PEPTIDASE AND ENDORPHINS
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Endorphin
INTRODUCTION
The perception of
pain and pleasure is comprehended by the brain through
transmission of impulses. Nerve impulses are relayed by
chemical messengers known as neurotransmitters. Neurons
manufacture and subsequently release an array of
neurotransmitters upon the arrival of a stimulus.
Transmitter molecules diffuse from the terminal end of
one neuron and become associated with specific receptor
sites on the receiving neuron, thereby relaying
chemical information. Endorphins are included in a new
family of brain chemicals that relay information: the
neuropeptides.
Neuropeptides are chains of amino acids ranging in
length. Neuropeptides are actually chemical messengers
slightly different from neurotransmitters and should be
termed neuromodulators (6). The term neuromodulatory is
often used in reference to a peptide's action. A unique
feature of the neuropeptides in the brain is the global
nature of some of their effects. Thus, they serve a
multitude of roles associated with particular
functions, such as pain or pleasure (5).
The pain-killing and pleasurable effects of morphine,
the narcotic drug derived from the opium poppy, is
widely known. Endorphins and enkephalins (a smaller
amino acid¿e of the endorphin molecule) are chemicals
that bear a surprising similarity to morphine. It is
interesting to note that the term "endorphin" is a
contraction of "endogenous morphine" (that is, morphine
formed within the body)(12). It was wondered why
morphine and other opiate drugs should produce such
powerful effects on the nervous system. Thus, the
discovery of endorphins followed the realization that
certain regions of the brain bound opiate drugs with
high affinity.
The binding occurs at receptor sites known as opiate (opioid)
receptors. The opiate receptors were detected by
measuring the binding of radioactively labeled opiate
compounds to membrane fragments of neurons. Three
research groups, led by Solomon H. Synder and Candace
B. Pert at Johns Hopkins University School of Medicine,
Eric J. Simon at the New York University School of
Medicine and by Lars Terenius at the University of
Uppsala, developed the receptor-labelling technique.
They found that the opiate receptors were concentrated
in those regions of the mammalian brain and spinal cord
that are involved in the perception and integration of
pain and emotional experience (7).
In 1975, John Hughes and Hans W. Kosterlitz of the
University of Aberdeen isolated two naturally occurring
peptides in the brain that bound tightly to the opiate
receptors and named them enkephalins. The endorphin
molecule was subsequently isolated from the pituitary
gland (5). Isolation of endorphin and enkephalin
substantiated that the opioid receptors normally binds
the peptide endorphin and only secondarily and
coincidentally do they bind the narcotic opiates. Other
studies have suggested that several procedures that
treat chronic pain (acupuncture, direct electrical
stimulation of the brain and even hypnosis) may act by
inducing the release of enkephalins or endorphins in
the brain and spinal cord. This hypothesis is based on
the finding that the effectiveness of treating pain
implemented by these procedures is blocked by
administration of naloxone, a drug that specifically
blocks the binding of morphine to the opiate receptor.
Subsequent pages will discuss the structure, function,
and regulation/control of endorphins.
STRUCTURE
Endorphin Structure
1. Discovery
2. 3 types of endorphins
3. Similarity to morphine
4. Production of endorphins
DISCOVERY
Endorphins are the
body's own natural pain killers, or "feel-good" drugs.
Ever since their discovery, it seems that endorphins
may behave like opiate drugs such as morphine and
function as an internal mechanism for controlling pain
sensations. Modern research hopes to develop a more
natural substitute for morphine that is not addictive.
The natural functions of endorphins have a wide range,
covering everything from temperature to sense of
well-being (13).
THREE TYPES OF ENDORPHINS
Enkephalins: Met- and Leu-
Endorphins
Dynorphins
Endorphins are
neuropeptides that can range from 2 to 39 amino acids
in length. Neuropeptides are peptide molecules produced
and released in the nervous system that act like
transmitters (2). There are three different
neuropeptide sequences including enkephalins,
endorphins, and dynorphins. Each arises from its own
gene (13). Two different structures exist for
enkephalins. Although both consist of 5 amino acids,
they differ in their terminal amino acid. One has
methionine and the other has leucine. Endorphins are
larger with 30 or more amino acids. Dynorphins are
similar in structure to leu-enkephalin, but is much
more potent and mediates more sedative actions at the
cortical level.
