Molecular adaptation

The reason for such a behavior becomes apparent when the molecule is drawn in three-dimensions (1-15). The rigidity of the steroid skeleton thus helps in bringing the two functions in proper orientation where catalysis combining one intramolecular and one intermolecular catalyst takes place. 

The proximal hydroxyl group can cooperate in the hydrolysis by hydrogen bonding and the carbonyl function of the ester becomes a better electrophilic center for the solvent molecules. In this mechanism one can perceive a general acid-base catalysis of ester solvolysis (Chapter 4). 

These simple examples illustrate that many of the basic active site chemistry of enzymes can be reproduced with simple organic models in the absence of proteins. The role of the latter is of substrate recognition and orientation and the chemistry is often carried out by cofactors (coenzymes) which also have to be specifically recognized by the protein or enzyme. The last chapter of this book is devoted to the chemistry of coenzyme function and design. 

Some pharmacological examples will illustrate the principle. The two neurotransmitters, acetylcholine (1-16) and carbachol (1-17), have similar muscarinic action. 

The shaded area represents the bioisosteric equivalence. Muscarine (1-18) is an alkaloid which inhibits the action of acetylcholine. It is found for instance in Amanita muscaria (Fly Agaric) and other poisonous mushrooms. Its structure infers that, in order to block the action of acetylcholine on receptors of smooth muscles and glandular cells, it must bind in a similar fashion. 

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Bodine SC (2006) Related mTOR Signaling and the Molecular Adaptation to Resistance Exercise. Med Sci Spoils Exerc 38 1950-1957... 

Capaccio, M., Gavalas, V.G., Meier, M.S., Anthony, J.E., and Bachas, L.G. (2005) Coupling biomolecules to fullerenes through a molecular adapter. Bioconjugate Chem. 16, 241-244. 

Upregulation of the cAMP second-messenger pathway is a well-established molecular adaptation 916... 

Jaenicke, R. (1991). Protein stability and molecular adaptation to extreme conditions. Ewr.J. Biochem. 202, 715—728. 

In view of the fact that neutrophils isolated from some inflammatory sites have been exposed to agents that selectively activate their gene expression (which may result in the expression of FcyRI see Fig. 7.9 and 8.9), such molecular adaptation of neutrophils to their environment may indeed occur. 

J. Coyette, M. Nguyrn-Disteche, J. Lamotte-Brasseur, B. Joris, E. Fonze, J. M. Frere, Molecular Adaptation in Resistance to Penicillins and Other /3-Lactam Antibiotics, Adv. Comp. Environ. Physiol. 1994, 20, 233-267. 

Antidepressant drugs, by contrast, require long-term administration for their therapeutic effects to become evident. Thus, it is clear that the acute actions of these drugs, which are most often to enhance synaptic levels of monoamines, are not sufficient in themselves to mediate their therapeutic effects. Neither is the effect of increased monoamines on postsynaptic second messenger systems, which occurs relatively quickly as well, adequate to account for the therapeutic actions of antidepressants. The most obvious explanation, then, is that molecular adaptations in response to chronic exposure to these drugs are what underlie their therapeutic effects. Consistent with this idea, several hypotheses as to the nature of the relevant molecular adaptations have been proposed. Two models focus on adaptations of the 5-HTia receptor. One theory proposes that desensitization of presynaptic somatodendritic 5-HTia autoreceptors is responsible for the therapeutic action... 

LESSONS LEARNED FROM Hb MOLECULAR ADAPTATION STUDIES... 

Poyart, C., H. Wajcman and J. Kister (1992). Molecular adaptation of hemoglobin functions in mammals. Resp. Physiol. 90 3-17. 

Brooks, G.A., T.D. Fahey, and T.P. White (1996). Exercise Physiology—Human Bioenergetics and Its Applications. London Mayfield Publishing. Bunn, H.F., and R.O. Poyton (1996). Oxygen sensing and molecular adaptation to hypoxia. Physiol. Rev. 76 839-885. 

Feldpausch DL, Needham LM, Stone MP, Althaus JS, Yamamoto BK, Svensson KA, Merchant KM (1998) The role of dopamine D4 receptor in the induction of behavioral sensitization to amphetamine and accompanying biochemical and molecular adaptations. J Pharmacol Exp Ther 255 497-508. 

Gu, L. Q., Braha, O., Conlan, S., Cheley, S., and Bayley, H. (1999). Stochastic sensing of organic analytes by a pore-forming protein containing a molecular adapter. Nature 398, 686-690. 

Das, D. K. Engelman, R. M. Kimura, Y. Molecular adaptation of cellular defences following preconditioning of the heart by repeated ischaemia. Cardiovasc. Res. 27 578-584 1993. 

As an extension of the concept of molecular adaption, the internal cavity of an oligo(m-phenylene ethynylene) helix was also anticipated to be complementary in shape to rodlike chain molecules of appropriate diameter.422 Molecular interactions of this type, while quite unlike those typical of biomacromolecules, were sought to reveal oligomeric... 

Bunn HF, Poyton RO. 1996. Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76 839-885. 

For an interaction to occur with a putative brassinosteroid receptor, both stereospeciflcally arranged vicinal diol functions in the ring A, as well as in the side chain, can be assumed as important. In our synthetic program for modified brassinosteroids, we were especially interested in new types of analogs with the ring A- and B-seco structure to study the influence of the geometry of this molecular adaptation on biological activity. 

The sensitivity of supramolecular assemblies such as microtubuli and flagellin suggests that we may expect that cells are quite sensitive to pressure. Without much hesitation we may consider the cell as a molecular factory. This is supported by the observations on viruses. Very small pressures induce changes that make viruses biologically inactive although the structure may be little affected. The molecular adaptation mechanisms that play a role in the composition of bacterial membranes may be interpreted along the same lines. 

There is extensive literature documenting biochemical/molecular adaptations of herbivorous insects to host toxins, though almost none of it deals with bark beetles. Beyond noting the toxicity of various components to different beetles, little is known about the biochemical adaptations that bark beetles have evolved to... 

The hydrophobic nature of triglycerides means that special molecular adaptations have evolved for their digestion, absorption, and intertissue transport. 

Fuchs H, Bachran C, Li T et al. (2007) A cleavable molecular adapter reduces side effects and concomitantly enhances efficacy in tumor treatment by targeted toxins in mice. J Control Release 117 342-350... 

Astier, Y, Braha, O., and Bayley, H. Toward single molecule DNA sequencing Direct identification of ribonucleoside and deoxyribonucleoside 5 -monophosphates hy using an engineered protein nanopore equipped with a molecular adapter. Journal of the American Chemical Society 128, 1705-1710... 

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