrates
are good
Hormones and Second Messengers
• Hormone: an intracellular messenger produced in
the ductless glands of the endocrine system
• Transported from the site of synthesis to the site(s) of
action by the bloodstream
• Types include
• Steroids, such as estrogens and androgens
• Polypeptides such as insulin and glucagon
• Amino acid derivatives such as epinephrine
• Roles include
• Maintenance of homeostasis
• Regulation of growth and development
Hormones (Cont’d)
Selected Human Hormones
Selected Human Hormones (Cont’d)
Control Mechanisms
• Simple feedback mechanisms

• More sophisticated control mechanisms involve the

action of the hypothalamus, pituitary, and specific
endocrine glands
Control Mechanisms (Cont’d)
Second Messengers
• A hormone binds to its
receptor site on the
target cell
• Its binding triggers the
production of cAMP from
ATP, catalyzed by
adenylate cyclase
• Cyclic AMP is one
example of a second
messenger
• cAMP brings about the
changes
Cyclic AMP
• Reactions of cyclic AMP are mediated by a stimulatory G
protein
• The G protein is bound to the plasma membrane
• It consists of three subunits: , , and 
• It is inactive when GDP is bound to the  subunit
• Binding of hormone to its receptor site causes exchange of
GTP for GDP, which activates the G protein
• The active G protein stimulates adenylate cyclase, which
catalyzes the conversion of ATP to cAMP and
pyrophosphate
• cAMP in turn stimulates a protein kinase by binding to its
regulatory subunits
Cyclic AMP (Cont’d)
• The catalytic subunits of the kinase are released and, in
turn, catalyze the phosphorylation of a target enzyme
• The target enzyme then elicits the response of the target
cell to the hormonal signal
• The usual site of phosphorylation by the kinase is the OH
group of a serine or threonine
• This scheme applies to the case where phosphorylation
activates the target enzyme; cases exist in which
phosphorylation inactivates the target enzyme
• The active G protein (active when its  subunit is bound to
GTP) has GTPase activity; hydrolysis of GTP to GDP
returns the G protein to its inactive form
Adenylate Cyclase Activation by G Proteins
Control of Adenylate Cyclase
Activation of Adenylate Cyclase by
Hormones
• Adenylate cyclase can be activated by the binding of
hormone to the receptor and the mode of action of
cAMP
PIP2 and Ca2+ as a Second Messenger
• Calcium ion is involved in another ubiquitous second-
messenger scheme
• PIP2 is also involved in this scheme
• A hormone binds to its receptor and activates phospholipase
C in a process mediated by the G protein
• Phospholipase C catalyzes the hydrolysis of PIP2 to inositol
1,4,5-triphosphate (IP3) and a diacylglycerol (DAG)
• IP3 is the actual second messenger in this scheme
• IP3 stimulates the release of Ca2+ from intracellular reservoirs
in the endoplasmic reticulum (ER)
• Ca2+ forms a complex with calmodulin, a calcium binding
protein
• This complex activates a cystolic protein kinase for
phosphorylation of a target enzyme
PIP2 and Ca2+ as a Second Messenger
(Cont’d)
• The diacylglycerol (DAG) remains bound to the
plasma membrane where it activates a membrane-
bound protein kinase C (PKC)

• PKC is involved in the phosphorylation of a number

of target enzymes

• PKC also phosphorylates channel proteins that

control the flow of Ca2+ in and out of the cell
PIP2 and Ca2+ as a Second Messenger
(Cont’d)
Receptor Tyrosine Kinases
• Receptor tyrosine kinases span the membrane of the
cell and have a hormone receptor on the outside and a
tyrosine kinase portion on the inside
• There are several subclasses of these receptors
 Summary