SIMILARITY TO MORPHINE
The main purpose of
endorphins is to depress activity in the cerebral
cortex and thalamus. Endorphins have an amazing
similarity to morphine (5). This was discovered upon
the realization that particular parts of the brain have
a high affinity for opiate drugs li`ine. These
receptors were concentrated in areas of the brain and
spinal cord that are involved with the perception and
integration of pain (5). It has been found that there
is an antagonist to morphine called naloxone. This drug
blocks the binding of morphine to the opiate receptor.
The structure of naloxone is such that it not only
blocks stimulation- induced analgesia, but also blocks
placebo analgesia (12). The similarity of morphine to
endorphins is demonstrated by the fact that naloxone
decreases the pain reducing effects (analgesia) of
natural endorphins as well as morphine (5). Naloxone
and morphine are quite similar in structure as
they both contain a number of benzene rings within the
compound.
PRODUCTION OF ENDORPHINS
POMC ---> ß-lipotropin ---> ß-endorphin & met-enkephalin
Pro-enkephalin ---> met-enkephalin & leu-enkephalin
Pro-dynorphan ---> dynorphan & leu-enkephalin
The naturally
occurring endorphins are produced by pro-hormones.
Beta-endorphin is made in the pituitary (11).
Methionine and Leucine enkephalins are made in the
chromaffin cells of the adrenal medulla (10). Pro-opiomelanocortin
(POMC) is a precursor for beta lipotropin (6). The POMC
gene is expressed in the pituitary and its products are
released into the blood as a result of stress. Beta-lipotropin
contains beta-endorphin and met-enkephalin (14). The
beta-lipotropin will undergo hydrolysis by a trypsin-like
enzyme to yield beta endorphin (B-End) (263). Pro-enkephalin
will yield the two types of enkephalin molecules.
Specifically, it will release 4 copies of the Met-enkephalin
and one copy of the Leu-enkephalin. Pro-dynorphin
results in the release of three copies of
leu-enkephalin and a series of dynorphins. Dynorphin is
an opioid tridecapeptide with an NH2 terminus
resembling leu enkephalin. It is found in the
pituitary, hypothalamus, and spinal cord (10).
The endorphins serve a very useful purpose in the body.
They act in serious situations when you must act
quickly to situations such as child birth. Their broad
range of actions makes them an invaluable part of the
human body.
FUNCTION
Function:
1.Role in Evolution
2.Modulation of Pain: Pain Pathway
3.Endorphins and Hormones
4.Endorphins and Stress
5.Endorphins and Live Birth
6.Endorphins and Behavior
7.Endorphins and Emotions
8 Endorphins and Runner's High
9.Endorphins and Schizophrenia
ROLE IN EVOLUTION
It has been argued
that endorphins have provided the foundation for change
in brain structure. The change has occurred throughout
the brain's long evolutionary journey and has provided
changes of behavior that modulates pain reception and
emotion so that organisms can respond in an adaptive
way to eliminate or cope with the causes of pain. These
feelings have made possible our gradual mastery of the
environment (7).
The feeling of analgesia has proved to be extremely
advantageous toward survival. Endorphins ensure that
survival comes first, and recuperation comes later (7).
Pain would ordinarily produce behaviors that would hurt
your chances of survival. For instance, if an animal is
attacked and stops to lick its wounds instead of
fleeing away from its attacker, the animal's life is
put in danger. But, the emotion of fear triggers an
endorphin system that inhibits the processing of pain.
Therefore, it is an evolutionary advantage for species
who have developed a degree of pain control in times of
stress. A phylogenetic study has shown that endorphins
exist in the brain in all vertebrates from hagfish to
humans (14). Humans can view themselves as part of a
biological heritage. This heritage produced an
endorphin system for the control of pain also known as
analgesia. (7).
MODULATION OF PAIN: THE PAIN PATHWAY
The main function of
endorphins is the control of pain. The arrival of a
pain stimulus comes from pain receptors in the skin.
