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Natural Molecular Space and Us

July 26, 2011

In the previous post, we looked at the world of natural biomolecules, which can be considered as a ‘natural molecular space’. Before that, the notion was raised of ‘chrestomolecules’, or general molecular entities of economic significance in the most general sense. Now, it’s appropriate to bring these together and take a look at the relevance of natural molecular space to human beings, with a particular glance at a ‘why’ question: If molecules found within natural molecular space are especially useful to us, why should that be so?

Within the last few hundred years, certain observations can only have reinforced the supposition that the natural world was a source of cures for all humanity’s innumerable ailments. Let’s consider one case as an exemplar of this. In the early 18th century, the navies and merchant marines of European countries were plagued on oceanic voyages by the terrible affliction of scurvy, which often cut like a scythe through the hapless ranks of seafarers. We know today the exact problem and molecular details of the solution, which of course is correcting the deficiency of Vitamin C (ascorbic acid), a cofactor for enzymes involved in collagen formation and other functions. As such, scurvy (and other vitamin deficiency diseases) are in a very different category to infectious diseases and other human pathological conditions. But before this was clarified, to common sailors and ‘learned’ physicians alike, scurvy was bundled in with other diseases and just as mysterious (although no shortage of erroneous theories were proffered by the latter). It was eventually found that certain plant products and citrus fruits were ‘anti-scorbutic’, and could often completely reverse the shocking physical ravages of the disease. A ship’s surgeon witnessing near-miraculous recoveries of his sickening and dying charges, and ignorant of the underlying causes of the condition, might speculate that if some plant products could cure otherwise-terminal scurvy with such incredible efficacy, might not other diseases have a comparable natural cure somewhere in the world? If only one could find them…..

We then can jump from the former intuitive appreciation of ‘mother nature’ to current understanding of the tumultuous diversity of the Earth’s biosphere at the molecular level, which is a worthy and interesting intellectual pursuit in its own right. Humans being constituted as they are, however, such higher-level goals usually tend to take a back seat in favor of more pragmatic questions along the line of, ‘What’s in it for me?’. If the question concerns the bounty and application of natural molecules, the answer is ‘Plenty’. It might seem that asking why a situation exists is primarily driven by scientific curiosity, and should take a back seat in favor of more practical issues. Yet even a partial answer explaining the reason for observed circumstances can have potential practical pay-offs.. So let’s take a closer look….

Common origin, convergence, or co-incidence?

Why should a fungal biomolecule, or any other natural product for that matter, provide therapeutic benefit to a human being? Pragmatically, this ‘why’ question is often side-stepped, and emphasis given to studies on how potentially useful biomolecules work in mammalian cells. Obviously the latter focus is important for pharmacology. Yet a deeper understanding of why a molecule from the biological environment should have impact on human biology in the first place may also have practical pay-offs, as well as purely scientific advancement. A first basic point to note is the common origin of life on Earth, which ensures that many biomolecules and biomolecular systems have functional homologs across wide evolutionary gulfs, thereby raising the probability that metabolites from (for example) fungi will influence human biology. Furthermore, it has been pointed out that the diversity of protein structural folds is much less than protein sequence diversity alone would suggest, and that this has implications for the range of low-molecular natural bioproducts as well. The crux of this argument is that despite the great diversity of protein sequences, all types of natural protein folding shapes can be grouped into a much smaller set. This nevertheless remains a small number compared with corresponding set of primary protein sequences. Consequently, molecules selected by evolution to bind to such folds will tend to have special features promoting such interactions. For example, molecular volumes of most natural products are within the volume size range found within protein cavities. Through these constraints, natural biomolecules are a highly non-random representation of the totality of chemical space. To consider it from a different viewpoint, there is a much better chance of finding a binding molecule for a specific protein fold category in natural molecular space than in a totally random collection of chemical structures.  This has been borne out by studies with artificial chemical libraries.

