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The Molecular Basis of Olfactory Chemoreception.

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Chemistry of Odor Perception
The Molecular Basis of Olfactory Chemoreception**
Uwe J. Meierhenrich,* Jrme Golebiowski, Xavier Fernandez,
and Daniel Cabrol-Bass
bioorganic chemistry · fragrances · gene expression ·
protein models · protein structures
is the aptitude of
living organisms to identify natural or
synthetic chemical compounds in their
environment and to evaluate their concentration.[1, 2] In April 1970, the organic
chemist Robert Luft was asked how
volatile odorant molecules are perceived by the olfactory system. “Si vous
rpondez ) cette question,” he replied,
“le Prix Nobel est ) vous”.[3] The 2004
Nobel Prize in Medicine was awarded 34
years later to Richard Axel and Linda B.
Buck of the Howard Hughes Medical
Institute, who deciphered the molecular
basis for the perception of odors and the
corresponding information preprocessing in the olfactory system. From the
viewpoint of a chemist, these studies
offer fascinating perspectives.
Olfaction is initiated by a molecular
interaction of chemical compounds
called odorants with the olfactory neurons located in the epithelium of the
nasal cavity. The required molecular
properties of odorants were determined
[*] Priv.-Doz. Dr. U. J. Meierhenrich,
Dr. J. Golebiowski, Dr. X. Fernandez,
Prof. Dr. D. Cabrol-Bass
Universit* de Nice-Sophia Antipolis
Facult* des Sciences
Laboratoire “Ar0mes, Synth1ses et
Parc Valrose, 06108 Nice (France)
Fax: (+ 33) 4-9207-6125
Priv.-Doz. Dr. U. J. Meierhenrich
Laboratoire de Chimie Bioorganique
Unit* Mixte de Recherche 6001 CNRSUNSA
[**] This Highlight was written to coincide with
the awarding of the 2004 Nobel Prize in
Medicine and is dedicated to Prof. Dr. R.
Luft, initiator of research on odorants in
the late 1960s at the Universit* de NiceSophia Antipolis.
Dedicated to Professor R. Luft
to be a moderate molecular weight, low
polarity, a certain water solubility, high
vapor pressure, and lipophilicity.[1] The
existence of peripheral olfactory receptor (OR) proteins located in the cilia of
sensory neurons in the epithelium had
been postulated but remained unproven
prior to the work of Axel and Buck.[4]
Numerous theories had been formulated concerning the mode of interaction
between odorant molecules and the
olfactory neurons, including the vibrational theory,[5, 6] the membrane-diffusion theory,[7] the Piezzo effect,[8] complexation,[9] the polarization theory,[10]
the chromatography analogy,[11] the hydrogen-bond-dispersion model,[12] and
the tunneling vibrational theory.[13, 14]
Since 1949, it had been thought that
only the characteristic molecular shape
of an odorant determined its odor.[15, 16]
Based on the identification of a number
of different types of anosmia (the lack of
a sense of smell), it was concluded that
as many (between 7 and 30) specific
receptors with the capacity to recognize
different molecular shapes must exist.
Thus, the existence of an “alphabet” of
odor types with corresponding molecular shapes was postulated. The combination of the letters of this alphabet
should lead to the perception of a multitude of different odors.[17] Since then,
numerous chemical studies have been
devoted to the elucidation of structure–
odor relationships.[18, 19] Despite some
success with specific series of molecules
and their odors (e. g. musks, ambergris,
sandalwood), numerous discrepancies
and exceptions remained.[1] Furthermore, it remained impossible to predict
the odor of a molecule from its molecular structure. These difficulties are not
surprising, as structure–odor relation-
ships are several orders of magnitude
more complex than their pharmacological counterparts, structure–activity relationships.[13] More recently, the simplifying “steric theory” of Amoore has
evolved into the olfactophore concept.
Olfactophores, like pharmacophores,
describe the spatial molecular arrangement of interacting groups and were
found to be helpful for the computeraided design of new odorants.[20] Such
models were constructed without prior
knowledge about the receptor site.
In 1991, Axel and Buck published a
study that contributed considerably to
our understanding of the molecular
basis for the olfactory perception process.[4] To assess the presence of potential receptors in the olfactory epithelium
they postulated that OR proteins belong
to the family of G-protein-coupled receptors (GPCR). GPCR proteins are
embedded in the surface membrane of
cells and cross this membrane seven
times. They are made up of seven
helices, which are joined together by
three extracellular and three intracellular loops. These transduction proteins
can receive chemical signals outside the
cell and transmit them into the interior
of the cell. The receptor activates the
intracellular G protein, which causes
effectors to produce a second signal
inside the cell. This second signal causes
the cell to react to the original external
chemical signal. A simplified schematic
representation of the transmembrane
protagonists is presented in Figure 1.