The pain receptors in the skin generate nerve impulses
that travel a pathway up the spinal cord to the
thalamus and then to the sensory and motor cortices
(4). The pain receptor's impulses signal the body of
pain by releasing excitatory neurons containing a
transmitter called substance P. Substance P is a
neuropeptide found in neurons on each side of the
dorsal horns of the spinal cord and functions as a
transmitter of pain. Substance P provokes other neurons
in the spinal cord to fire. These transmitter neurons,
containing substance P, diffuse across the fluid-filled
cleft between neurons and bind to specific receptor
sites on the postsynaptic membrane of the dorsal horns
on either side of the spinal cord. The neurons
sensitive to substance P then proceed to send the pain
message to the brain .
The dorsal horns also house endorphin-containing
neurons. The endorphin-containing neurons release
enkephalin. Enkephalin is the smaller five amino acid
chain of the endorphin family. Enkephalins released
from the endorphin-containing neurons inhibit the
release of substance P by synapsing between the
terminal end of one neuron and the receiving surface of
another pain transmitting neuron. This causes the
receiving neuron in the spinal cord to receive less
excitatory stimulation and hence sends fewer
pain-related impulses to the brain (5).
ENDORPHINS AND HORMONES
Effects of narcotic
analgesics on pituitary hormone release are observed
with the endorphins. Endorphins can be injected either
intraventricularly or parenterally . Like morphine,
they stimulate the release of growth hormone, prolactin,
ACTH, and anti diuretic hormone and inhibit the release
of luteinizing hormone, follicle stimulating hormone,
and thyrotropin. All of these effects are reversible by
naloxone. The mechanism of opioid effects on pituitary
hormone secretion is not understood. However, the
evidence points to an action at the level of the
hypothalamus, rather than effects directly on the
pituitary gland (14). The hypothalamus is important in
mediating some of the output of the limbic system as
well as it being essential to the normal functioning of
the pituitary gland, which lies directly beneath it and
whose importance lies in the fact that many hormones
are stored and released here. The hypothalamus also has
a role in the control of feeding, drinking and the
expression of emotional behavior (1).
STRESS AND ENDORPHINS:
There is a behavioral
linkage between stress and endorphin release. Beta
endorphin and adrenocorticotropin, the classic stress
hormones were found to originate from the same
precursor molecule that has been located in a range of
places in the body such as the hypothalamus and other
areas of the brain, as well as several peripheral
tissues including the placenta and gastrointestinal
tract. The pro-opiomelanocortin gene is expressed in
the pituitary, and its peptide products are released
into the blood stream in response to stress (7).
ENDORPHINS AND LIVE BIRTH
Endorphins counter
stress of live birth with their analgesic powers.
During the gestation period, the placenta provides
necessary nourishment for the development of the fetus.
The placenta also contains the crucial precursor
molecule pro-opiomelanocortin from which beta
endorphin, met-enkephalin and adrenocorticotropin are
all derived (11). In the human placenta, beta-endorphin
and met-enkephalin are present in the placental tissue
and placental blood at higher levels than usual during
pregnancy and labor.
ENDORPHINS AND BEHAVIOR
The limbic system
contains prominent structures that include the amygdala,
septum pellucidum, hippocampus and cingulate cortex
(7). All of these structures act with the hypothalamus
as the integrator of emotional responses. The limbic
system contains some of the highest concentrations of
opiate receptors and endorphins in the brain. The
evidence for linkage between brain endorphins and the
concept of social behavior began to emerge in 1978 from
experiments that administered morphine to young puppies
and guinea pigs. They became less inclined to cry when
they were separated from their mothers. The symptoms of
separation distress were reduced. The antagonist
naloxone, on the other hand increased the incidence of
separation cries. This implicated the role of
endorphins in this critical behavior of social bonding.
ENDORPHINS AND EMOTIONS
Neuroscientists have
agreed that emotions are mediated by the limbic system
of the brain. The amygdala and the hypothalamus are
both classically considered the main components of the
limbic system. Experiments were performed showing the
connection between emotions and the limbic system.
Neurologists found that when they used electrodes to
stimulate the cortex over the amygdala they could evoke
a whole array of emotional displays--- powerful
reactions of grief, pain, pleasure associated with
profound memories and also the total somatic
accompaniment of emotional states. A map locating the
opiate receptors in the brain, by a method involving
radioactive molecules, found that the limbic system was
highly enriched with opiate receptors, forty-fold
higher than in other areas in the brain. These hot
spots correspond to very specific nuclei or cellular
groups that physiological psychologists have identified
as mediating such processes as sexual behavior,
appetite, and water balance in the body (8).
