Identifying human diamine sensors for death related putrescine and cadaverine molecules

Abstract

Pungent chemical compounds originating from decaying tissue are strong drivers of animal behavior. Two of the best-characterized death smell components are putrescine (PUT) and cadaverine (CAD), foul-smelling molecules produced by decarboxylation of amino acids during decomposition. These volatile polyamines act as ‘necromones’, triggering avoidance or attractive responses, which are fundamental for the survival of a wide range of species. The few studies that have attempted to identify the cognate receptors for these molecules have suggested the involvement of the seven-helix trace amine-associated receptors (TAARs), localized in the olfactory epithelium. However, very little is known about the precise chemosensory receptors that sense these compounds in the majority of organisms and the molecular basis of their interactions. In this work, we have used computational strategies to characterize the binding between PUT and CAD with the TAAR6 and TAAR8 human receptors. Sequence analysis, homology modeling, docking and molecular dynamics studies suggest a tandem of negatively charged aspartates in the binding pocket of these receptors which are likely to be involved in the recognition of these small biogenic diamines.

Full rescue of an inactive olfactory receptor mutant by elimination of an allosteric ligand-gating site

“…Exactly the same position, 6.58, appears to fulfil a similar function in several neurotransmitter and hormone receptors 30 , beta adrenergic receptors 13 and the gonadotropin releasing hormone receptor 27 , 33 . In a recent modelling study on two human TAARs, 6.58 was hypothesized to serve as floodgate to remove the solvent shell from the ligand, before it reaches the internal binding site 34 .…”

Sex differences in main olfactory system pathways involved in psychosexual function

“…77 Notably, a recent study reported an association between the VN1R1 polymorphisms and sexual behavior (in particular, number of one-night stands) in women, but not in men. 82 At this point, it is unclear whether TAAR-induced signaling affects psychosexual functions in humans. 74 Interestingly, the TAAR5 ligand trimethylamine occurs at high levels in adult male mouse urine and is equally attractive to both sexes.…”

“…79 Human TAAR5 is also activated by trimethylamine, 80 but as well by a substance in rotting (but not fresh) fish 81 ; a purely computational approach predicts that the molecules putrescin and cadavarine are ligands for human TAAR6 and TAAR8, respectively. 82 At this point, it is unclear whether TAAR-induced signaling affects psychosexual functions in humans.…”

Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion

“…Isopentylamine is a reported endogenous agonist for TAAR3 (11), while agmatine is only currently described as an agonist for TAAR 13c that has currently only been found to be expressed in zebra fish [24]. The diamine binding site through which agmatine interacts with TAAR13c is, however, conserved in both human and rodent TAAR6 and TAAR8 isoforms [24,25] making them potential sites through which agmatine effects might be mediated. The N,N-dimethylalkylamines, meanwhile, are agonists at TAAR7 and TAAR9 isoforms [16].…”