although it shares only 20 and 17 %, respectively,
of their sequences [248]. Only one molecule of
the bioactive peptide may arise from the precursor (e.g. prepro-insulin), but in most cases several
are produced; these may be identical (e.g.
prepro-caerulein), just similar [e.g. preproencephalin, prepro-endorphin, prepro-glucagon,
prepro-vasoactive intestinal polypeptide (VIP)],
or completely different (e.g. vasopressinlneurophysin, oxytocinlneurophysin, pro-opiomelanocortin). Precursors giving rise to several bioactive
peptides are known as polyproteins. The first typical polyprotein to be discovered (in 1977) was
pro-opiomelanocortin, and at present almost
20 mammalian polyproteins are known. Several
peptide hormones of the invertebrates have also
been shown to have larger precursors, e.g. the
egg-laying hormone of various snails [75].
The peptides arising by cleavage of a precursor
may be further modified at the N-terminus by
formation of a pyroglutamyl residue or by Nacetylation, and at the C-terminus by aamidation. The amide group orginates in a Cterminal glycine from which a carbohydrate chain
is removed as glyoxylate. The reaction requires
molecular oxygen and ascorbic acid, which is
oxidized to dehydroascorbate. The amidating
monoxygenases are specific for the amidated
amino acids [24, 248]. The genes of the preprohormones often show subdivision of the exons
corresponding to the organization of the polypeptide chain into individual domains or active peptides, e.g. in prepro-glucagon, vasopressinlneurophysin and calcitoninlCGRP (calcitonin generelated peptide). In contrast the genes of the proencephalins and pro-opiomelanocortins show no
correspondence between exon and domain
boundaries. Alternative splicing of the primary
transcription product of one and the same gene
can lead to different mRNAs and peptides; thus,
expression of the calcitoninlCGRP gene results in
calcitonin in the C cells of the thyroid and CGRP
in the brain [59].
By the use of highly sensitive immunological
methods or the analysis of corresponding
mRNAs, it has recently been shown that typical
peptide hormones of the alimentary system are
also present in the central nervous system and
vice versa: hence the term "neuro-intestinal peptide". Many of these regulatory peptides are synthesized and secreted by nerve cells. Such peptido genic neurons are found in large numbers in,
for example, the hypothalamus and the neurohypophysis, but they also occur in the gut wall.
However, bioactive peptides do not only arise in
8 Peptide Hormones
289
neurons; for example, the adenohypophysis corresponds to an epithelial gland, and endocrine
gland cells are present in the pancreas associated
with the islets of Langerhans. Growth factors are
produced by many different types of cell. Some
peptides, e.g. cholecystokinin, are produced both
in gland cells of the intestine and in neurons, e.g.
in the limbic system of the brain.
Some peptides act as neurotransmitters during the excitation of synapses. This has been
demonstrated for substance P, ~-endorphin, encephalin and somatostatin, and probably also
applies to VIP, pancreas polypeptide (PP), angiotensin, adrenocorticotropic hormone (ACTH),
and cholecystokinin (CKK). Approximately onehalf of the synapses in the human brain function
with classical neurotransmitters, such as acetylcholine, biogenic amines (dopamine, noradrenalin, serotonin) and amino acids (y-aminobutyric
acid, glycine, glutamic acid and aspartic acid);
the rest are possibly all peptidergic. Neuromodulator functions of peptides refer to their activities
over longer distances, longer times or as inhibitors, in contrast to a normal neurotransmitter.
Apart from nerve cells, other cell types can also
effect neighbouring cells via active substances
(paracrine functions). This applies to the biogenic
amines, like histamine and serotonin, and also to
the peptide somatostatin and the growth factors.
If a peptide is to function as a hormone, neurotransmitter, neuromodulator or growth factor on
a target cell, the latter must carry on its surface
the appropriate acceptor molecules. In biochemical language these integral membrane proteins
are referred to as "receptors", a term the biologist reserves for whole cells or even whole organs.
Interestingly, there are peptides that function as
sexual lures, i.e. they serve as pheromones for
signal transfer between individuals. An example
is aphrodisin in the vaginal secretions of the
hamster Mesocricetus auratus; this is a glycoprotein of 151 amino acids from the super-family of
the Uzu-globulins and stimulates copulatory
behaviour in the males via the accessory olfactory
system [77].