Beyond these general considerations lies the issue of the specific selective pressures determining the structural features of ecobiomolecules. These are simple to define if both the function of such a molecule in its natural context and its applicability to humans appears to coincide, as found in the case of antibiotics. Yet things are often not so clear-cut, and some bioproducts are in a gray area even from the viewpoint of their putative beneficial effects. Consider in this context the example of phytoestrogens. These are plant-derived molecules which mimic the action of specific mammalian steroidal sex hormones (estrogens), by binding to the estrogen nuclear receptor which transmits estrogen signaling. Phytoestrogens fall into four main different structural groups, including the isoflavonoids which are found within soybeans, a major food item in many cultures. A long-standing controversy has run concerning putative health benefits of dietary isoflavonoids (reducing breast and prostate cancer risk) and possible negative effects on human reproductive cycles or other areas. Although phytoestrogens may be viewed as ‘natural food additives’ as considered above, it may thus be premature to refer to isoflavonoids as ‘chrestomolecules’ (see an earlier post). In any case, let us get back to the ‘why’ question posed above. Why should plants produce chemicals which mimic mammalian sex hormones?

Note for Figure: Structures of an estrogen (17-β-estradiol) and three examples of different phytoestrogen classes (genistein [an isoflavanoid], resveratrol, and coumestrol). Also shown is a representative brassinosteroid (castasterone), with its steroid-like scaffold shaded in gray. Castasterone is metabolized into the more potent brassinolide, which has a seven-membered ring, indicated with an arrow. Also shown is the protein structure of estrogen receptor-β ligand binding domain in complex with genistein. (genistein ligand black; α-helical regions of protein red, β-strands green, loops light blue). The binding mode for genistein is similar but non-identical to that observed with 17-β-estradiol.

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One possible answer, of course, is that plants do not gain anything from the mimicry itself. In this view, whatever the natural plant function of isoflavonoids (and other phytoestrogens), their effects on certain human nuclear hormone receptors is an accidental evolutionary cross-reaction. Or to rephrase this proposal, however important isoflavonoids might become to humans, it is of no evolutionary consequence to the plants which produce them. This in turn postulates that the selective pressures which resulted in plants synthesizing these compounds in the first place had no input from mammalian biological interactions. A somewhat more subtle version of this ‘pure chance’ viewpoint (along the lines of above discussions of natural molecular space) would hold that owing to the limited number of protein folds observed in nature, a certain level of spurious cross-binding between receptors and ligands from evolutionary divergent species is inevitable. Alternatively, it could be quite feasibly proposed that both plant and mammalian receptors for phytoestrogens happen to share a common (albeit distant) evolutionary origin, such that (despite functional divergence) they also share certain structural features which enable cross-binding of their respective ligands. Such proposed effects boost the attractiveness of natural molecular space as a source of useful bioactive compounds.

A defining chemical feature of estrogens and other steroids is their molecular ‘skeleton’, the perhydrocyclopentanophenanthrene fused ring structure (This is seen in the core ring composition of 17-β-estradiol in the above figure). Although (as noted above) several structural classes of phytoestrogens exist, none possess this basic steroidal feature (as in the above Figure, with coumestrol, resveratole, and genistein as examples). Structural studies with the phytoestrogen genistein have revealed that its binding to the estrogen receptor-β (one of the estrogen-binding nuclear receptors) shares many features to that seen for the natural ligand 17-β-estradiol, although genistein’s binding is suboptimal for the induced structural changes necessary for activation of the receptor. This finding is consistent with the observation that genistein (like other phytoestrogens) is estrogenic, but more weakly than the natural estrogen hormones themselves. Structural data thus show that compounds without a complete steroid ring system can recapitulate many of the appropriate binding contacts with the estrogen receptor, but cannot in themselves inform us as to the ultimate source of this mimicry.

Interestingly, despite its absence in phytoestrogens, the characteristic steroid ring is found in certain plant sources, including useful drugs such as cardiac glycosides. In fact, some plant steroid-like compounds, such as hecogenin, have frequently been used as source material for beginning synthesis of steroidal drugs. Most significantly, though, an important class of plant hormones possess the steroid ring system or a very close analog of it (See castasterone in the above Figure). These ‘brassinosteroids’ are synthesized by enzymes which have been shown to be homologous between plants and animals, pointing to a common (albeit distant) evolutionary origin between plant and animal steroid hormones. (Looking at the enzymes involved in natural product formation is the best way to trace the evolutionary ancestries of the natural small molecules themselves). So the existence of bona fide plant steroids is not at all a coincidence, yet these brassinosteroids have not been described as phytoestrogens, while several other distinct molecular structural classes (lacking the steroid ring system) have proven estrogenic activity (as in the above Figure). This seems at least superficially surprising, and might be taken as supporting the chance-mimicry hypothesis for phytoestrogens.  But this is not quite the end of the story….

