The role of metals in mammalian olfaction of low molecular weight organosulfur compounds

Abstract

While suggestions concerning the possible role of metals in olfaction and taste date back 50 years, only recently has it been possible to confirm these proposals with experiments involving individual olfactory receptors (ORs). A detailed discussion of recent experimental results demonstrating the key role of metals in enhancing the response of human and other vertebrate ORs to specific odorants is presented against the backdrop of our knowledge of how the sense of smell functions both at the molecular and whole animal levels. This review emphasizes the role of metals in the detection of low molecular weight thiols, sulfides, and other organosulfur compounds, including those found in strong-smelling animal excretions and plant volatiles, and those used in gas odorization. Alternative theories of olfaction are described, with evidence favoring the modified “shape” theory. The use of quantum mechanical/molecular modeling (QM/MM), site-directed mutagenesis and saturation-transfer-difference (STD) NMR is discussed, providing support for biological studies of mouse and human receptors, MOR244-3 and OR OR2T11, respectively. Copper is bound at the active site of MOR244-3 by cysteine and histidine, while cysteine, histidine and methionine are involved with OR2T11. The binding pockets of these two receptors are found in different locations in the three-dimensional seven transmembrane models. Another recently deorphaned human olfactory receptor, OR2M3, highly selective for a thiol from onions, and a broadly-tuned thiol receptor, OR1A1, are also discussed. Other topics covered include the effects of nanoparticles and heavy metal toxicants on vertebrate and fish ORs, intranasal zinc products and the loss of smell (anosmia).

Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by ( R )-muscone and diverse other musk-smelling compounds

“…Generated 3D-QSAR models also confirm that both H-bond acceptor and nonpolar parts of the odorants affect the response to OR5AN1. The significant differences seen in the IR spectra of the macrocyclic ketones, the nitromusks, and thiacyclopentadecane 1-oxide 5, all of which are good-to-excellent ligands for OR5AN1, provide further evidence for the implausibility of the vibrational theory of olfaction (39), in accord with other recent reports (79)(80)(81)(82). Furthermore, the various therapeutic activities of musk compounds have yet to be linked to their respective drug targets in vivo.…”

CHCA-1 is a copper-regulated CTR1 homolog required for normal development, copper accumulation, and copper-sensing behavior in Caenorhabditis elegans

“…Could there be a copper-sensing olfactory receptor? Whereas the vertebrate olfactory system has a single receptor gene expressed in each sensory neuron (55), worms have limited numbers of chemosensory neurons, with multiple receptors expressed in one sensory neuron. There are ϳ1300 receptor genes found based on phylogenetic analysis.…”

Copper-mediated thiol potentiation and mutagenesis-guided modeling suggest a highly conserved copper-binding motif in human OR2M3

“…The consensus sequence "HxxC[DE]" can be found in 74% of all human ORs, which led them to propose ORs as metalloproteins [28]. The role of metals in mammalian olfaction is the subject of recent reviews [35,36].…”