Also, in the case of the peptide hormones,
attempts have been made to assign similar
sequences to families and derive their common
ancestors. Difficulties are encountered with short
sequences in that convergent evolution cannot
always be excluded. It is very relevant to concepts
of peptide hormone evolution that many hormones initially discovered in vertebrates are also
found in invertebrates. For example, peptides
corresponding in their immunological and biolo-
of their sequences [248]. Only one molecule of
the bioactive peptide may arise from the precursor (e.g. prepro-insulin), but in most cases several
are produced; these may be identical (e.g.
prepro-caerulein), just similar [e.g. preproencephalin, prepro-endorphin, prepro-glucagon,
prepro-vasoactive intestinal polypeptide (VIP)],
or completely different (e.g. vasopressinlneurophysin, oxytocinlneurophysin, pro-opiomelanocortin). Precursors giving rise to several bioactive
peptides are known as polyproteins. The first typical polyprotein to be discovered (in 1977) was
pro-opiomelanocortin, and at present almost
20 mammalian polyproteins are known. Several
peptide hormones of the invertebrates have also
been shown to have larger precursors, e.g. the
egg-laying hormone of various snails [75].
The peptides arising by cleavage of a precursor
may be further modified at the N-terminus by
formation of a pyroglutamyl residue or by Nacetylation, and at the C-terminus by aamidation. The amide group orginates in a Cterminal glycine from which a carbohydrate chain
is removed as glyoxylate. The reaction requires
molecular oxygen and ascorbic acid, which is
oxidized to dehydroascorbate. The amidating
monoxygenases are specific for the amidated
amino acids [24, 248]. The genes of the preprohormones often show subdivision of the exons
corresponding to the organization of the polypeptide chain into individual domains or active peptides, e.g. in prepro-glucagon, vasopressinlneurophysin and calcitoninlCGRP (calcitonin generelated peptide). In contrast the genes of the proencephalins and pro-opiomelanocortins show no
correspondence between exon and domain
boundaries. Alternative splicing of the primary
transcription product of one and the same gene
can lead to different mRNAs and peptides; thus,
expression of the calcitoninlCGRP gene results in
calcitonin in the C cells of the thyroid and CGRP
in the brain [59].
By the use of highly sensitive immunological
methods or the analysis of corresponding
mRNAs, it has recently been shown that typical
peptide hormones of the alimentary system are
also present in the central nervous system and
vice versa: hence the term "neuro-intestinal peptide". Many of these regulatory peptides are synthesized and secreted by nerve cells. Such peptido genic neurons are found in large numbers in,
for example, the hypothalamus and the neurohypophysis, but they also occur in the gut wall.
However, bioactive peptides do not only arise in
8 Peptide Hormones
289
neurons; for example, the adenohypophysis corresponds to an epithelial gland, and endocrine
gland cells are present in the pancreas associated
with the islets of Langerhans. Growth factors are
produced by many different types of cell. Some
peptides, e.g. cholecystokinin, are produced both
in gland cells of the intestine and in neurons, e.g.
in the limbic system of the brain.
Some peptides act as neurotransmitters during the excitation of synapses. This has been
demonstrated for substance P, ~-endorphin, encephalin and somatostatin, and probably also
applies to VIP, pancreas polypeptide (PP), angiotensin, adrenocorticotropic hormone (ACTH),
and cholecystokinin (CKK). Approximately onehalf of the synapses in the human brain function
with classical neurotransmitters, such as acetylcholine, biogenic amines (dopamine, noradrenalin, serotonin) and amino acids (y-aminobutyric
acid, glycine, glutamic acid and aspartic acid);
the rest are possibly all peptidergic. Neuromodulator functions of peptides refer to their activities
over longer distances, longer times or as inhibitors, in contrast to a normal neurotransmitter.
Apart from nerve cells, other cell types can also
effect neighbouring cells via active substances
(paracrine functions). This applies to the biogenic
amines, like histamine and serotonin, and also to
the peptide somatostatin and the growth factors.
If a peptide is to function as a hormone, neurotransmitter, neuromodulator or growth factor on
a target cell, the latter must carry on its surface
the appropriate acceptor molecules. In biochemical language these integral membrane proteins
are referred to as "receptors", a term the biologist reserves for whole cells or even whole organs.
Interestingly, there are peptides that function as
sexual lures, i.e. they serve as pheromones for
signal transfer between individuals. An example
is aphrodisin in the vaginal secretions of the
hamster Mesocricetus auratus; this is a glycoprotein of 151 amino acids from the super-family of
the Uzu-globulins and stimulates copulatory
behaviour in the males via the accessory olfactory
system [77].
Also, in the case of the peptide hormones,
attempts have been made to assign similar
sequences to families and derive their common
ancestors. Difficulties are encountered with short
sequences in that convergent evolution cannot
always be excluded. It is very relevant to concepts
of peptide hormone evolution that many hormones initially discovered in vertebrates are also
found in invertebrates. For example, peptides
corresponding in their immunological and biolo-