At this point we must compare the natural functions of phytoestrogens with their estrogenic activities in mammals. One ascribed phytoestrogen natural role beneficial to their plants of origin is antimicrobial activity. Genistein is the precursor of other known plant antimicrobial compounds, and has some antibacterial effects itself. But this does not readily explain its activation of estrogen receptors. Other ecological functions for phytoestrogens have been postulated, such that their effect on mammalian hormone receptors is not coincidental. Certainly the reproductive systems of ruminant herbivores can be seriously affected by consumption of phytoestrogen-bearing plants, and this has been proposed to have selective benefit to such plants by control of herbivore population size. For this to occur, though, one would have to invoke an evolutionary group selection mechanism. (If herbivore populations were reduced through consumption of a plant species where a minority of variant individuals produced toxic or inhibitory phytoestrogens, all members of the plant group would gain a survival advantage, not just those bearing the genes enabling phytoestrogen synthesis).  Evolutionary selection at group levels has been a problematic and contentious issue. But in any case, there is an alternative explanation.

Relatively recently, information has emerged suggestive of a real ecological role for phytoestrogens in chemical communication between plants and beneficial bacterial symbionts. There is good evidence that at least isoflavonoids are involved in signaling between nitrogen-fixing bacteria (Rhizobium and related genera) and their leguminous plant hosts, by means of direct interaction with the bacterial transcriptional regulator NodulationD1 (NodD1). It then follows that it is of considerable interest to compare NodD1 and estrogen receptors.  Although they share no significant sequence homology suggestive of a common evolutionary antecedent, folding (shape) homologies between the two cannot be ruled out until further structural information is available. It has been suggested that NodD1 and estrogen receptors have undergone ‘convergent evolution’ in response to estrogen-like molecules as signaling agents. Such a contention does not in itself explain what selective forces drove both systems towards a related end-point, and why some other receptor-ligand system could not have served equally well in either case (obviously other receptor-ligand systems exist in both organisms). Chance again at a different level, or were additional selective pressures operative (as with the possible role of herbivore control for the phytoestrogens)? These considerations serve to demonstrate the complexities which can arise in attempting to unravel the evolutionary origins of ecobiomolecules.

So what is the take-home message at the end of this rumination (so to speak) on phytoestrogens, herbivores, and more? The phytoestrogen story also shows that one must be wary in ascribing any apparent molecular cross-reactivity purely to chance, given the possibility of signaling mechanisms between ecologically associated organisms of diverse evolutionary lineage.  Based on bacterial-eukaryotic relationships, ‘inter-kingdom’ signaling has been proposed to extend beyond responses to pathogens alone, and the symbiotic relationship between nitrogen-fixing bacteria and certain plants (noted in the context of phytoestrogens) is a case in point. An enthusiastic view of the importance of ecology would hold that most (if not all) biological chrestomolecules owe their usefulness to specific inter-relationships ultimately traceable to the molecular level. In other words, such an opinion would hold little place for coincidence in the provenance of biomolecular human utility. Yet even if the estrogenic activity of molecules such as genistein is explained through structural similarities between its natural target bacterial receptors and mammalian estrogen receptors, we should remember that many phytoestrogens possess multiple activities in animal cells. Genistein is something of a champion in this regard, and it becomes unlikely that all of these effects have an underlying evolutionary rationale.