ENDORPHINS AND RUNNER'S HIGH
Euphoria and
exhilaration are reported by many runners while in the
course of their run (7). It has been tempting to relate
these feelings ("the runners high") to an increase in
brain endorphins. There is circumstantial evidence that
a connection might exist. It has been found that
physically untrained volunteers going through a
two-month exercise program produced significantly
higher levels of adrenocorticotropin and beta-endorphin
in their blood system. In another study, for trained
runners, beta-endorphin levels in blood plasma
increased after an eight-mile race to levels three and
a half times higher than levels taken immediately
beforehand. It is possible however, that the endorphin
increases could have been secondary to the
adrenocorticotropin increases and that we might be
seeing a general response to the stress of physical
exertion (7).
SCHIZOPHRENIA AND ENDORPHINS
Schizophrenia is a
mental disorder consisting of agitation,
disorientation, delusions and frequent hallucinations.
Possible connections between schizophrenia and
endorphins have been drawn by several experimental
observations. It has been suggested that levels of
endorphins are related to schizophrenia. This
suggestion is based on the appearance of a
catatonic-like state in injected animals. Other studies
showed a high endorphin level in the cerebrospinal
fluid of schizophrenics (7).
REGULATION & CONTROL
Regulation/Control of Endorphins
1. Overview of Function
2. Control of endorphin function by receptorsA. Receptors
i. Definition and role in function
ii. Receptor types and distribution
iii. Properties of Receptors3. Receptors in relation to pharmaceuticals
A. Goal of pharmaceutical industry
B. Mu receptor subtypes4.Regulation of endorphins by enzymes
A. Enzymatic degradation
i. Specific enzymes involved
OVERVIEW OF FUNCTION
Neurons containing endorphins show high concentration
levels in regions of the brain and spinal cord involved
in the perception and integration of pain and emotional
experience. The neurons release endorphins upon a
stimulus. The existence of opioid receptors sites on
nearby neurons enable endorphins to fulfill their
function in relatively low concentrations (6). The
endorphin molecule is released from the axon terminal
and travels rapidly across the fluid filled space to
the membrane of the receiving neuron. There the
endorphin interacts with specific receptor sites on the
synaptic regions of the neuron. The endorphin molecule
binds to a receptor site on an adjacent neuron causing
inhibition. For example, the release of enkephalins is
followed by binding to the receptor site of a neuron
containing substance P (a transmitter of pain). Binding
causes the neuron to reduce the release of substance P.
This inhibitory effect disrupts the pain pathway and
less pain is felt as a result.
CONTROL OF ENDORPHIN FUNCTION BY RECEPTORS
---Definition of receptor and role in function
Receptors enable endorphins to perform their specific function. Opioid receptors are large protein molecules embedded in the semi-fluid matrix of the cell membrane of the receiving neuron. The surface of the receptor protein contains a region that is the precise size and shape to match the structure of the endorphin molecule. The endorphin molecule precisely fits into the specific receptor site. The binding of the neuropeptide with its specific receptor (opioid receptor) alters the three-dimensional shape of the receptor protein, thereby causing a neuron to be excited or inhibited (10). As in the case of endorphins, inhibition of the neuron will reduce the release of substance P. In other words, the opioid receptor translates the precise messages encoded by the molecular structure of the endorphin molecule into a specific physiological response. Thus, receptors act as a control mechanism thereby regulating the function of endorphins.
--Receptor types and distribution
-
µ receptor
-
n receptor
-
/ receptor
The three main types of opioid receptors are µ (mu), n(delta), and /(kappa). The receptors are defined by the types of opiate and opioid peptide molecules that bind to them. Different classes of opioid receptors mediate different actions depending upon their location and type of endorphin bound to it. In other words, receptors located in different regions of the brain help regulate function by controlling the binding of specific molecules.
The µ receptor preferentially binds enkephalins. It also binds morphine and its antagonist naloxone. Naxolone and its derivatives are the only known molecules that block the receptor; thus they are defined as antagonist. When the naloxone drug occupies the receptor, neither the opiates nor the enkephalins can bind to the receptor. The µ receptor is localized primarily in the pain pathways in the brain.