Prior to their interaction with transmembrane OR proteins, odorants are
thought to be associated with odoranttransport (OT) proteins present in mucus.[21, 22] OT proteins belong to a class of
carrier proteins present in physiological
DOI: 10.1002/anie.200462322
Angew. Chem. Int. Ed. 2004, 43, 6410 –6412
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 1. Schematic illustration of odorant binding and signal activation. The transduction
mechanism of chemical reception through the cilia is initiated by the binding of an odorant
molecule o from the gaseous phase A to a water-soluble OT protein,[21] which transports the
odorant to the OR protein through the olfactory mucus M. Subsequently, the intracellular (I)
G protein G is activated, and this protein in turn activates adenine cyclase AC, resulting in an
opening of the ion channels located in the cell membrane C. The cell is depolarized through the
entry of Ca2+ ions and leaving of Cl ions.
fluids. They contribute actively to the
transportation of the odorant from the
inhaled air stream through the mucus to
the cilia of the olfactory neurons.
The basic approach of Axel and
Buck was to design probes that could
recognize DNA sequences that encode
proteins located in the olfactory epithelium. A new class of genes were found
that express a previously unknown family of GPCR-type proteins, the so-called
OR proteins. The derived molecular
structure of an OR protein is depicted
in Figure 2 together with a complex of
the odorant 2-isobutyl-3-methoxypyrazine with an OT protein.
Gene analysis revealed that the OR
proteins had highly variable sequences
and that they were only encoded in the
olfactory epithelium. From then on, a
tremendous number of studies were
performed to determine the number
and functions of OR proteins.[24, 25] By
searching the human genome database,
Buck and co-workers identified 339
intact OR genes and 297 OR pseudogenes. Sequence comparison led to the
classification of the human OR proteins
into 172 families.[26] It was shown that a
single OR protein can be activated by
Angew. Chem. Int. Ed. 2004, 43, 6410 –6412
multiple odorants,[27–31] and that a single
odorant can activate several OR proteins.[29] As a consequence, different
odorants are recognized by different
combinations of receptors, some of
which are closely related to one another. Numerous odorants activate distinct
sets of OR proteins, even if overlaps
between these sets can exist.[29] From
these results, the molecular basis for the
first steps of olfaction was identified,
namely, that olfactory perception proceeds through a combinatorial process.
Indeed, given the large number of OR
proteins, this combinatorial process
could permit discrimination between a
vast range of chemicals. Buck and coworkers estimated that even if an odorant activated only three receptors (in
fact many more are activated), the
number of theoretically discriminable
odorants should be close to a billion.[29]
The biological method of chemical recognition is therefore far removed from
the simple “lock and key” analogy.
These findings are fully consistent with
the potential discrimination of a very
large number of chemical compounds
with different structures and shapes, as
well as distinct odors.
Figure 2. Three-dimensional structure of a
complex between the odorant 2-isobutyl-3-methoxypyrazine and a water-soluble OT protein
located in the mucus (top).[23] It is assumed
that the odorant molecule is transferred to the
transmembrane GPCR olfactory receptor (bottom).[22]
The sequence of the OR proteins
was determined indirectly through examination of the DNA sequence. Generally, three-dimensional protein structures can be determined through direct
measurements by X-ray crystallography,
spectroscopy. These techniques are,
however, suitable only for water-soluble
proteins, and not for GPCR proteins,
which require precisely balanced physicochemical conditions for structural
and functional integrity. As such conditions are difficult to achieve, new
techniques, such as two-dimensional
cryomicroscopy, have to be employed
to attempt the elucidation of these
structures.[32] Therefore, the amount of
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
experimental information available on
the three-dimensional structure of
GPCR proteins is limited. So far, only
the rhodopsin GPCR structure has been
determined by direct measurements,[33]
and the structures of OR proteins have
been derived from rhodopsin-based
models.[34] Recent studies started to
evaluate the differential responses of a
receptor to a broad variety of agonists.[35] Much progress has been made
towards understanding the molecular
basis of olfactory perception, but many
questions remain unanswered because
of its combinatorial nature.
The pioneering transdisciplinary
studies of Axel and Buck have tremendous implications for flavor and fragrance research. Knowledge about the
molecular interactions between OR proteins and odorants can contribute to the
evaluation of the interaction of a specific odorant with a given set of OR
proteins, a strategy that has already
been patented.[36] The combinatorial
aspect of information processing in the
olfactory bulb and the perception of
odor by pattern recognition throw light
on the success and failure of previous
approaches based on studies of structure–odor relationships and olfactophore modeling. After the confirmation
of the three-dimensional OR protein
structure, chemists will be in a better
position to undertake the rational design of odorants for the activation of
specific OR proteins. However, for
practical applications, odorants are seldom used as pure compounds, but rather
as mixtures, which may be very complex.
Thus, the successful application of odorants will always depend on their formulation. The field for the search for new
odorants, deodorants, and odor modifiers is wide open.
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[3] “If you can answer that question, the
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[21] Until now, the odorant-transport protein
was denoted odorant-binding (OB) protein. Herewith, we suggest the label OT
protein, because 1. the term “binding” is
not specific enough to describe the
hydrophobic chemical interaction between odorant and protein, and 2. the
term “transport” can describe the processes of inclusion, delivery, and release
of the odorant molecule to the OR
[22] P. Pelosi, Crit. Rev. Biochem. Mol. Biol.
1994, 29, 199 – 228.
[23] The structure of the OT protein was
taken directly from X-ray crystallographic data (PDB id. 1DZK). The
three-dimensional structure of the OR
protein was derived by analogy with the
experimentally determined structure of
rhodopsin; see reference [33].
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Angew. Chem. Int. Ed. 2004, 43, 6410 –6412
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