To find clear-cut cases of fortuitous interactions, we can look beyond biological molecules. Further inspection of the biology of estrogen receptors themselves reveals examples of molecular interactions which can only be attributed to chance. Since the advent of artificial chemical pesticides, many concerns have been raised about their safety. One important side-effect of many chlorinated hydrocarbon insecticides (including DDT) was revealed to be estrogenic activity, or mimicking of estrogens. DDT, for example, can directly bind and activate the estrogen receptor (albeit much more weakly than normal hormone), and DDT can even support the growth of estrogen-dependent tumor cells in culture. Now, the ‘selection’ for artificial insecticides was empirical searching for insect-killing abilities, and certainly not as ‘xenoestrogens’. It follows in turn that the interaction of such artificial compounds with estrogen receptors is an undirected chance event. (Although, as we have noted above, the probability for such events may be increased through the relatively limited number of protein folds in biological protein space). Interestingly, in an equivalent manner as for phytoestrogens, xenoestrogens can also interact (and interfere) with symbiotic nitrogen-fixing bacteria, another potential environmental problem associated with the use of such compounds. It is true of course that these artificial xenoestrogens are not derived from natural molecular space, but they do serve to demonstrate unanticipated molecular cross-binding, which could equally well occur in principle with a natural compound (if not more so, via their ‘pre-validation’ for natural protein folds). By the same token, completely artificial chemical libraries can yield ‘hits’ for modulation of biological processes, even if at low frequency.

Considering the impact of natural molecular space on humans in general, biases in favor of the activity of natural products thus exist both from a fundamental biological perspective, and in specific cases of ecological interaction. When chance plays a role, it may be in form of a negative side-effect, analogous to the xenobiotic DDT / estrogen receptor example. There are many examples of biological toxins deadly for humans which were never designed by evolution with humans as specific targets. The explanation for this, of course, is the sharing of a wide variety of biochemical pathways between humans and other organisms, especially our fellow mammals. Yet some quirks to this general rule illustrate the role of ‘molecular chance’ in the outcome of the interaction between humans and environmental biomolecules. For example, the venom of the Australian funnel web spider, one of the deadliest in the world towards humans, evolved for the purpose of quickly immobilizing its insect prey. Despite lethal effects of funnel web neurotoxins in humans and other primates, however, most other mammals are little bothered by them, apparently through neutralizing serum factors rather than at the level of the direct neural targets of the toxins themselves.

Having examined both artificial and natural undesirable chance-based molecular interactions, one could logically argue that bad results are likely to be much more frequent than beneficial ones. After all, (as with genetic mutations and many other things) it is far easier to damage an organized system by randomly plugging things into it than improve it. Still, beneficial random mutations do occur, and likewise a chance biomolecular interaction could have useful consequences. An obvious follow-up at this point is to ask for specific examples of valued biomolecules whose human utility is completely unlinked to the selective pressures by which such molecules originated. As we have seen with the phytoestrogens, judging this can be a complex undertaking, and it depends to some extent on what level of ‘co-incidence’ one is referring to. For example, marine organisms in general are hardly likely to be subject to direct selective pressures towards synthesizing effective anti-tumor drugs for humans, yet some such bioproducts are currently in clinical trials. But at another level, these cytotoxic or cytostatic anti-tumor effects are explicable owing to the evolution of chemical defenses in the sessile marine organisms from which they have been derived. Then it is only a matter of the correspondence between the biological systems and pathways of humans vs. those of the natural predators of the marine organisms against which the compounds are targeted.

Yet some aspects of the specific uses of natural products may indeed be chance-based, such as the effects of useful plant compounds called alkaloids (included within the  ‘Therapeutics’ of  the ‘chrestomolecule’ Table of an earlier post). As secondary metabolites, they are not essential for plant growth. The provision of an intensely bitter taste and toxicity may provide a selective advantage against herbivores in plants which produce them, although other functions (again analogously with phytoestrogens) cannot be ruled out. Useful effects of alkaloids on human cardiovascular or nervous systems (such as with reserpine or atropine) may nonetheless be hard to account for if not through fortuitous interactions. This may apply even more so to the dramatic effects some plant or fungal-derived psychotropic drugs have on human nervous systems. At a deeper level again, however, the ‘pre-validation’ of such molecules as protein-binding agents may greatly increase the likelihood that they will cross-react with other proteins (with related folds). As an example, to proceed from the premise that the intensely bitter taste of plant alkaloids was a selective factor in their evolutionary origins (providing a selectable advantage, through immediate deterrence of potential herbivores), a molecule selected for its binding to any of the mammalian bitter taste receptors might also fortuitously bind to other proteins with related structural features, with accompanying physiological effects. In fact, taste receptors are but one class among a large protein group called G Protein-Coupled Receptors, a huge target set for pharmacology.