The n receptor also displays a high affinity for enkephalins. This receptor is localized in limbic parts of the brain and may be related to influences on emotions.
The / receptor preferentially binds dynorphins. This receptor is believed to mediate more sedative actions at the cortical level(13).
--Properties of receptors
-
stereospecificity
-
temperature and pH
-
conformational changes
The following properties demonstrate the specific nature of receptors. Binding of an endorphin molecule will occur only under certain physiological conditions. Controlling the factors involved for binding, regulates the activity of the endorphin.
Receptors are very stereospecific, enabling only certain isomers of molecules to bind. The opioid peptide must reside in its D and not L configuration in order for binding to occur. The D configuration has a higher affinity of binding to the opiate receptor(1).
Specific binding has also been shown to be temperature and pH dependent. Maximum binding occurs at 37° Celsius. There is an optimum pH of 7.4 for specific binding. Binding does not occur below pH 5 or above pH 10. There is an obvious correlation of the binding constraints in relation to the atmosphere of the body(3).
The opiate receptor can exist in two conformational states by the presence of sodium ions. When sodium binds to the receptor it acts as allosteric effector which produces a conformational change in the receptor. Alteration of the shape decreases the ability to bind antagonists (naloxone)but increases the ability to bind antagonist (enkephalin and morphine)(14).
PHARMACEUTICAL IMPLICATIONS OF RECEPTORS
--Goal of the pharmaceutical industry
Morphine has been used for centuries to relieve pain; opiates are still considered the most effective drug. Opiates mimic the actions of endorphins by binding to opioid receptors. The major problem with the use of morphine is the adverse side effects: respiratory depression, constipation, and dependence. Studies have shown that the receptors responsible for many opiate side effects differ from the receptors responsible for controlling pain.
The receptor implicated in this finding is the µ receptor with subtypes µ1 and µ2. Identification of two subtype receptors of the µ receptor family has major implications in understanding opiate action. The pharmaceutical industry's aim is to produce a highly specific opiate drug that will bind only to the µ receptor subtype that is responsible for analgesia.
µ receptor subtypes
Morphine binds to µ2 and µ1 receptor while enkephalin preferentially bind to µ1 and n receptors. The µ1 receptor produces pain-killing effects with no adverse side effects. Furthermore, the µ1 receptor does not appear to mediate most of the signs of morphine withdrawal. The µ2 receptor has been implicated in causing respiratory depression and constipation (9). The discover of the µ subtypes provides a continued understanding of the action of opiates in the body and the role of multiple receptors. The ability to produce highly selective opiate drugs that only bind to the µ1 receptor is within site.
REGULATION OF ENDORPHINS BY ENZYMES
--Degradation of opioid peptide
Once the endorphin molecule has served its function which was mediated by receptors, the endorphins are rapidly inactivated, experiencing a relatively short life. Enzymatic degradation of endorphin molecules appears to be the principle mechanism for inactivation of neuropeptides. The class of enzymes that break down endorphins are peptidases.
--Specific enzymes involved in degradation
-
endopeptidase-24.11 known also as enkephalinase A
-
aminopeptidase
-
angiotensin converting enzyme (ACE)
The three specific enzymes involved in degradation are, endopeptidase-24.11 known also as enkephalinase A, aminopeptidase, and angiotensin converting enzyme (ACE). Endopeptidase 24.11 and aminopeptidase are important in enkephalin metabolism in the central nervous system while ACE serves its function in the cerebrospinal fluid (16). Hydrolysis occurs by cleaving amino acids from the free C-terminus. The enzymes cleave both [Leu]-and [Met] enkephalin which is a pentapeptide to a tri-and dipeptide making the enkephalin molecules inactive. Enkephalin metabolism revealed that the Gly3-Phe4 bond of enkephalins is a major site of hydrolysis (3). The enzyme uses an ionic interaction of an arginyl residue in the active site with the C-terminal carboxylate of enkephalins. The substrate enkephalin fits into the active site in this manner and the amino acids are cleaved (10). Endopeptidase-24.11 is more efficient in rapidly breaking down enkephalins.
MORPHINE AND ENDORPHINS
After studying the
structure of endorphins, morphine seems to be the most
easily linked structure to them. Both function in the
lessening of pain (analgesia) although endorphins are
naturally occurring and morphine is a drug.