• Sophisticated fine-tuning of metabolic processes in multicellular organisms

is possible through the actions of hormones and second messengers
• In humans, a complex hormonal system has evolved that requires
releasing factors (under the control of the hypothylamus), trophic
hormones (under the control of the pituitary), and specific hormones for
target organs (under the control of endocrine glands)
• Feedback control occurs at every level of the system
• One important system involves hormones that stimulate a membrane-
bound G protein, which then stimulates adenylate cyclase to produce
cAMP. In these cases, cAMP is the second messenger
• In another important system, a hormone stimulates a different G protein
that then stimulates phospholipase C. Phospholipase C converts
phosphatidylinositol 4,5-bisphosphate (PIP2) to DAG and IP3, both of
which stimulate the opening of calcium channels and the release of
calcium.
• Receptor tyrosine kinases are a third important type of membrane protein
involved in second-messenger systems
Hormones and the Control of Metabolism
• Three hormones play a
part in the regulation of
carbohydrate
metabolism: glucagon,
insulin, and
epinephrine
• Epinephrine is derived
from tyrosine
• Epinephrine acts on
muscle tissue to raise
glucose levels
Hormones and the Control of Metabolism
(Cont’d)
• Glucagon
• A polypeptide of 29 amino acid residues
• Released by the -cells of the islets of Langerhans
• Binds to specific receptor sites to set off a chain of
events to make glucose available to the organism
• Hormonal amplification
• Each time epinephrine or glucagon binds to its
specific receptor, it activates a number of stimulatory
G proteins
• Each activated G protein, in turn, stimulates adenylate
cyclase a number of times which increases the
production of cAMP
Hormones and the Control of Metabolism
(Cont’d)
• Increasing levels of cAMP in turn increase the activity
of cAMP-dependent protein kinases
• The cAMP-dependent protein kinases phosphorylate
and, thus, activate enzymes involved in
gluconeogenesis and glycogen breakdown, and
decrease the activity of enzymes involved in glycogen
storage
• This series of amplifying steps is called a cascade
• The operation of such a cascade is the reason why
small amounts of hormones have such strongly
marked effects
Epinephrine Action
Glucagon Action
Summary
• When a hormone binds to its receptor on the plasma membrane of a
target cell, it sets off a cascade of reactions by which second
messengers elicit the actual cellular response
• Two of the most important second messengers, cAMP, and PIP2,
activate protein kinases, which phosphorylate key enzymes. Calcium
ion is intimately involved in the action of PIP2
• Epinephrine stimulates adenylate cyclase in muscle cells, leading to
activation of cAMP-dependent protein kinase. This ultimately leads to
activation of glycogen phosphorylase and degradation of glycogen for
energy
• Glucagon stimulates adenylate cyclase in liver cells, leading to
activation of cAMP-dependent protein kinase. This leads to inhibition of
PFK-2 and activation of fructose bisphosphatase-2. This lowers the
level of fructose-2,6-bisphosphate, which suppresses glycolysis and
stimulates gluconeogenesis in the liver, leading to increased glucose
production
• Hormonal triggering can be added to other levels of control of
metabolism, such as allosteric activation and covalent modification, to
ensure an efficient response to the needs of the organism
Insulin and Its Effects
• Insulin is a peptide hormone
secreted from the pancreas
• It has two chains in its
active form, the A chain
and the B chain
Insulin Receptors
Insulin Affects Many Enzymes
• Insulin affects the activity of many enzymes, most of
which are involved in reducing glucose levels
Summary
• Insulin’s primary job is to stimulate the glucose transporters in
muscle, particularly the GLUT4 transporter- to take up
glucose from the blood
• In addition, insulin has a wide range of intracellular effects,
such as switching off glycogen breakdown and turning on
glycogen synthesis, stimulating glycolysis in the liver and
muscle, turning off gluconeogenesis in the liver, and
stimulating fatty-acid synthesis and storage
• A recent discovery is that elevated levels of insulin in the
blood may be related to Alzheimer’ disease
• Physical training appears to increase the sensitivity of the
GLUT4 transporter to insulin so that an athlete needs less
insulin to clear glucose out of the blood than a sedentary
person