‘Side-effects’ in general are unanticipated molecular interactions which are usually negative. Nevertheless, as we have seen, a useful property of an empirically-discovered natural product in principle might result from a beneficial ‘side-effect’ rather than its normal role. Yet even where the natural role and human application of a substance appear to perfectly coincide (as with antibiotics), it must be kept in mind that the usefulness of any biomolecule (especially in a therapeutic context) is also dependent on what it doesn’t do. In other words, irrespective of the origin of the useful activity of a molecule, we also hope for it to avoid a host of potentially troublesome side-effects. (‘Collateral damage’ and ‘magic bullets’ are mutually exclusive). And given the enormous complexity of living organisms, avoidance of side-effects will be fortuitous much of the time. To return to the example of antibiotics, the utility of penicillins depends not only on their anti-bacterial efficacy but also their low background toxicity. Clearly, fungal secondary metabolites of any description are not selected in favor of human biochemistry. Prediction of specific molecular side effects, from whole cell systems to whole animals, is dauntingly difficult and requires multiple rounds of empirical safety tests.

 Natural Molecular Space: All Good?

We have paid attention to the advantages provided by natural bioproducts as a result of their great diversity. Are there any inherent disadvantages in harvesting nature’s molecular bounty, as opposed to using completely artificial compounds occupying  regions of chemical space not present in the natural world? Perhaps not in general, but there is such an issue in the specific (but important) field of natural drugs against pathogens. Since many microbial organisms and humans have a common ‘need’ to control bacterial competitors or pathogens, then the existence of environmental antibiotics seems (with hindsight) entirely reasonable. Yet at the same time the seeds of future problems may exist from the same evolutionary logic. This is because (as we have seen in the previous post) the origin of antibiotics and their counter-measures are closely linked: organisms producing a potentially self-toxic molecule must simultaneously have the means for neutralizing the toxic activity towards itself. If counter-measures against an identified anti-bacterial drug already exist in the environment, there is also a high probability that they can be rapidly marshaled and spread. A compound which is derived by entirely non-natural means would not be associated with this problem, and counter-measures in the target organisms would need to newly evolve. This can occur by co-opting existing proteins or pathways into novel uses; gene duplication is a major route towards this end. From another viewpoint, binding of a cellular target protein by any small molecule inhibitor can be regarded as an extra ‘promiscuous’ (albeit non-natural) function of the protein itself, which usually involves intermolecular contacts outside of those which are essential for activity. Evolution towards resistance can thus arise by modifying promiscuous contacts rather than functionally vital ones.

So resistance to a natural anti-bacterial will tend to arise more rapidly than to a completely artificial one, and in general this is why natural metabolites tend to be more biodegradable and ‘eco-friendly’ than artificially-derived compounds. But a drug (whether natural or not) must have a target molecule of some kind, and the latter may in itself serve as the starting-point for evolved resistance. Thus there is evidence that β-lactamases, enzymes breaking down β-lactam antibiotics, themselves evolved from the original penicillin-binding protein targets of the antibiotics themselves, probably by gene duplication processes. Certainly there are many precedents for the development of microbial enzymatic activity against non-natural compounds. So in the end, resistance to natural vs. artificial molecules may be distinguished only by the speed of its onset.

To conclude, one can find an intersection of sorts between this post and as earlier one on astrobiology. How so? A completely alien biosphere would have its own ‘natural molecular space’, and there is no reason for assuming that it would have structural overlap with the natural molecular space with which we are familiar. Even if the alien biochemistry used proteins (perhaps an unwarranted assumption in itself), different amino acid alphabets might be used, and the range of protein folds might be radically different. The small molecules acting as drugs within such an alien ecosystem would therefore have no tendency to ‘fit’ our bio-world at all, although alien pharmacologists themselves would be well-advised to search their own specific biological backyard for molecules compatible with their biochemistry, mirroring the situation that we have found on Earth. The total set of alien biomolecules would then be no more beneficial for functional screening on our planet than a random chemical library– certainly an occasional promising hit would be found, but only through the vagaries of chance.