It is interesting to make the comparison between these
two compounds. Endorphins serve to suppress pain, as
for example in the immune response. Morphine can also
affect the immune system a great deal. It has been
shown that people who frequently ingest morphine
(cancer patients or even opiate addicts) have altered
immune responses (1). These consist of the following:
depressed phagocytic capability and depression of
respiratory burst activity by these cells (1).
Respiratory burst activity involves the metabolization
of oxygen to yield some toxic intermediates, with which
to fight infection (1). Morphine can also inhibit the
uptake of immunoglobulin G (IgG) complexes which are
essential in the immune response (1).
It is known that the drug Naloxone can inhibit the
effects of morphine. This is true for endorphins as
well. Naloxone was shown to inhibit the uptake of IgG
in experiments done by Singhal et al. thus inhibiting
immune response.
In a study of the analgesic effects of morphine after
surgery, it was concluded that there can be specific
local opioid receptors to help handle pain by binding
morphine in a particular area (2). This is similar to
the endorphins that also have very specific opiate
receptor binding sites.
LITERATURE CITED
1 Singhal, Pravin C. Et al "Effect of Morphine on
Uptake of immunoglobulin G complexes by mesangial cells
and macrophages." American Physiological Society.
17 Mar 1992: F859 F866.
2 Stein, Christoph et al. "Analgesic Effect of
Intraarticular Morphine after Arthroscopic Knee
Surgery." New England Journal of Medicine. 17
Oct 1991: 1123-1126.
MORPHINE AND
ENDORPHINS
After studying the
structure of endorphins, morphine seems to be the most
easily linked structure to them. Both function in the
lessening of pain (analgesia) although endorphins are
naturally occurring and morphine is a drug.
It is interesting to make the comparison between these
two compounds. Endorphins serve to suppress pain, as
for example in the immune response. Morphine can also
affect the immune system a great deal. It has been
shown that people who frequently ingest morphine
(cancer patients or even opiate addicts) have altered
immune responses (1). These consist of the following:
depressed phagocytic capability and depression of
respiratory burst activity by these cells (1).
Respiratory burst activity involves the metabolization
of oxygen to yield some toxic intermediates, with which
to fight infection (1). Morphine can also inhibit the
uptake of immunoglobulin G (IgG) complexes which are
essential in the immune response (1).
It is known that the drug Naloxone can inhibit the
effects of morphine. This is true for endorphins as
well. Naloxone was shown to inhibit the uptake of IgG
in experiments done by Singhal et al. thus inhibiting
immune response.
In a study of the analgesic effects of morphine after
surgery, it was concluded that there can be specific
local opioid receptors to help handle pain by binding
morphine in a particular area (2). This is similar to
the endorphins that also have very specific opiate
receptor binding sites.
LITERATURE CITED
1 Singhal, Pravin C. Et al "Effect of Morphine on
Uptake of immunoglobulin G complexes by mesangial cells
and macrophages." American Physiological Society.
17 Mar 1992: F859 F866.
2 Stein, Christoph et al. "Analgesic Effect of
Intraarticular Morphine after Arthroscopic Knee
Surgery." New England Journal of Medicine. 17
Oct 1991: 1123-1126.
The time course and
extent of neuropeptide action is determined, in part,
by the mechanisms involved in the reduction of the
neuropeptide concentration around the receptor.
Enzymatic degradation is the principle mechanism for
inactivation of neuropeptides.
Peptidases catalyze the hydrolysis of peptide bonds in
endorphins (6).
In general, proteolytic enzymes are described as either
exopeptidases or endopeptidases. The exopeptidases
hydrolyze peptides from either their C-or N-terminal
regions by removal of single amino acids (or dipeptides).
The endopeptidase acts in the interior of the peptide
chain by cleaving internal bonds to convert the
neuropeptide into a biologically inactive peptide.
Endopeptidases often show specificity with regard to
the nature of the peptide bond but are rarely specific
to only one type of substrate. A probable reason for
this is that the specificity of cleavage is determined
by the three-dimensional structure (conformation) of
the peptide substrate and the peptidase (6).The
substrate region containing the susceptible peptide
bond must match the active site of the enzyme for
hydrolysis to occur. Thus, peptidases may degrade
diverse substrates with homologous conformations. This
is very similar to how receptors will bind different
substances with common conformations such as morphine
and enkephalin(14).