And on that general theme, a biopoly-verse comment:

Most people offer only shrugs

If questioned why nature yields drugs

Yet the secret is told

Via ways many-fold

In proteins, from humans to bugs.

 References & Details

(In order of citation. In most cases, cited references are examples from numerous possible sources)

‘…..the navies and merchant marines of European countries were plagued …. by the terrible affliction of scurvy….’    For a good history of scurvy and its solution, see Bown, S. R. Scurvy : how a surgeon, a mariner and a gentleman solved the greatest medical mystery of the age of sail. (Viking Press, Melbourne, 2003).

‘…..all types of natural protein folding shapes can be grouped into a much smaller set……’   /   ‘…….a small number compared with corresponding set of primary protein sequences….’     Protein ‘sequence space’ is hyperastronomically vast. Consider that even a chain of 100 amino acids (small by protein standards) can have 20100 combinations, given the 20 usual biological amino acids. But the numbers of sequences which are actually used in biology (capable of folding into specific structures) is a tiny subset of these. A fundamental protein subunit is called a domain, often defined as an autonomous folding unit which can be combined with other domains on a modular basis. Several thousand domain folding types are known, and from combinations of these at least 10,000 protein families have been defined. For basic information about protein domains and families, see Koehn & Carter 2005Orengo & Thornton 2005.

‘….molecular volumes of most natural products are within the volume size range found within protein cavities…..’    See Koch et al. 2005.

‘……borne out by studies with artificial chemical libraries……’    Initial screening of artificial libraries (generated through combinatorial chemical methods were disappointing, since many primary hits lacked ‘drug-like’ character which would see them through later stages of screening. (for example, see Gribbon & Sewing 2005) Methods which integrate natural scaffolds and chemical diversification have been developed. See Krier et al. 2005; Bauer et al. 2010.

‘…….by binding to the estrogen nuclear receptor…..’     Other effects of estrogen mimics not operating via the conventional estrogen receptors have also been reported (See Rosselli et al. 2000). In particular, some act as inhibitors of protein kinases, which transfer phosphate groups to substrate proteins or peptides. The isoflavone phytoestrogen genistein (Shown in the above figure) is a tyrosine kinase inhibitor, along with other distinct functions in mammalian cells (See Dixon & Ferreira 2002).

‘……..which transmits estrogen signaling…..’    See Krishnan et al. 2000Dusza et al. 2006.

Phytoestrogens fall into four main different structural groups…..’     See Cos et al. 2003.

A long-standing controversy ….. concerning putative health benefits of dietary isoflavonoids….’     See Cassidy 2003; Bar-El & Reifen 2010.

Additional notes and references for above structural figure:   ‘Castasterone is metabolized into the more potent brassinolide, which has a seven-membered ring…’    See Fujioka & Yokota 2002.  ‘……..the protein structure of estrogen receptor-beta ligand binding domain in complex with genistein….The binding mode for genistein is similar but non-identical to that observed with 17-β-estradiol….’     See Pike et al. 1999. Source: Protein Data Bank (See Berman et al. 2003) 1QKM. Images generated with Protein Workshop (See Moreland et al. 2005).

‘……genistein’s binding is suboptimal for the induced structural changes necessary for activation of the [estrogen] receptor.’    See Pike et al. 1999.

‘……drugs such as cardiac glycosides…..’     The non-sugar (aglycone) cores of drugs such as digoxin (from the Digitalis [foxglove] plant) have the same perhydrocyclopentanophenanthrene ring system.

‘…….some plant steroid-like compounds…….have frequently been used as source material for beginning synthesis of steroidal drugs.’    See Heusler & Kalvoda 1996.

‘……pointing to a common (albeit distant) evolutionary origin between plant and animal steroid hormones….’     See Li et al. 1996; Russell 1996.

Genistein is the precursor of other known plant antimicrobial compounds, and has some antibacterial effects itself…..’     See Dixon & Ferreira 2002; Hong et al., 2006.