Examples of exopeptidases that degrade endorphins are
carboxidipeptidases known as endopeptidase-24.11 also
termed enkephalinase A. Endopeptidase-24.11 functions
as an exopeptidase in its action, but it is considered
an endopeptidase because it hydrolyses some C
terminally extended enkephalins efficiently. The enzyme
uses an ionic interaction of an arginyl residue in the
active site with the C-terminal carboxylate of
enkephalins. The substrate enkephalin fits into the
active site in this manner and the amino acids are
cleaved. Endopeptidase-24.11 is most efficient in
rapidly breaking down enkephalins (3,16).
LITERATURE CITED
1 Barker, R. A. Neuroscience. New York: Ellis
Horwood, 1991.
2 Eckert, R. Animal Physiology. New York: W. H.
Freeman and Co., 1988.
3 Ehrenpreis, S. and F. Sicuteri. Degradation of
Endogenous Opioids: its Relevance in Human Pathology
and Therapy. New York: Raven Press, 1983.
4 Hopson, J. and N. Wessells. Essentials of Biology
New York: McGraw Hill Publishing Co.,
1990.
5 Iverson, L. The Brain: Scientific American Book.
New York: McGraw Hill Publishing Co.,
1979.
6 Kandel, E. R. and J. H. Schwartz. Principles of
Neural Science. 2nd ed. New York: Elsevier
Science Publishing Co., 1985.
7 Levinthal, C. Messengers of Paradise: Opiates and
the Brain. New York: Doubleday, 1988.
8 Ornstein, R. and C. Swencionis. The Healing Brain.
New York: The Guiford Press, 1991.
9 Pasternak, G. "Morphine and Enkephalin Receptors and
the Relief of Pain." Journal of the American Medical
Association. 4 Mar 1988: 1243-45.
10 Prosser, C. L. Neural and Integrative Animal
Physiology. New York: John Wiley and Sons,
Inc., 1991.
11 Restak, R. The Mind. New York: Bantam Books,
1988.
12 Rosenzwig, M. and A. Leiman. Physiological
Psychology. Lexington: D.C. Heath and Co., 1982.
13 Shepherd, G. M. Neurobiology. 2nd ed. New
York: Oxford Press, 1988.
14 Siegal, G. Basic Chemistry. 3rd ed. Boston:
Little Brown and Co., 1981.
15 Smith, A. The Mind. New York: Viking Press,
1984.
16 Turner, A. Neuropeptides and their peptidases.
New York: Ellis Horwood, 1987.
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Personal Message: When you send a personal message to Karl Loren, you will receive a personal reply as per his instructions. Karl pledges that every personal message will get a personal answer. When you provide your mail address, we will send you free information including our free catalog and a cassette tape lecture by Karl Loren about heart disease, no charge, by mail, even if outside the US. You can select particular information you would like to receive, along with the free cassette tape and catalog.
You can reach Vibrant Life in many ways, including by mail to Vibrant Life, 2808 N. Naomi St., Burbank, CA 91504. Within the US and Canada, use the toll free number: (800) 523-4521, the local number: (818) 558-1799, the FAX: (818) 558-7299, eMail to kimberly@oralchelation.com or any one of the hundreds of message forms throughout the 50 web sites. Vibrant Life normally ships the same day we get an order. There are message forms on each of the 100,000+ pages on this and other sites where you can communicate with Vibrant Life. Check out our companion site, at: http://www.oralchelation.net where Karl's 2000 page book is published. Karl Loren is the author and webmaster for this BOOK, as well as for another web site about ORAL CHELATION. His personal philosophical articles are at PHILOSOPHY.
Copyright © May 20, 2008 6:24 AM by Karl Loren on behalf of Vibrant Life, ALL RIGHTS RESERVED. Permission is granted for non-commercial downloading, copying, distribution or redistribution on two conditions: One, that some form of copyright notice is included in every copy distributed or copied, showing the copyright belonging to Vibrant Life, Burbank, CA, at www.oralchelation.com . The second condition is that the material is not to be used for any purpose contrary to the purposes and objectives of this site. This permission does not extend to materials on this site which are copyrighted by others.