‘…..the reproductive systems of ruminant herbivores can be seriously affected by consumption of phytoestrogen-bearing plants….’    See Adams 1995    ‘……this has been proposed to have selective benefit to such plants by control of herbivore population size….’     See Wynne-Edwards 2001.

Evolutionary selection at group levels has been a problematic and contentious issue….’    For a discussion of this (among numerous other issues), see Richard Dawkins’ The Extended Phenotype; Oxford University Press 1982.

There is good evidence that at least isoflavonoids are involved in signaling between nitrogen-fixing bacteria ……and their leguminous plant hosts….’     See Peck et al. 2006.

‘….homologies between the two [NodD1 and estrogen receptors] cannot be ruled out until further structural information is available….’     See Fox 2004.

‘……have undergone ‘convergent evolution’ in response to estrogen-like molecules…..’    See Fox 2004. Convergence in evolutionary terms occurs when organisms lacking a recent common evolutionary origin independently acquire comparable phenotypes in response to similar environmental pressures. This can be observed at the morphological level, as (for example) the gross similarities between certain marsupial and placental mammalian carnivores (the extinct Tasmanian ‘tiger’ or thylacine and placental canids).

‘….‘inter-kingdom’ signaling has been proposed to extend beyond responses to pathogens alone….’     See the previous post for a brief discussion of quorum sensing and its extension to inter-kingdom communication. Also see Sperandio 2004; Shiner et al. 2005.

Genistein is something of a champion in this regard [for multiple activities in animal cells]…..’     See Dixon & Ferreira 2002.

One important side-effect of many chlorinated hydrocarbon insecticides …….was revealed to be estrogenic activity……’     See Rosselli et al. 2000; Robison et al. 1985a; Steinmetz et al. 1996.

‘….DDT….can directly bind and activate the estrogen receptor…’     See Kuiper et al. 1998    ‘…..DDT can even support the growth of estrogen-dependent tumor cells…’    See Robison et al. 1985b.

‘……the ‘selection’ for artificial insecticides was empirical searching for insect-killing abilities…..’     DDT was subsequently shown to be an insect neurotoxin by binding to the voltage-gated sodium channel in insect neurons. It appears that only a three amino acid residue difference in the human vs, insect sodium channel is the determinant of the differential toxicity of DDT to insects (See O’Reilly et al. 2006).

‘……xenoestrogens can also interact ….. with symbiotic nitrogen-fixing bacteria…….’    See Fox et al. 2004.

‘…..taste receptors are but one class among a large protein group called G Protein-Coupled Receptors, a huge target set for pharmacology…..’     For some information about human G Protein-Coupled Receptors (GPCRs), see Fredriksson et al. 2003.

‘……artificial chemical libraries yield ‘hits’ for modulation of biological processes…..’    See Golebiowski et al. 2001.

‘…….the venom of the Australian funnel web spider…….evolved for the purpose of quickly immobilizing its insect prey….’     See Tedford et al. 2004.

Despite lethal effects of funnel web neurotoxins in humans ….. most other mammals are little bothered by them…..’     See Sheumack et al. 1991.

‘…..cytotoxic or cytostatic anti-tumor effects are explicable owing to the evolution of chemical defenses……’     See O’Hanlon 2006. It must be inferred that such marine organisms have self-protective mechanisms against their own toxins, in an analogous manner depicted in a Figure of a previous post. .

‘……the ‘pre-validation’ of such molecules as protein-binding agents….’    See Koehn & Carter 2005.

Evolution towards resistance can thus arise by modifying promiscuous contacts…..’    For a discussion of the role of general protein promiscuity as an evolutionary opportunity, see Aharoni et al. 2005; Tokuriki & Tawfik 2009.

‘……why natural metabolites tend to be more biodegradable….’     See Saxena & Pandey 2001.

‘…….there is evidence that β-lactamases ….. evolved from the original penicillin-binding protein targets of the antibiotics……’     See Meroueh et al. 2003.

‘…..there are many precedents for the development of microbial enzymatic activity against non-natural compounds….’     See Fisher et al. 1978; Scanlan & Reid 1995.

Next post: Two weeks from now.

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